add app.py, documents, and requimrents

app.py

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+import os
+import openai
+from pathlib import Path
+
+from langchain.embeddings.openai import OpenAIEmbeddings
+from langchain.indexes import VectorstoreIndexCreator
+from langchain.document_loaders import TextLoader
+from langchain.chat_models import ChatOpenAI
+
+import gradio as gr
+
+def index_txt(directory):
+    files = directory.glob("*.txt")
+    loaders = [TextLoader(str(file)) for file in files]
+    return VectorstoreIndexCreator().from_loaders(loaders)
+
+def vector_search(natural_lang_query):
+    llm = ChatOpenAI(temperature=0, model_name="gpt-4")
+    query_result = index.query_with_sources(natural_lang_query, llm=llm)
+    final_result = "Answer: " + query_result['answer']
+    final_result += f"\n Sources: {query_result['sources']}"
+    return final_result
+
+def create_gradio_interface(title, description):
+    """Create a Gradio interface with a single text input and a single text output."""
+    interface = gr.Interface(
+        fn=vector_search,
+        inputs=[
+            gr.inputs.Textbox(label="What would you like to ask your data?")
+        ],
+        outputs=gr.outputs.Textbox(label="Results"),
+        title=title,
+        description=description
+    )
+    return interface
+
+# Define path for documents
+output_dir = Path("docs/")
+
+# Launch the interface
+index = index_txt(output_dir)
+
+interface = create_gradio_interface(title="ChatBot - Question answering across Pfizer Comirnaty Documents",
+    description=(
+        "Semantic search: Enter a query to receive an answer with cited source documents.\n\n"
+        "DISCLAIMER: This is an early alpha product and not intended for production use.")
+)
+interface.launch()

docs/April 20, 2023 Approval Letter COMIRNATY.txt

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+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+Our ST: BL 125742/214
+SUPPLEMENT APPROVAL
+BioNTech Manufacturing GmbH
+Attention: Leslie Sands
+Pfizer, Inc.
+500 Arcola Road
+Collegeville, PA 19426
+April 20, 2023
+Dear Ms. Sands:
+We have approved your request received October 18, 2022, to supplement your Biologics License Application (BLA) submitted under section 351(a) of the Public Health Service Act for COVID-19 Vaccine, mRNA (COMIRNATY), manufactured at the Pfizer Manufacturing Belgium NV, Puurs, Belgium (Pfizer, Purs), Pharmacia & Upjohn Company LLC, Kalamazoo, Michigan (Pfizer, Kalamazoo) and Hospira, Inc., McPherson, Kansas (Pfizer, McPherson) facilities, to update the Package Inserts for the PBS/Sucrose 30 mcg and Tris/Sucrose 30 mcg formulations of COMIRNATY to include
+"dizziness" in Section 6.2 Postmarketing Experience.
+LABELING
+We hereby approve the draft content of labeling: Package Inserts submitted under amendment 2, dated April 11, 2023.
+CONTENT OF LABELING
+As soon as possible, but no later than 14 days from the date of this letter, please submit the final content of labeling (21 CFR 601.14) in Structured Product Labeling (SPL) format via the FDA automated drug registration and listing system (eLIST), as described at http://www.fda.gov/For|ndustry/DataStandards/StructuredProductLabeling/ default.htm. Content of labeling must be identical to the Package Inserts submitted on April 11, 2023. Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida nces/UCM072392.pdf.
+The SPL will be accessible via publicly available labeling repositories.
+All final labeling should be submitted as Product Correspondence to this BLA, ST BL 125742, at the time of use and include implementation information on Form
+FDA 356h.
+U.S. Food & Drug Administration
+10903 New Hampshire Avenue
+Silver Spring, MD 20993
+www.fda.gov
+
+Page 2 - ST BL 125742/214 - Leslie Sands
+ADVERTISING AND PROMOTIONAL LABELING
+You may submit two draft copies of the proposed introductory advertising and promotional labeling with Form FDA 2253 to the Advertising and Promotional Labeling
+Branch at the following address:
+Food and Drug Administration
+Center for Biologics Evaluation and Research
+Document Control Center
+10903 New Hampshire Ave.
+WO71-G112
+Silver Spring, MD 20993-0002
+You must submit copies of your final advertising and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).
+All promotional claims must be consistent with and not contrary to approved labeling.
+You should not make a comparative promotional claim or claim of superiorit over other products unless you have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).
+Please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that includes this change.
+We will include information contained in the above-referenced supplement in your BLA
+files.
+Sincerely,
+Joseph G. Toerner, MD, MPH
+Acting Deputy Director - Clinical
+Division of Vaccines and
+Related Products Applications
+Office of Vaccines
+Research and Review
+Center for Biologics
+Evaluation and Research
+

docs/August 23, 2021 Approval Letter - Comirnaty.txt

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+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+Our ST: BL 125742/0
+BLA APPROVAL
+BioNTech Manufacturing GmbH
+Attention: Amit Patel
+Pfizer Inc.
+235 East 42nd Street
+New York, NY 10017
+August 23, 2021
+Dear Mr. Patel:
+Please refer to your Biologics License Application (BLA) submitted and received on May 18, 2021, under section 351(a) of the Public Health Service Act (PHS Act) for COVID-19 Vaccine, mRNA.
+LICENSING
+We are issuing Department of Health and Human Services U.S. License No. 2229 to BioNTech Manufacturing GmbH, Mainz, Germany, under the provisions of section 351(a) of the PHS Act controlling the manufacture and sale of biological products. The license authorizes you to introduce or deliver for introduction into interstate commerce, those products for which your company has demonstrated compliance with establishment and product standards.
+Under this license, you are authorized to manufacture the product, COVID-19 Vaccine, mRNA, which is indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older.
+The review of this product was associated with the following National Clinical Trial
+(NCT) numbers: NCT04368728 and NCT04380701.
+MANUFACTURING LOCATIONS
+Under this license, you are approved to manufacture COVID-19 Vaccine, mRNA drug substance at Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC, 1 Burtt Road,
+Andover, Massachusetts. The final formulated product will be manufactured, filled, labeled and packaged at Pfizer Manufacturing Belgium NV, Riksweg 12, Puurs, Belgium and at Pharmacia & Upjohn Company LLC, 7000 Portage Road, Kalamazoo, Michigan. The diluent, 0.9% Sodium Chloride Injection, US, will be manufactured at Hospira, Inc., (b) (4)
+and at Fresenius Kabi
+USA, LLC, (b) (4)
+U.S. Food & Drug Administration
+10903 New Hampshire Avenue
+Silver Spring, MD 20993
+www.fda.gov
+
+Page 2 - ST BL 125742/0 - Elisa Harkins
+You may label your product with the proprietary name, COMIRNATY, and market it in 2.0 mL glass vials, in packages of 25 and 195 vials.
+We did not refer your application to the Vaccines and Related Biological Products
+Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues that would have benefited from an advisory committee discussion.
+DATING PERIOD
+The dating period for COVID-19 Vaccine, mRNA shall be 9 months from the date of manufacture when stored between -90°C to -60°C (-130°F to -76°F). The date of manufacture shall be no later than the date of final sterile filtration of the formulated drug product (at Pharmacia & Upjohn Company LLC in Kalamazoo, Michigan, the date of manufacture is defined as the date of sterile filtration for the final drug product; at Pfizer Manufacturing Belgium NV in Purs, Belgium, it is defined as the date of the (o) (4)
+Following the final sterile filtration, (b) (4)
+, no
+reprocessing/reworking is allowed without prior approval from the Agency. The dating period for your drug substance shall be b) (4) when stored at (b) (4)
+We have
+approved the stability protocols in your license application for the purpose of extending the expiration dating period of your drug substance and drug product under 21 CFR
+601.12.
+FDA LOT RELEASE
+Please submit final container samples of the product in final containers together with protocols showing results of all applicable tests. You may not distribute any lots of product until you receive a notification of release from the Director, Center for Biologics Evaluation and Research (CBER).
+BIOLOGICAL PRODUCT DEVIATIONS
+You must submit reports of biological product deviations under 21 CFR 600.14. You should identify and investigate all manufacturing deviations promptly, including those associated with processing, testing, packaging, labeling, storage, holding and distribution. If the deviation involves a distributed product, may affect the safety, purity, or potency of the product, and meets the other criteria in the regulation, you must submit a report on Form FDA 3486 to the Director, Office of Compliance and Biologics Quality, electronically through the eBPDR web application or at the address below.
+Links for the instructions on completing the electronic form (eBPDR) may be found on CBER's web site at https://www.fda.gov/vaccines-blood-biologics/report-problem-center-biologics-evaluation-research/biological-product-deviations:
+Food and Drug Administration
+Center for Biologics Evaluation and Research
+Document Control Center
+
+Page 3 - STN BL 125742/0 - Elisa Harkins
+10903 New Hampshire Ave.
+WO71-G112
+Silver Spring, MD 20993-0002
+MANUFACTURING CHANGES
+You must submit information to your BLA for our review and written approval under 21
+CFR 601.12 for any changes in, including but not limited to, the manufacturing, testing, packaging or labeling of COVID-19 Vaccine, mRNA, or in the manufacturing facilities.
+LABELING
+We hereby approve the draft content of labeling including Package Insert, submitted under amendment 74, dated August 21, 2021, and the draft carton and container labels submitted under amendment 63, dated August 19, 2021.
+CONTENT OF LABELING
+As soon as possible, but no later than 14 days from the date of this letter, please submit the final content of labeling (21 CFR 601.14) in Structured Product Labeling (SPL) format via the FDA automated drug registration and listing system, (eLIST) as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ default.htm. Content of labeling must be identical to the Package Insert submitted on August 21, 2021. Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guida nces/UCM072392.pdf.
+The SPL will be accessible via publicly available labeling repositories.
+CARTON AND CONTAINER LABELS
+Please electronically submit final printed carton and container labels identical to the carton and container labels submitted on August 19, 2021, according to the guidance for industry Providing Regulatory Submissions in Electronic Format - Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-regulatory-submissions-electronic-format-certain-human-pharmaceutical-product-applications.
+All final labeling should be submitted as Product Correspondence to this BLAST BL
+125742 at the time of use and include implementation information on Form FDA 356h.
+ADVERTISING AND PROMOTIONAL LABELING
+
+Page 4 - STN BL 125742/0 - Elisa Harkins
+You may submit two draft copies of the proposed introductory advertising and promotional labeling with Form FDA 2253 to the Advertising and Promotional Labeling
+Branch at the following address:
+Food and Drug Administration
+Center for Biologics Evaluation and Research
+Document Control Center
+10903 New Hampshire Ave.
+WO71-G112
+Silver Spring, MD 20993-0002
+You must submit copies of your final advertising and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR
+601.12(f) (4)).
+All promotional claims must be consistent with and not contrary to approved labeling.
+You should not make a comparative promotional claim or claim of superiority over other products unless you have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).
+ADVERSE EVENT REPORTING
+You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CF 600.80), and you must submit distribution reports at monthly intervals as described in 21 CFR
+600.81. For information on adverse experience reporting, please refer to the guidance for industry Providing Submissions in Electronic Format -Postmarketing Safety Reports for Vaccines at https://www.fda.gov/requlatory-information/search-fda-guidance-documents/providing-submissions-electronic-format-postmarketing-safety-reports-vaccines. For information on distribution reporting, please refer to the guidance for industry Electronic Submission of Lot Distribution Reports at
+http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation
+/Post-MarketActivities/LotReleases/ucm061966.htm.
+PEDIATRIC REQUIREMENTS
+Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are reauired to contain an assessment of the safetv and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.
+We are deferring submission of your pediatric studies for ages younger than 16 years for this application because this product is ready for approval for use in individuals 16 years of age and older, and the pediatric studies for younger ages have not been completed.
+
+Page 5 - STN BL 125742/0 - Elisa Harkins
+Your deferred pediatric studies required under section 505B(a) of the Federal Food, Drug, and Cosmetic Act (FDCA) are required postmarketing studies. The status of these postmarketing studies must be reported according to 21 CFR 601.28 and section 505B(a)(4)(C) of the FDCA. In addition, section 506B of the FDCA and 21 CFR 601.70 require you to report annually on the status of any postmarketing commitments or required studies or clinical trials.
+Label your annual report as an "Annual Status Report of Postmarketing Study Requirement/Commitments" and submit it to the FDA each vear within 60 calendar davs of the anniversary date of this letter until all Reguirements and Commitments subject to the reporting requirements under section 506B of the FDCA are released or fulfilled. These required studies are listed below:
+1. Deferred pediatric Study C4591001 to evaluate the safety and effectiveness of
+COMIRNATY in children 12 years through 15 years of age.
+Final Protocol Submission: October 7, 2020
+Study Completion: May 31, 2023
+Final Report Submission: October 31, 2023
+2. Deferred pediatric Study C4591007 to evaluate the safety and effectiveness of
+COMIRNATY in infants and children 6 months to <12 years of age.
+Final Protocol Submission: February 8, 2021
+Study Completion: November 30, 2023
+Final Report Submission: May 31, 2024
+3. Deferred pediatric Study C4591023 to evaluate the safety and effectiveness of
+COMIRNATY in infants <6 months of age.
+Final Protocol Submission: January 31, 2022
+Study Completion: July 31, 2024
+Final Report Submission: October 31, 2024
+Submit the protocols to your IND 19736, with a cross-reference letter to this BLAST BL 125742 explaining that these protocols were submitted to the IND. Please refer to the PMR sequential number for each study/clinical trial and the submission number as shown in this letter.
+Submit final study reports to this BLA ST BL 125742. In order for your PREA PMRs to be considered fulfilled, you must submit and receive approval of an efficacy or a labeling
+
+Page 6 - STN BL 125742/0 - Elisa Harkins
+supplement. For administrative purposes, all submissions related to these required pediatric postmarketing studies must be clearly designated as:
+• Required Pediatric Assessments)
+We note that you have fulfilled the pediatric study requirement for ages 16 through 17 ears for this application.
+POSTMARKETING REQUIREMENTS UNDER SECTION 505(0)
+Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C. 355(o)(3)(A)).
+We have determined that an analysis of spontaneous postmarketing adverse events reported under section 505(k)(1) of the FDCA will not be sufficient to assess known serious risks of myocarditis and pericarditis and identify an unexpected serious risk of subclinical myocarditis.
+Furthermore, the pharmacovigilance system that FDA is required to maintain under section 505(k)(3) of the FDCA is not sufficient to assess these serious risks.
+Therefore, based on appropriate scientific data, we have determined that you are required to conduct the following studies:
+4. Study C4591009, entitled "A Non-Interventional Post-Approval Safety Study of the Pfizer-BioNTech COVID-19 mRNA Vaccine in the United States," to evaluate the occurrence of myocarditis and pericarditis following administration of COMIRNATY.
+We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule:
+Final Protocol Submission: August 31, 2021
+Monitoring Report Submission: October 31, 2022
+Interim Report Submission: October 31, 2023
+Study Completion: June 30, 2025
+Final Report Submission: October 31, 2025
+5. Study C4591021, entitled "Post Conditional Approval Active Surveillance Study
+Among Individuals in Europe Receiving the Pfizer-BioNTech Coronavirus
+
+Page 7 - STN BL 125742/0 - Elisa Harkins
+Disease 2019 (COVID-19) Vaccine," to evaluate the occurrence of myocarditis and pericarditis following administration of COMIRNATY.
+We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule:
+Final Protocol Submission: August 11, 2021
+Progress Report Submission: September 30, 2021
+Interim Report 1 Submission: March 31, 2022
+Interim Report 2 Submission: September 30, 2022
+Interim Report 3 Submission: March 31, 2023
+Interim Report 4 Submission: September 30, 2023
+Interim Report 5 Submission: March 31, 2024
+Study Completion: March 31, 2024
+Final Report Submission: September 30, 2024
+6. Study C4591021 substudy to describe the natural history of myocarditis and pericarditis following administration of COMIRNATY.
+We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule:
+Final Protocol Submission: January 31, 2022
+Study Completion: March 31, 2024
+Final Report Submission: September 30, 2024
+7. Study C4591036, a prospective cohort study with at least 5 years of follow-up for potential long-term sequelae of myocarditis after vaccination (in collaboration with Pediatric Heart Network).
+We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule:
+Final Protocol Submission: November 30, 2021
+Study Completion: December 31, 2026
+
+Page 8 - ST BL 125742/0 - Elisa Harkins
+Final Report Submission: May 31, 2027
+8. Study C4591007 substudy to prospectively assess the incidence of subclinical myocarditis following administration of the second dose of COMIRNATY in a subset of participants 5 through 15 years of age.
+We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this assessment according to the following schedule:
+Final Protocol Submission: September 30, 2021
+Study Completion: November 30, 2023
+Final Report Submission: May 31, 2024
+9. Study C4591031 substudy to prospectively assess the incidence of subclinical myocarditis following administration of a third dose of COMIRNATY in a subset of participants 16 to 30 years of age.
+We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule:
+Final Protocol Submission: November 30, 2021
+Study Completion: June 30, 2022
+Final Report Submission: December 31, 2022
+Please submit the protocols to your IND 19736, with a cross-reference letter to this BLA ST BL 125742 explaining that these protocols were submitted to the IND. Please refer to the PMR sequential number for each study/clinical trial and the submission number as shown in this letter.
+Please submit final study reports to the BLA. If the information in the final study report supports a change in the label, the final study report must be submitted as a supplement to this BLA ST BL 125742. For administrative purposes, all submissions related to these postmarketing studies required under section 505(o) must be submitted to this BLA and be clearly designated as:
+• Required Postmarketing Correspondence under Section 505(o)
+• Required Postmarketing Final Report under Section 505(o)
+Supplement contains Required Postmarketing Final Report under Section 505(0)
+Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise
+
+Page 9 - ST BL 125742/0 - Elisa Harkins
+undertaken to investigate a safety issue. In addition, section 506B of the FDCA and 21
+CFR 601.70 require you to report annually on the status of any postmarketing commitments or required studies or clinical trials.
+You must describe the status in an annual report on postmarketing studies for this product. Label your annual report as an Annual Status Report of Postmarketing Requirements/Commitments and submit it to the FDA each year within 60 calendar davs of the anniversary date of this letter until all Requirements and Commitments subject to the reporting requirements of section 506B of the FDCA are fulfilled or released. The status report for each study should include:
+• the sequential number for each study as shown in this letter;
+• information to identify and describe the postmarketing requirement;
+• the original milestone schedule for the requirement;
+• the revised milestone schedule for the requirement, if appropriate;
+• the current status of the requirement (i.e., pending, ongoing, delayed, terminated, or submitted); and,
+an explanation of the status for the study or clinical trial. The explanation should include how the study is progressing in reference to the original projected schedule, including, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment).
+As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our website at http://www.fda.qov/Drugs/Guidance ComplianceRegulatoryInformation/Post-marketingPhaselCommitments/default.htm.
+We will consider the submission of your annual report under section 506B of the FDCA and 21 CFR 601.70 to satisfy the periodic reporting requirement under section
+505(o)(3)(E)(¡i) provided that you include the elements listed in section 505(o) and 21
+CFR 601.70. We remind you that to comply with section 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to periodically report on the status of studies or clinical trials required under section 505(o) may be a violation of FDCA section 505(o)(3)(E)(¡i) and could result in regulatory action.
+POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
+UNDER SECTION 506B
+We acknowledge your written commitments as described in your letter of August 21, 2021 as outlined below:
+10. Study C4591022, entitled "Pfizer-BioNTech COVID-19 Vaccine Exposure during Pregnancy: A Non-Interventional Post-Approval Safety Study of Pregnancy and Infant Outcomes in the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry.'
+Final Protocol Submission: July 1, 2021
+
+Page 10 - ST BL 125742/0 - Elisa Harkins
+Study Completion: June 30, 2025
+Final Report Submission: December 31, 2025
+11. Study C4591007 substudy to evaluate the immunogenicity and safety of lower dose levels of COMIRNATY in individuals 12 through <30 years of age.
+Final Protocol Submission: September 30, 2021
+Study Completion: November 30, 2023
+Final Report Submission: May 31, 2024
+12. Study C4591012, entitled "Post-emergency Use Authorization Active Safety
+Surveillance Study Among Individuals in the Veteran's Affairs Health System Receiving Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) Vaccine."
+Final Protocol Submission: January 29, 2021
+Study Completion: June 30, 2023
+Final Report Submission: December 31, 2023
+13. Study C4591014, entitled "Pfizer-BioNTech COVID-19 BNT1622 Vaccine
+Effectiveness Study - Kaiser Permanente Southern California."
+Final Protocol Submission: March 22, 2021
+Study Completion: December 31, 2022
+Final Report Submission: June 30, 2023
+Please submit clinical protocols to your IND 19736, and a cross-reference letter to this BLA ST BL 125742 explaining that these protocols were submitted to the IND. Please refer to the PMC sequential number for each study/clinical trial and the submission number as shown in this letter.
+If the information in the final study report supports a change in the label, the final study report must be submitted as a supplement. Please use the following designators to prominently label all submissions, including supplements, relating to these postmarketing study commitments as appropriate:
+• Postmarketing Commitment - Correspondence Study Update
+• Postmarketing Commitment - Final Study Report
+• Supplement contains Postmarketing Commitment - Final Study Report
+
+Page 11 - ST BL 125742/0 - Elisa Harkins
+For each postmarketing study subject to the reporting requirements of 21 CFR 601.70, vou must describe the status in an annual report on postmarketing studies for this product. Label your annual report as an Annual Status Report of Postmarketing Requirements/Commitments and submit it to the FDA each year within 60 calendar davs of the anniversary date of this letter until all Requirements and Commitments subject to the reporting requirements of section 506B of the FDCA are fulfilled or released. The status report for each study should include:
+• the sequential number for each study as shown in this letter;
+• information to identify and describe the postmarketing commitment;
+• the original schedule for the commitment;
+• the status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted); and,
+• an explanation of the status including, for clinical studies, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment).
+As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our website at http://www.fda.gov/Drugs/Guidance ComplianceRegulatoryInformation/Post-marketingPhaselVCommitments/default.htm.
+POST APPROVAL FEEDBACK MEETING
+New biological products qualify for a post approval feedback meeting. Such meetings are used to discuss the qualitv of the application and to evaluate the communication process during drug development and marketing application review. The purpose is to learn from successful aspects of the review process and to identify areas that could benefit from improvement. If you would like to have such a meeting with us, please contact the Regulatory Project Manager for this application.
+Sincerely,
+Mary A. Malarkey
+Director
+Office of Compliance and Biologics Quality
+Center for Biologics
+Evaluation and Research
+Marion F. Gruber, PhD Director
+Office of Vaccines
+Research and Review
+Center for Biologics
+Evaluation and Research
+

docs/August-25-2022-Approval-Letter-COMIRNATY.txt

@@ -0,0 +1,52 @@
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+Our ST: BL 125742/175
+SUPPLEMENT APPROVAL
+BioNTech Manufacturing GmbH
+Attention: Adrienne Stafford
+Pfizer Inc.
+4300 Oak Park Road
+Sanford, NC 27330
+August 25, 2022
+Dear Ms. Stafford:
+We have approved your request received on June 10, 2022, to supplement your Biologics License Application (BLA) under section 351 (a) of the Public Health Service Act for COVID-19 Vaccine, mRNA (COMIRNATY), manufactured at the Pfizer Manufacturing Belgium NV, Puurs, Belgium (Pfizer, Purs), Pharmacia & Upjohn Company LLC, Kalamazoo, Michigan (Pfizer, Kalamazoo) and Hospira, Inc., McPherson, Kansas (Pfizer, McPherson) facilities, to include the introduction of the Monovalent Tris/Sucrose (30 mcg) Single Dose Vial with 0.48 mL Fill Volume to be filled on b) (4)
+(b) (4) and (b) (4)
+filling lines at the Purs, Belgium
+location, and associated labeling changes.
+LABELING
+We hereby approve the draft content of labeling including the Package Insert submitted under amendment 5, dated August 25, 2022.
+CONTENT OF LABELING
+As soon as possible, but no later than 14 days from the date of this letter, please submit the final content of labeling (21 CFR 601.14) in Structured Product Labeling (SPL) format via the FDA automated drug registration and listing system, (eLIST) as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
+Content of labeling must be identical to the Package Insert submitted on
+August 25, 2022. Information on submitting SPL files using LIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida nces/UCM072392.pdf.
+The SPL will be accessible via publicly available labeling repositories.
+All final labeling should be submitted as Product Correspondence to this BLA, ST BL 125742, at the time of use and include implementation information on Form FDA 356h.
+U.S. Food & Drug Administration
+10903 New Hampshire Avenue
+Silver Spring, MD 20993
+www.fda.gov
+
+Page 2 - ST BL 125742/175 - Adrienne Stafford
+ADVERTISING AND PROMOTIONAL LABELING
+You may submit two draft copies of the proposed introductory advertising and promotional labeling with Form FDA 2253 to the Advertising and Promotional Labeling
+Branch at the following address:
+Food and Drug Administration
+Center for Biologics Evaluation and Research
+Document Control Center
+10903 New Hampshire Ave.
+WO71-G112
+Silver Spring, MD 20993-0002
+You must submit copies of your final advertising and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).
+All promotional claims must be consistent with and not contrary to approved labeling.
+You should not make a comparative promotional claim or claim of superiorit over other products unless you have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).
+Please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that includes these changes.
+We will include information contained in the above-referenced supplement in your BLA file.
+Sincerely,
+Jerry P. Weir, Ph.D.
+Director
+Division of Viral Products
+Office of Vaccines
+Research and Review
+Center for Biologics
+Evaluation and Research
+

docs/Benefit-Risk Assessment Review Memo - COMIRNATY.txt

@@ -0,0 +1,2115 @@
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+Department of Health and Human Services
+Food and Drug Administration
+Center for Biologics Evaluation and Research
+MEMORANDUM
+Date:
+To:
+From:
+September 13, 2021
+Ramachandra Naik
+Hong Yang, Ph.D., Patrick Funk, Ph.D., and Osman N. Yogurtcu, Ph.D.
+Analytics and Benefit-Risk Assessment Team
+ОВЕ
+Through:
+Re:
+Richard Forshee, Ph.D.
+Acting Deputy Office Director
+ОВЕ
+ST 125742/0: review memo for benefit-risk assessment
+
+Page 2 - Hong Yang - 125742/0
+Review Memo on Benefit-Risk Assessment of Pfizer Vaccines for Age 16-17 yrs
+Reference submission: BLA 125742/0
+Reviewers: Hong Yang, Patrick Funk, and Osman Yogurtcu Date: August 20, 2021
+Contents
+1. Executive Summary
+2. Background and regulatory questions.
+3. Methods.
+3.1. Model Overview
+3.2. Benefits...
+3.3. Risks...
+4. Results..
+4.1. Scenario 1: Base case.
+4.2. Scenario 2: Most likely scenario.
+4.3. Scenario 3: Worst case scenario.
+5. Conclusions and discussion..
+6. Limitations ..
+
+7. Acknowledgements
+References.
+List of Tables.
+List of Figures.
+Supplementary Materials.
+5
+..9
+..9
+..9
+.9
+..10
+11
+..12
+13
+14
+14
+26
+
+Page 3 - Hong Yang - 125742/0
+1. Executive Summary
+FDA conducted a benefit-risk assessment to inform the review of the Biologics License Application (BLA) for use of the Pfizer-BioNTech COVID-19 mRNA vaccine (also referred to as BNT162b2) among ages 16 vears and older. We assessed the benefits and risks per million individuals who are vaccinated with two complete doses of BNT162b2. The analysis was conducted for the groups stratified by combinations of sex and age (12-15, 16-17, 18-24, and 25-29 years). The model assesses the benefits of vaccine-preventable COVID-19 cases, hospitalizations, intensive care unit (ICUs) visits, and deaths, and the risks of vaccine-related excess myocarditis/pericarditis cases, hospitalizations, and deaths. The major sources of data include age/sex specific COVID-19 case and hospitalization incidences reported on COVID NET on July 10, 2021, the myocarditis/pericarditis case rate attributable to vaccine obtained from the OPTUM health claims database, and the vaccine related myocarditis/pericarditis deaths reported through VAERS.
+We constructed scenarios for both the most likely short-term moving direction of the pandemic and the worst case, which used the most conservative assumptions for all model inputs.
+The most likely scenario:
+We assumed vaccine protection duration of 6-months, 10 COVID-19 case incidence and 4x COVID-19 hospitalization incidence as of July 10, 70% vaccine efficacy against COVID-19 cases, 80% vaccine efficacy against hospitalization, and no vaccine-related myocarditis death. The model results indicate that, for all age/sex groups and across all model outcomes, the benefits clearly outweigh the risks. For males 16-17 years old-the group with the highest risk of myocarditis/pericarditis-the model predicts that prevented COVID cases, hospitalizations, ICUs, and deaths are 135,771, 506, 166, and 4, respectively. The excess myocarditis/pericarditis cases, associated hospitalizations, and deaths attributable to vaccine are 196, 196, and 0, respectively.
+The worst-case scenario:
+We used the most conservative assumptions for all the model inputs in this scenario. We assumed 6-months vaccine protection, the COVID-19 case and hospitalization incidence as of July 10, 2021, 70% vaccine efficacy against COVID-19 case, 80% vaccine efficacy against COVID-19 hospitalization, and 0.002% myocarditis/pericarditis death rate.
+For males 16-17 years old, the model predicts that prevented COVID cases, hospitalizations, ICUs, and deaths are 13,577, 127, 41, and 1, respectively. The excess myocarditis/pericarditis cases and associated hospitalizations and deaths attributable to the vaccine are 196, 196, and 0, respectively. Even with the conservative assumption on the myocarditis/pericarditis death rate, the model predicted 0 deaths associated with myocarditis/pericarditis. The model predicted a higher number of myocarditis/pericarditis related hospitalizations compared to prevented COVID-19 hospitalizations.
+However, considering the differential clinical outcomes of the hospitalization from two difference causes, we consider the benefits of the vaccine still outweigh the risks for the highest risk group, males 16-17 years old, under this worst-case scenario.
+Our results demonstrate that the benefits of BNT162b2 clearly outweigh its risks for all age and sex
+
+Page 4 - Hong Yang - 125742/0
+groups we analyzed. However, the benefit-risk estimates are highly uncertain due to the dynamics of pandemics. Other major uncertainties in benefits are vaccine efficacy and duration of protection in the face of emerging virus variants. The major risk uncertainty is the data on vaccine-related myocarditis cases and deaths.
+2. Background and regulatory questions
+The Pfizer-BioNTech COVID-19 mRNA vaccine (also referred to as BNT162b2) has been recommended for persons 12 years of age and older in the United States under FDA's Emergency Use Authorization (EUA).
+Since authorization of mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna), real-world evidence has indicated the vaccines are effective in preventing COVID-19 cases and related hospitalizations and deaths. However, increased cases of myocarditis and pericarditis have been reported in the United States associated with mRNA COVID-19 vaccination, particularly in adolescents and young adults (Marshall et al. 2021; Shay et al. 2021; Watkins, et al., 2021). FDA conducted a benefit-risk assessment to inform regulatory decisions related to the Biologics License Application (BLA) for use of BNT162b2 vaccines among ages 16 years and older. The regulatory question to be answered is whether the benefits of vaccination outweigh the risks among various age and sex subgroups being considered for approved use of the vaccine (and in particular, males, age 16-17 years old), considering the potentially elevated myocarditis/pericarditis risk after vaccination suggested by post-authorization safety surveillance.
+3. Methods
+3.1. Model Overview
+We assessed the benefits and risks per million individuals who are vaccinated with two complete doses of BNT162b2. The analysis was conducted for the groups stratified by combinations of sex and age (12-15, 16-17, 18-24, and 25-29 years). The model assesses the benefits of vaccine-preventable COVID-19 cases, hospitalizations, intensive care unit (ICUs) visits and deaths, and the risks of vaccine related excess myocarditis/pericarditis cases, hospitalizations, and deaths (Figure 1). The key model inputs include duration of vaccine protection, vaccine efficacy against COVID-19 cases and hospitalizations, age/sex specific COVID-19 case and hospitalization incidence rates, age/sex specific vaccine-attributable myocarditis case rate, and myocarditis death rate (Table 1). To evaluate the impact of uncertainty of these key model inputs on the benefits and risks, low and high values of these model inputs are used for sensitivity analysis.
+Our model generates benefit-risk outcomes for seven scenarios (Table 2 and Supplement Table
+S1) with different combinations of the input values. The three most important scenarios are presented in the main body of this report: Scenario 1, a base scenario using the COVID-19 incidence on July 10; Scenario 2, the most likely scenario; and Scenario 3, the worst-case scenario. Other scenarios are summarized in the supplementary materials of the report.
+
+Page 5 - Hong Yang - 125742/o
+3.2. Benefits
+3.2.1. Calculation of benefits
+Our benefit-risk model has four benefit endpoints (Figure 1): preventable COVID-19 cases hospitalizations, Intensive Care Unit admissions (ICUs), and deaths. To calculate the potential
+COVID-19 cases preventable by vaccine (Cp), we use Equation 1
+Cp =
+ICID Ec
+Pu
+Eq. 1
+where Ic is the COVID-19 case incidence rate, Pu is the proportion of the population that is at risk (i.e., unvaccinated), L is the duration of vaccine protection, D is the number of second vaccine doses administered (fixed at 1 million), and E is the vaccine efficacy against COVID-19 cases. For preventable COVID-19 hospitalizations (H), we use a similar equation (Equation 2) in which we consider the COVID-19 hospitalization incidence rate (I and vaccine efficacy against hospitalization (EH).
+Hp =
+브LDEn
+Pu
+Eq. 2
+The preventable COVID-19 ICUs (Ip) and preventable COVID-19 deaths (D) are fractions of Hp,
+such that Ip = fim Hp and Dp = faH Hp.
+We perform these calculations over the individual age and sex groups and combined male and female groups.
+3.2.2. Data and assumptions
+3.2.2.1.
+Duration of vaccine protection
+We assume the vaccine has at the least 6 months of protection since this is the period examined by Pfizer in their ongoing study (Thomas et al., 2021). The model assesses the benefits for a period of 6 months post 2nd dose of vaccination. For the sensitivity analysis in the supplement, we use a protection period of 12 months as an upper bound. For simplicity, the model does not account for the benefits of partial vaccination (protection between the first and second dose) or the second order benefits of reducing the risk of transmission of COVID-19.
+3.2.2.2.
+Incidences of COVID-19 case, hospitalization, ICU, and death
+We assume the incidence rates of COVID-19 case and hospitalization remain constant over the assessment period (next 6 or 12 months). The incidence rates of COVID-19 cases as of week July 10 are obtained from COVID NET for all sex/age groups. Four-week averages of incidence (6/26-7/10) are used due to the variability in rates given
+
+Page 6 - Hong Yang - 125742/0
+the small numbers of hospitalizations per age sex groups. The percent of hospitalizations going to ICU and the percent of hospitalized patients who die are estimated based on cumulative rates of hospitalizations, ICUs, and deaths for each sex/age groups reported on COVID NET since March 2020. All the incidence data for these factors are summarized in Table 3. Comparing the incidence from the 2nd week of August with those reported at the lowest point in the summer, we find a 10-time incidence and 4-time hospitalization increase over a 6-week period. Considering the great uncertainty in COVID-19 incidence during the pandemic, we conduct a sensitivity analysis using a 10-times multiplier for case incidence and 4-times multiplier for hospitalization incidence in the sensitivit analvsis. The multipliers were derived from the public data in COVID data tracker and COVID NET, respectively, to project the increase in COVID-19 infections/hospitalizations.
+3.2.2.3.
+Unvaccinated population
+We estimate the unvaccinated population among each age/sex groups using US census data and "Age groups of people with at least one dose" from COVID data tracker. Data for Texas is not contained in COVID data tracker so we impute proportional vaccination counts based on population averages from the census data.
+The incidence of COVID-19 cases and hospitalization, described in section 2.2.2.2
+"Incidences of COVID-19 case, hospitalization, ICU and death," are converted into the incidence of COVID-19 cases and hospitalizations among unvaccinated individuals of each age sex group.
+3.2.2.4.
+Vaccine efficacy
+We use vaccine efficacy rates of protection against COVID-19 cases of 70% and 90% and vaccine efficacy rates of protection against COVID-19 hospitalizations of 80% and 90% in different scenarios. The high efficacy of 90% represents the lower bound of the confidence interval from the clinical trial data (Oliver et al. 2020). The low efficacy of 70% for cases and 80% for hospitalization represents a conservative efficac rate given the uncertainty of the vaccine's protection against the Delta variant. Early studies on the vaccine's efficacy against cases from the Delta variant suggest 79% in Scotland (Sheikh et al., 2021), 87% in Canada (Nasreen et al., 2021), and 88% in India (Lopez Bernal et al., 2021). To remain conservative in the face of uncertainty in this rapidly changing pandemic, we use a lower bound of vaccine efficacy from these early reports.
+3.3. Risks
+3.3.1. Calculation of risks
+Our benefit-risk model has three risk endpoints (Figure 1): excess myocarditis/pericarditis cases, hospitalizations, and deaths. Estimates of excess cases of mvocarditis/pericarditis are calculated by subtracting the background rate of myocarditis in Optum's sample population from 2019 from
+
+Page 7 - Hong Yang - 125742/0
+the rate of myocarditis in the study window from 12/10/2020 - 07/10/2021. We use Equation 3 to calculate excess cases of myocarditis/pericarditis (Mex) per one million fully vaccinated individuals.
+MExc = (Mobs1 - MExp1 + Mobs2 - MExp2) * F
+Eq. 3
+Mobs1 and MExp1 are observed and expected myocarditis/pericarditis case rates post dose 1, Mobs and MExp2 are corresponding case rates post dose 2, and F is a multiplier for unit conversion.
+Expected myocarditis/pericarditis case rates are the predicted background case rate unassociated with vaccine.
+The number of mvocarditis hospitalization (M- and deaths (Mo) are fractions of excess
+myocarditis/pericarditis cases (MExc), such that MH = MExc* Frmand MD = Mexc* fom.
+3.3.2. Data and assumptions
+3.3.2.1.
+Myocarditis/pericarditis attributable to vaccine
+We use myocarditis/pericarditis reports data provided by Acumen LLC that are derived from the Optum health claims database (Table 5). Acumen reports cases of myocarditis in 7-, 21-, and 42-day risk windows from each vaccine dose. Our analysis focuses on the 7-day risk window where most cases are found for all groups. The database contains rates of expected (MExp 1 and MExp2) and observed (Mobs1 and Mobs2) myocarditis/pericarditis in 100k person-vears for the 1st and 2nd dose of the vaccine.
+Converting from 100k person-years in the risk window to one million vaccinated
+individuals' daily risk, we multiply the rates by a factor F = (7*10)/365. This factor is
+used to convert the rate per 100k person years to an expected case count for one million full vaccinations assuming a 7-day risk window. Confidence intervals for the myocarditis cases are calculated using the chi-square method for Poison distribution of rare events (Garwood, 1936).
+3.3.2.2.
+Myocarditis/pericarditis hospitalization and death rate
+Almost all adolescent and young adult patients with suspected myocarditis/pericarditis cases are hospitalized and monitored for the condition. In this model, we assume all myocarditis/pericarditis cases are hospitalized, but Vaccine Adverse Events Reporting System (VAERS) data show median stay lengths of one day for observation.
+A total of 1,061 myocarditis cases among US <30 ears old after vaccination with BNT162b2 are reported through VAERS. Among them, two deaths are reported. The search terms used for query and the narratives for two deaths who had vaccination with BNT162b2 are included in the supplement. Review of the available data b FDA
+
+Page 8 - Hong Yang - 125742/0
+and CDC indicates that both cases are unlikely to be related to the vaccine. In our model, we assume the death rate related to vaccine is most likely to be zero in the base case and most likely scenarios (Scenario 1 and 2). However, we use 2/1,061 as the death rate for the worst-case scenario (Scenario 3) to account for the very unlikely outcome of these two deaths being attributed to vaccine related myocarditis/pericarditis.
+
+Page 9 - Hong Yang - 125742/0
+4. Results
+This section summarizes the results for three major model scenarios.
+4.1. Scenario 1: Base case
+Our model scenarios start with the base case that is using the most recent available incidence data on July 10, 2021 and assume a 6-month vaccine protection period, 90% vaccine efficacy against both COVID-19 case and hospitalization, and zero myocarditis/pericarditis death rate.
+Figures 2, 3, and 4 summarize the results for analyses of combined male/female, male only, and female only, respectively. The results indicate that benefit-risk is more favorable for male and female combined, female only, and male >18 years old. The model predicted far more prevented
+COVID-19 cases compared to excess myocarditis/pericarditis for male 12-15 and 16-17 years old, but the model predicted 142 prevented COVID-19 hospitalizations vs. 196 myocarditis/pericarditis hospitalizations for male age 16-17 years old and 122 prevented COVID-19 hospitalizations vs. 179 myocarditis/pericarditis hospitalizations for male 12-15 years old.
+However, hospitalizations associated with COVID-19 have more severe clinical outcomes than those associated with myocarditis/pericarditis. For this reason, we consider that the benefits of the vaccine outweigh the risks in this scenario even for male age 12-15 and 16-17 years old. See Table 5 for details and the benefit-risk results for 16-17 year olds.
+4.2. Scenario 2: Most likely scenario
+We constructed a scenario that most likely represents the short-term moving direction of the pandemic. We assume 6-month vaccine protection, and 10X higher COVID-19 case incidence and 4X higher COVID-19 hospitalizations incidence compared to the incidence on July 10. We also assume lower vaccine efficacy (70% against COVID-19 case, 80% against hospitalization) against newly emerging virus variants such as Delta strain. We assumed zero myocarditis death rate based on our best knowledge on the vaccine related myocarditis.
+Figures 5, 6, and 7 summarize the results for analyses of combined male/female, male only, and female only, respectively. For all age/sex groups and across all attributes, the benefits clearly outweigh the risks in this scenario. See Table 5 for details and benefit-risk results for 16-17 year olds.
+4.3. Scenario 3: Worst case scenario
+We also constructed the worst-case scenario using the most conservative assumptions for all the model inputs. We assumed 6-month vaccine protection, the COVID-19 incidence as of July 10, 2021, 70% vaccine efficacy against COVID-19 case, 80% vaccine efficacy against COVID-19 hospitalization, and 0.002% (2/1,061) myocarditis/pericarditis death rate.
+Figures 8, 9, and 10 summarize the results for analyses of combined male/female, male only, and female only, respectively. Even with the conservative assumption on
+
+Page 10 - Hong Yang - 125742/0
+myocarditis/pericarditis death rate, the model predicted 0 deaths associated with myocarditis/pericarditis compared to 1 prevented COVID-19 death for both male 12-15 and 16-17 year old groups. The model predicted 127 prevented COVID-19 hospitalizations vs 196 myocarditis/pericarditis hospitalizations for male age 16-17 years old and 109 prevented COVID-19 hospitalizations vs 179 myocarditis/pericarditis hospitalizations for male 12-15 years old.
+Considering the differential clinical outcomes of the hospitalization from two different causes, we consider the benefits of the vaccine still outweigh the risks in this "worst case scenario". See Table 5 for details and the benefit-risk results for 16-17 year olds.
+5. Conclusions and discussion
+Our results demonstrate that the benefits of BNT162b2 clearly outweigh its risks for all age and sex groups we analyzed. Under the base case scenario and the worst-case scenario (Scenario 1 and 3), we predicted a higher number of myocarditis hospitalizations than the COVID-19 hospitalizations among male 16-17 years old; however, considering the differential clinical implications of COVID-19 and myocarditis hospitalization, we consider the benefits of the vaccine still outweigh its risks. Moreover, under all other scenarios including the most likely (Scenario 2), our model predicted that preventable COVID-19 cases, hospitalizations, and deaths exceed the myocarditis cases and related hospitalizations and deaths for all age and sex groups.
+We note that COVID-19 incidence highly influences the predicted benefits of the vaccine. If the disease incidence is higher, the benefits of the vaccine will be greater, and vice versa. Therefore, the benefit-risk conclusion may change if the COVID-19 incidence rate becomes very low in the future. Also, "the worst-case scenario" presented here is the worst only among the modelled scenarios. Scenarios worse than Scenario 3 could occur if the data fall outside the ranges of model inputs we used, such as lower COVID-19 incidence than those reported on July 10, lower vaccine effectiveness against COVID-19 cases (<70%) and against hospitalizations (<80%), and shorter vaccine protection duration (<6 months).
+
+Page 11 - Hong Yang - 125742/0
+6. Limitations
+• (BENEFIT) The constant COVID-19 incidence rate assumption in our model generates high uncertainty on the estimate of benefits considering the uncertain dynamics of the pandemic. Additionally, estimated benefits of the vaccine would decrease if the vaccine becomes less effective against novel variants of COVID-19. The durability of vaccine protection is another source of uncertainty for the model. Any significant waning of vaccine-induced immunity before 6 or 12 months would reduce the benefit of the vaccine.
+• RISK) There is uncertainty in the myocarditis case and death rates attributable to the vaccine. In the US, two deaths among those less than 30 years old occurred following the administration of BNT162b2 and were evaluated by FDA and CDC. Based on the review of the available clinical information, the causes of death for both cases are not thought to be related to vaccination. To estimate myocarditis/pericarditis risk attributable to the vaccine, health claims data are used, which have inherent limitations such as small sample sizes for these rare outcomes. The cases have not been validated by medical chart review. The crude myocarditis rate in our model was adjusted using myocarditis 2019 background rate, which did not account for COVID-19 infection related risk of myocarditis/pericarditis and may lead to overestimating the risk attributed to the vaccine.
+• (BENEFIT-RISK BALANCE) Some benefit-risk endpoints in our assessment are difficult to compare directly, for example, hospitalizations from COVID-19 and myocarditis hospitalizations. This benefit-risk assessment does not consider the potential long-term health impacts of COVID-19 or myocarditis. Also, it does not include secondary benefits and risks, such as any potential impact on the public trust in COVID-19 vaccines and the benefit ofthe vaccine in reducing the viral transmission in the population. In this analysis, we did not investigate the benefits and risks of subpopulations with comorbidity due to limited information. The benefit-risk profile could be different depending on the individual's health condition.
+
+Page 12 - Hong Yang - 125742/0
+7. Acknowledgements
+We thank J. Rosser Matthews, Ph.D., and Katherine Scott, M.D., for editing this Benefit-Risk review memo.
+
+Page 13 - Hong Yang - 125742/0
+References
+1. Garwood, F. "Fiducial limits for the Poison distribution." Biometrika 28.3/4 (1936): 437-442.
+2. Lopez Bernal, Jamie, et al. "Effectiveness of Covid-19 vaccines against the B. 1.617. 2 (delta) variant." New England Journal of Medicine (2021).
+3. Marshall, Mayme, et al. "Symptomatic acute myocarditis in seven adolescents following Pfizer-BioNTech
+COVID-19 vaccination." Pediatrics (2021): 2.
+4. Nasreen, Sharifa, et al.
+"Effectiveness of COVID-19 vaccines against variants of concern,
+Canada." Medrxiv (2021).
+5. Oliver, Sara E., et al. "The advisory committee on immunization practices' interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine- United States, December 2020." Morbidity and Mortality Weekly Report
+69.50 (2020): 1922.
+6. "Population-Level Risk-Benefit Analysis." Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 5 May 2021, www.cdc.gov/vaccines/covid-19/info-by-product/janssen/risk-benefit-analysis.html.
+7. Shay, David K., Tom T. Shimabukuro, and Frank DeStefano. "Myocarditis occurring after immunization with mRNA-based COVID-19 vaccines." JAMA cardiology (2021).
+8. Sheikh, Aziz, et al. "SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness." The Lancet (2021).
+9. Thomas, Stephen J., et al. "Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19
+Vaccine." medRxiv (2021).
+10. Watkins, Kevin, et al. "Myocarditis after BNT162b2 vaccination in a healthy male." The American Journal of Emergency Medicine (2021).
+
+Page 14 - Hong Yang - 125742/0
+List of Tables
+Table 1. Low and high values for model input parameters considered in our sensitivity analysis
+...... 15
+Table 2. The three main model scenarios with different combinations of model input values that are shown on Table 1...
+Table 3. Vaccine coverage and COVID incidences by sex and age groups
+...15
+..15
+Table 4. Optum-reported myocarditis cases for 1 million fully vaccinated individuals by age and sex.
+95% confidence intervals for the rates are shown in brackets ......
+................. 15
+Table 5. Model predicted benefit-risk outcomes of Scenarios 1-3 for the 16-17-year-old groups..........16
+List of Figures
+Figure 1. Benefits-risks value tree.
+Figure 2. Results of Scenario 1 for combined male and female populations
+Figure 3. Results of Scenario 1 for the male population ...
+Figure 4. Results of Scenario 1 for the female population ....
+Figure 5. Results of Scenario 2 for combined male and female populations....
+Figure 6. Results of Scenario 2 for the male population ....
+Figure 7. Results of Scenario 2 for the female population..
+Figure 8. Results of Scenario 3 for combined male and female populations
+Figure 9. Results of Scenario 3 for the male population.
+Figure 10. Results of Scenario 3 for the female population.....
+16
+.....17
+..18
+...19
+....... 20
+.21
+.22
+.23
+24
+.25
+
+Page 15 - Hong Yang - 125742/0
+Table 1. Low and high values model input parameters considered in our sensitivity analysis
+Model inputs
+Vaccine protection period
+Vaccine efficacy against cases
+Vaccine efficacy against hospitalization
+COVID-19 case incidence rate
+COVID-19 hospitalization case incidence rate
+Myocarditis death rate
+Low
+6 months
+70%
+80%
+July 10 rate
+July 10 rate
+0%
+High
+12 months
+90%
+90%
+10X July 10 rate
+4X July 10 rate
+0.002%
+Table 2. The three main model scenarios with different combinations of model input values that are shown on
+Table 1
+Scenario
+Scenario 1
+Scenario 2
+(Most Likelv)
+Scenario 3
+(Worst Case
+Protection
+period
+Low
+Efficacy against
+Efficacy against
+cases hospitalization
+High
+High
+COVID-19
+case incidence
+Low
+COVID-19 hospitalization incidence
+Low
+Vaccine attributable myocarditis death rate
+Low
+Low
+Low
+Low
+High
+High
+Low
+Low
+Low
+Low
+Low
+Low
+High
+Table 3. Vaccine coverage and COVID incidences by sex and age groups
+COVID-19 Hospitalizati Percent of Percent of
+Vaccinated cases/100k ons/100k hospitalized hospitalized
+Sex
+Female
+Male
+Age group
+12-15
+16-17
+18-24
+25-29
+12-15
+16-17
+18-24
+25-29
+Population1 population?
+persons persons3 going to ICU3 who die
+8,183,216
+2,886,252
+4,119,686
+1,985,672
+14,923,948
+8.033.040
+11,428,122
+5,918,524
+8,535,307
+2,815,693
+4,300,731
+1,826,299
+15,633,953
+7,217,945
+12,036,982
+5,592,473
+37.3
+47.9
+64.6
+68.6
+33.1
+42.9
+53.3
+57.8
+0.671
+23.9
+1.593
+19.5
+2.025
+8.1
+2.45
+5.9
+0.35
+31.8
+0.35
+32.7
+0.8
+22.2
+0.875
+22.7
+0
+0.7
+1
+0.3
+0.9
+0.7
+0.6
+1.5
+Source: 1-CDC Wonder, 2-COVID Data Tracker, 3-COVID NET
+Table 4. Estimated excess number of myocarditis/pericarditis cases for 1 million fully vaccinated individuals with Pfizer BNT162b2 by age and sex. 95% confidence intervals for the rates are shown in brackets
+Rate of excess myocarditis/pericarditis per 1 million fully vaccinated and 95%
+Sex
+Male
+Female
+Age (years)
+12-15
+16-17
+18-25
+26-35
+12-15
+16-17
+18-25
+26-35
+confidence intervals
+179 [38, 332]
+196 [36, 424]
+131 [27, 224]
+49 [0, 123]
+32 [0, 235]
+36 [0, 298]
+57 [9, 147]
+2 [0. 801
+Source: Optum Database pre-adiudicated claims 12/11/2020 - 07/10/2021
+
+Page 16 - Hong Yang - 125742/0
+Table 5. Model predicted benefit-risk outcomes of Scenarios 1-3 for the 16-17-year-old groups
+Benefits
+Prevented
+Prevented Prevented Prevented
+COVID-19
+COVID-19
+COVID-19 COVID-19 Myocarditis
+Scenario
+Cases Hospitalizations
+ICUs
+Deaths
+Risks
+Excess
+Excess
+Excess
+Myocarditis Myocarditis
+Cases Hospitalizations
+Deaths
+Males & Females
+Scenario 1
+Scenario 2
+Scenario 3
+19,425
+151.080
+15.108
+Males only
+Scenario 1
+Scenario 2
+Scenario 3
+17.456
+135,771
+13.577
+Females only
+Scenario 1
+Scenario 2
+Scenario 3
+21,657
+168,443
+16.844
+Figure 1. Benefits-risks value tree.
+Benefits
+241
+855
+214
+142
+506
+127
+350
+1245
+311
+59
+210
+52
+2
+6
+1
+116
+116
+116
+47
+166
+41
+1
+4
+1
+196
+196
+196
+68
+243
+61
+2
+9
+2
+36
+36
+36
+Preventable COVID cases
+Preventable COVID hospitalizations
+Preventable COVID ICUs
+116
+116
+116
+196
+196
+196
+36
+36
+36
+Preventable COVID deaths
+0
+0
+o 00
+O
+Pfizer-BioNTech
+COVID-19 Vaccine
+Risks
+Excess myocarditis/pericarditis cases
+Excess myocarditis/pericarditis hospitalizations
+Excess myocarditis/pericarditis deaths
+Source : Reviewer Analysis
+
+Page 17 - Hong Yang - 125742/o
+Figure 2. Results of Scenario 1 for combined male and female populations
+BENEFITS
+12-15 yo
+Preventer counstepains
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+160
+12,489
+Prevented COVID-19 Cases
+400
+300
+200
+100
+16-17 Yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+19.425
+Prevented COVID.19 Cases
+400
+300
+200
+100
+106
+106
+200
+116
+116
+100
+200
+300
+18-24 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+CERO
+Prevented COVID-19 Hospitalizations
+27,539
+Prevented COVID-19 Cases
+400
+200
+100
+100
+200
+300
+25-29 yo
+Prevented COVID-19 Deaths
+Prevented COVID.19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases29,032
+Source: Reviewer Analvsis
+400
+300
+200
+100
+100
+200
+300
+RISKS
+400
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess MyoPericarditis Hospitalization!
+Excess Myo/Pericarditis Cases
+500
+
+Page 18 - Hong Yang - 125742/0
+Figure 3. Results of Scenario 1 for the male population
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUS
+Prevented COVID-19 Hospitalizations g 581
+prevented countere casas
+300
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations 17.456
+Prevented COVID-19 Cases
+400
+300
+12-15 vo
+122
+200
+100
+16-17 yo
+142
+200
+100
+18-24 yo
+Prevented COVID-19 Deaths
+Prevented COVID.19 Hospitalizations
+23,183
+Prevented COVID-19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID.19 ICUs
+Prevented COVID-19 Hospitalizations
+25.249
+Source : Reviewer Analysis
+400
+382
+400
+300
+200
+100
+87
+25-29 yo
+300
+200
+• 179
+• 179
+10
+200
+300
+196
+196
+100 200
+300
+131
+131
+100
+200
+300
+200
+300
+RISKS
+400
+400
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Mvo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+
+Page 19 - Hong Yang - 125742/o
+Figure 4. Results of Scenario 1 for the female population
+BENEFITS
+12-15 yo
+Prevented COVID-19 Deaths
+Prevented soneteos
+Prevented COVID-19 Hospitalizations
+13,479
+199
+Prevented COVID-19 Cases
+37
+200
+16-17 yo
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+350
+400
+100
+200
+18-24 yo
+10 I
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+1,026
+Prevented COVID-19 Cases
+400
+200
+57
+100
+100
+70
+200
+25-29 vo
+Prevented COVID-19 Deaths
+Prevented COVID.19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases 33,317
+Source : Reviewer Analysis
+400
+200
+100
+200
+300
+300
+300
+RISKS
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Fycess Muo Pericarditis Case
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+
+Page 20 - Hong Yang - 125742/0
+Figure 5. Results of Scenario 2 for combined male and female populations
+BENEFITS
+12-15 yo
+Prevented COVID.19 Deaths
+Prevented COVID-19 ICUs
+156
+Prevented COVID-19 Hospitalizations
+Prevented COVID.19 Cases
+97,136
+400
+300
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+210
+855
+Prevented COVID-19 Hospitalizations
+151,080,
+400
+300
+200
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+298
+Prevented COVID-19 Hospitalizations
+214,189
+400
+300
+200
+100
+16-17 yo
+100
+18-24 yo
+21 M
+100
+106
+106
+200
+116
+116
+100
+200
+94
+94
+100
+200
+300
+300
+25-29 yo
+Prevented COVID.19 Deaths
+Prevented COVID-19 ICUs
+2,715
+Prevented COVID-19 Hospitalizations
+225,807
+Prevented COVID.19 Cases
+400
+Source : Reviewer Analysis
+■95
+300
+200
+100
+100
+200
+300
+RISKS
+400
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+EXCEsS MvoPericarditis Deaths
+Excess Mo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+
+Page 21 - Hong Yang - 125742/0
+Figure 6. Results of Scenario 2 for the male population
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+435
+89,767
+Prevented COVID-19 Cases
+12-15 yo
+100
+16-17 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+18-24 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations 1,236
+Prevented COVID-19 Cases 180,31
+300
+200
+100
+25-29 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID.19 Hospitalizations
+Prevented COVID-19 Cases
+300
+200
+100
+Source : Reviewer Analysis
+179
+196
+300
+137
+100
+200
+300
+RISKS
+Excess Myo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+Dexcess mivovercarenus eacns
+excess myoPericarditis Mospitalizations
+400
+a00
+500
+500
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+Excess Myo/Pericarditis Hospitalizations
+
+Page 22 - Hong Yang - 125742/0
+Figure 7. Results of Scenario 2 for the female population
+BENEFITS
+12-15 yo
+Prevented COVID-19 Death:
+Prevented COVID.19 ICI
+160
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+200
+100
+Prevented COVID.19 Deaths
+Prevented COVID-19 ICUS
+Prevented COVID-19 Hospitalization:
+Prevented COVID-19 Cases
+1,245
+400
+300
+243
+20
+16-17 yo
+200
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID.19 Cases
+300
+200
+100
+100
+18-24 yo
+36
+25-29 vo
+Prevented COVID-19 Deaths
+Provented on aTe enc
+Prevented COVID-19 Hospitalization:
+Prevented COVID-19 Cases 259,1
+Source : Reviewer Analysis
+300
+200
+100
+100
+200
+200
+200
+200
+300
+300
+300
+RISKS
+Excess Mvo/Pericarditis Deaths
+Excess Mo/Pericarditis Hospitalizations
+Excess Mvo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+400
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+400
+500
+Excess Myo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalizations
+Excess MyoPericarditis Cases
+400
+
+Page 23 - Hong Yang - 125742/0
+Figure 8. Results of Scenario 3 for combined male and female populations
+BENEFITS
+12-15 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 Hospitalizations
+9,714
+Prevented COVID-19 Cases
+RISKS
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+300
+16-17 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+15,108
+Excess Myo/Pericarditis Deaths
+excess myoPericarditis Mospitalizations
+excess vonvercardias cases
+10
+100
+300
+18-24 yo
+5 I
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+587
+Prevented COVID-19 Hospitalizations
+Prevented cOVID-19 cases
+300
+200
+100
+200
+300
+400
+25-29 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases 22,581
+Source : Reviewer Analysis
+• 26
+200
+100
+200
+300
+400
+500
+500
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Mvo Pericarditis Cases
+EXCESS MyoPericarditis Death:
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+
+Page 24 - Hong Yang - 125742/0
+Figure 9. Results of Scenario 3 for the male population
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUS
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases 8,977 |
+300
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+13,577
+Prevented COVID-19 Cases
+12-15 yo
+109
+200
+100
+16-17 yo
+127
+400
+300
+200
+100
+18-24 yo
+Prevented COVID-19 Deaths
+Prevented COVID.19 Hospitalizations
+Prevented COVID-10 Cases 18,031
+200
+400
+300
+200
+100
+25-29 yo
+provenred covinste pains
+Prevented COVID.19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases 19,638
+400
+Source : Reviewer Analysis
+300
+100
+100
+• 179
+• 179
+200
+300
+196
+196
+200
+300
+131
+131
+200
+300
+200
+300
+RISKS
+400
+400
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Mvo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+
+Page 25 - Hong Yang - 125742/0
+Figure 10. Results of Scenario 3 for the female population
+BENEFITS
+12-15 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+10,484
+Prevented COVID-19 Cases
+400
+300
+200
+100
+100
+16-17 yo
+Prevented COVID-19 Death‹
+Prevented COVID-19 ICU‹
+Prevented COVID.19 Hospitalizations
+16.844
+Prevented COVID-19 Cases
+311
+400
+200
+Prevented COVID-19 Deaths
+Prevented COVID.19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID.19 Cas
+25,451
+200
+Prevented COVID.19 Deaths
+Prevented COVID.19 ICUs
+Prevented COVID.19 Hospitalizations
+Prevented COVID-19 Cases 25,913
+Source : Reviewer Analvsis
+300
+200
+100
+18-24 yo
+9 I
+74 L
+25-29 yo
+62 B
+100
+100
+100
+200
+200
+200
+300
+200
+300
+RISKS
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+400
+500
+excoss ivorPericardiris earns
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+400
+400
+400
+500
+Excess Myo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+
+Page 26 - Hong Yang - 125742/0
+Supplementary Materials
+Text S1. Narratives of Myocarditis Death cases and Terms Used in VAERS Search
+Table S1. Additional model scenarios with different combinations of model input values that are shown on Table 1 in the main text
+Figure S1: Results of Scenario 4 for combined male and female populations.
+Figure S2: Results of Scenario 4 for the male population.
+Figure S3: Results of Scenario 4 for the female population.
+Figure S4: Results of Scenario 5 for combined male and female populations.
+Figure S5: Results of Scenario 5 for the male population.
+Figure S6: Results of Scenario 5 for the female population.
+Figure S7: Results of Scenario 6 for combined male and female populations.
+Figure S8: Results of Scenario 6 for the male population.
+Figure S9: Results of Scenario 6 for the female population.
+Figure S10: Results of Scenario 6 for combined male and female populations.
+Figure S11: Results of Scenario 6 for the male population.
+Figure S12: Results of Scenario 6 for the female population.
+
+Page 27 - Hong Yang - 125742/0
+Text S1. Narratives of Myocarditis Death cases and Terms Used in VAERS Search
+Narratives of Myocarditis Death Cases
+Pfizer BioNTech Vaccine
+VAERS ID 1406840: 13 years old male with attention deficit hyperactivity disorder and developmental coordination disorder experienced flu-like symptoms for is days and then was found deceased; onset of symptoms 1-day post-vaccination. The preliminary autopsy report revealed cardiomegaly with biventricular dilatation, bilateral serous pulmonary effusions and serous pericardial effusion, marked pulmonary edema and congestion, and moderate degree of diffuse cerebral edema. COVID-19 and influenza A/B tests were negative. Additional testing on autopsy found this patient died of sepsis due
+Clostridium septicum.
+VAERS ID 1486852: 21 years old female who experienced fever, confusion, seizure, cardiac arrest days post vaccination. Autopsy revealed histology with extensive lymphocytic/plasmocytic myocarditis with rare eosinophils no granuloma. Additional review by pathologists at CDC found the patient had severe myocarditis with intravascular leukocytosis suggestive of sepsis.
+Reviewer Comment: Both of these death cases had alternate etiologies likely related to non-COVID-19 infections and were not attributed to vaccine.
+VAERS Search Terms
+Atypical mycobacterium pericarditis, Autoimmune myocarditis, Autoimmune pericarditis, Bacterial pericarditis,
+Coxsackie myocarditis,
+Coxsackie pericarditis, Cytomegalovirus myocarditis,
+Cytomegalovirus pericarditis, Enterovirus myocarditis, Eosinophilic myocarditis, Hypersensitivity myocarditis, Immune-mediated myocarditis, Myocarditis, Myocarditis bacterial, Myocarditis helminthic, Myocarditis infectious, Myocarditis meningococcal, Myocarditis mycotic, Myocarditis post infection, Myocarditis septic, Pericarditis, Pericarditis adhesive, Pericarditis constrictive, Pericarditis helminthic, Pericarditis infective, Pericarditis mycoplasmal, Pleuropericarditis, Purulent pericarditis, Viral myocarditis, Viral pericarditis.
+
+Page 28 - Hong Yang - 125742/0
+Table S1. Additional model scenarios with different combinations of model input values that are shown on Table 1 in the main text.
+Efficacy
+Scenario
+4
+5
+6
+7
+Protection period
+Low
+High
+Low
+Low
+against cases
+High
+High
+Low
+Low
+Efficacy against hospitalization
+High
+High
+Low
+Low
+Note: Additional scenarios are used to examine the impact of specific changes to model inputs
+COVID-19
+COVID-19 case hospitalization
+incidence
+incidence
+High
+High
+Low
+Low
+Low
+Low
+High
+High
+Vaccine attributable myocarditis death rate
+Low
+Low
+Low
+High
+
+Page 29 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations 639
+Prevented COVID-19 Cases
+124,889
+400
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUS 962
+Prevented COVID-19 Hospitalizations 194,245,
+Prevented COVID.19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUS 2.639
+Prevented COVID-19 Hospitalizations
+335
+275,386,
+Prevented COVID.19 Cases
+400
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+3,055
+Prevented COVID-19 Hospitalizations
+290.32
+Prevented COVID.19 Cases
+400
+300
+236
+300
+300
+176
+200
+200
+200
+200
+12-15 yo
+100
+16-17 yo
+18-24 yo
+24 B
+o
+100
+25-29 yo
+106
+106
+100
+200
+• 116
+• 116
+94
+94
+100
+200
+1 26
+300
+300
+300
+100
+RISKS
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+о
+100
+2∞ 300
+400
+500
+Figure S1: Results of Scenario 4 for combined male and female populations
+
+Page 30 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases 15.415
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+569
+Prevented COVID-19 Hospitalizations
+174 56'
+Prevented COVID-19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+1,391
+Prevented COVID-19 Hospitalizations
+231,833
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+1.530
+Prevented COVID-19 Hospitalizations
+400
+300
+400
+300
+309
+400
+300
+252.490
+Prevented COVID-19 Cases
+400
+200
+186
+200
+200
+300
+200
+100
+100
+12-15 yo
+16-17 yo
+18-24 yo
+25-29 vo
+100
+179
+100
+200
+300
+196
+100
+200
+300
+| 131
+| 131
+300
+100 200
+RISKS
+400
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Figure S2: Results of Scenario 4 for the male population
+
+Page 31 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+795
+Prevented COVID-19 Hospitalizations
+134,791
+Prevented COVID.19 Cases
+12-15 yo
+400
+190
+200
+300
+273
+100
+0
+16-17 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+1,400
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases 16,570
+| 36
+100
+100
+200
+300
+RISKS
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+4,105
+327,222
+Prevented COVID.19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+4,757
+Prevented COVID-19 Hospitalizations
+333,171
+Prevented COVID.19 Cases
+333
+300
+400
+300
+200
+500
+200
+400
+18-24 yo
+41 1
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+100
+200
+300
+400
+500
+25-29 Yo
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizatior
+Excess Myo/Pericarditis Cases
+200
+100
+0
+100
+200
+300
+400
+500
+Figure S3: Results of Scenario 4 for the female population
+
+Page 32 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID.19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+320
+25,046
+Prevented COVID.19 Cases
+400
+300
+12-15 yo
+RISKS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+38 956
+Prevented COVID-19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+1.323
+Prevented COVID-19 Hospitalizations
+55,228
+Prevented counseencase
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+1,531
+Prevented COVID-19 Hospitalizations
+Prevented COVID.19 Case
+88
+200
+100
+16-17 yo
+118
+200
+18-24 yo
+12 1
+o
+168
+300
+200
+100
+25-29 yo
+181
+| 106
+| 106
+100
+• 116
+• 116
+94
+| 94
+100
+200
+1 26
+300
+300
+400
+300
+200
+100
+400
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+100
+2∞ 300
+400
+500
+Figure S4: Results of Scenario 5 for combined male and female populations
+
+Page 33 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID.19 Hospitalizations
+35.00
+Prevented COVID-19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID.19 Case
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+400
+Prevented COVID.19 Hosnitalizations
+Prevented COVID-19 Cases 50,637
+400
+245
+300
+300
+200
+200
+155
+200
+174
+300
+200
+100
+100
+100
+12-15 yo
+16-17 yo
+18-24 yo
+25-29 vo
+12
+100
+179
+179
+100
+200
+300
+196
+100
+200
+300
+| 131
+| 131
+200
+300
+RISKS
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+100 200
+400
+500
+Figure S5: Results of Scenario 5 for the male population
+
+Page 34 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID.19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+27,032
+Prevented COVID-19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+702
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+2,058
+Prevented counselecase
+65,624
+400
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+2,385
+Prevented COVID-19 Hospitalizations
+Prevented ounselecas
+es 66,817
+400
+300
+300
+12-15 yo
+95
+200
+100
+100
+16-17 yo
+137
+36
+100
+18-24 yo
+21 B
+167
+200
+100
+200
+200
+200
+25-29 yo
+141
+300
+200
+100
+100
+200
+300
+300
+300
+RISKS
+400
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+400
+500
+Figure S6: Results of Scenario 5 for the female population
+
+Page 35 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+9,714
+Prevented COVID-19 Cases
+300
+142
+200
+200
+12-15 yo
+39 П
+100
+16-17 yo
+52
+RISKS
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+15,108,
+Prevented COVID-19 Cases
+214
+| 106
+| 106
+100
+200
+• 116
+• 116
+300
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+300
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+587
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+21,419
+74 I
+100
+18-24 yo
+о
+25-29 yo
+94
+|94
+100
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+400
+300
+200
+200
+300
+400
+500
+Prevented COVID-19 Deaths
+Excess Myo/Pericarditis Deaths
+Prevented COVID-19 ICUs
+679
+Prevented COVID-19 Hospitalizations
+22,581
+Prevented COVID.19 Cases
+26
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+400
+300
+200
+100
+100
+200 300
+400
+500
+Figure S7: Results of Scenario 6 for combined male and female populations
+
+Page 36 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID.19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+400
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+13,577
+Prevented COVID-19 Cases
+400
+300
+300
+200
+200
+109
+157 1
+12-15 yo
+35 E
+100
+16-17 yo
+100
+179
+200
+300
+RISKS
+400
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+196
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Mo Pericarditis Cases
+18-24 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases 18,031,
+200
+200
+131
+| 131
+200
+300
+400
+300
+400
+500
+500
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+25-29 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID.19 Hosnitalizations
+1300
+19.638
+Prevented COVID-19 Cases
+400
+300
+200
+100
+100 200
+Figure S8: Results of Scenario 6 for the male population
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+
+Page 37 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+10,484,
+Prevented COVID-19 Cases
+12-15 yo
+300
+177
+200
+1 32
+100
+RISKS
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+16,844
+Prevented COVID-19 Cases
+311
+200
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+912
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases 25,451
+100
+16-17 yo
+61
+18-24 yo
+9 I
+o
+74 I
+100
+200
+300
+1 36
+1 36
+100
+Excess My/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+300
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalization
+Excess Myo/Pericarditis Cases
+400
+300
+200
+100 200
+300
+400
+500
+25-29 yo
+Prevented COVID-19 Deaths
+Excess Myo/Pericarditis Deaths
+Prevented COVID-19 ICUs
+1,057
+Prevented COVID-19 Hospitalizations
+25,913
+Prevented COVID.19 Cases
+Excess Myo/Pericarditis Hospitalizatior
+Excess Myo/Pericarditis Cases
+400
+300
+200
+100
+100
+200
+300
+400
+500
+Figure $9: Results of Scenario 6 for the female population
+
+Page 38 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUS s68
+Prevented COVID-19 Hospitalization‹
+97,136
+Prevented COVID-19 Cases
+12-15 yo
+RISKS
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+excess ivorrencarcus cases
+Prevented COVID-19 Death:
+Prevented COVID-19 CUs
+Prevented COVID-19 Hospitalizations
+151,080
+Provented COVID.19 Cases
+Prevented COVID-19 Deaths
+Provented COVID.19 ICI
+Prevented COVID-19 Hospitalizations 3,346
+214,18
+Prevented COVID-19 Cases
+400
+Prevented COVID.19 Deaths
+Prevented cOVID-19ICUS
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+225,807,
+400
+300
+300
+200
+200
+200
+300
+200
+16-17 yo
+18-24 yo
+100
+25-29 yo
+106
+200
+300
+| 116
+116
+100
+200
+94
+100
+200
+1 26
+300
+300
+100
+100
+_ 200 300
+400
+400
+sOn
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Mo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+400
+500
+Figure S10: Results of Scenario 7 for combined male and female populations
+
+Page 39 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+435
+Prevented COVID-19 Cases
+12-15 yo
+RISKS
+Excess Mvo Pericarditis Death:
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+16-17 yo
+Prevented COVID-19 Deaths
+Prevented COVID.19 ICUs
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Cases
+506
+138
+166
+200
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+Droventer COVID 1o Desthe
+Provented COVID.19 ICIe
+Prevented COVID-19 Hospitalizations
+Prevented COVID-19 Case
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID-19 Hospitalizations
+Drovented COvID 1O caeor
+300
+2774
+200
+309
+196
+100
+100
+200
+18-24 vo
+100
+25-29 Yo
+30
+131
+131
+200
+400
+500
+400
+200
+100
+Excess Mo/Pericarditis Death:
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+300
+400
+500
+Figure S11: Results of Scenario 7 for the male population
+
+Page 40 - Hong Yang - 125742/0
+BENEFITS
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID.19 Hoenitalizations
+104.837
+Prevented COVID-19 Cases
+12-15 vo
+300
+169
+200
+31
+100
+200
+300
+16-17 yo
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+1.245
+Prevented COVID.19 Heenitalizations
+Prevented COVID-19 Cases
+400
+Prevented COVID-19 Deaths
+Prevented COVID-19 ICUs
+3,649
+Prevented COVID-19 Hospitalizations
+Prevented COVID.19 Cases
+300
+296
+300
+200
+100
+200
+300
+18-24 yo
+о
+RISKS
+400
+400
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+sOC
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+500
+Excess Myo/Pericarditis Deaths
+Excess My/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+400
+200
+100
+200
+300
+400
+25-29 yo
+Prevented COVID.19 Deaths
+Prevented COVID-19 ICUs
+Prevented COVID.19 Hospitalizations
+Prevented COVID-19 Cases 259,13.
+Excess Myo/Pericarditis Deaths
+Excess Myo/Pericarditis Hospitalizations
+Excess Myo/Pericarditis Cases
+200
+100
+100
+400
+500
+Figure S12: Results of Scenario 7 for the female population
+

docs/Bioresearch Monitoring Discipline Review Memo, August 13, 2021 - COMIRNATY.txt

@@ -0,0 +1,97 @@
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+DATE:
+August 13, 2021
+FROM:
+Haecin Chun, MS, Bioresearch Monitoring Branch (BMB)
+Division of Inspections and Surveillance (DIS
+Office of Compliance and Biologics Quality (OCBQ)
+THROUGH: Dennis Cato, Chief BMB THROUGH: Carrie Mampilly, MPH, Director DIS THROUGH: Mary A. Malarkey, Director OCBQ
+TO:
+Ramachandra Naik, PhD, Chair Susan Wollersheim, MD, Clinical Reviewer
+CAPT Ann Schwartz, MD, Clinical Reviewer
+CAPT Michael Smith, PhD, RPM Laura Gottschalk, PhD, RPM
+SUBJECT: Bioresearch Monitoring (BIMO) Discipline Review Memo
+SPONSOR: BioNTech Manufacturing GmbH
+PRODUCT: COVID-19 Vaccine, mRNA (COMIRNATY) BLA: ST 125742/0
+FINAL SUMMARY STATEMENT
+BIMO inspection assignments were issued for a total of nine (9) clinical study sites that participated in the conduct of Study Protocol C4591001. Three (3) of these inspection assignments focused on clinical study sites that enrolled the pediatric population and six (6) of the study sites enrolled the adult population. The inspections did not reveal findings that impact the Biologics License Application (BLA).
+BACKGROUND
+On February 4, 2020, the Secretary of the Department of Health and Human Services (HHS) determined that there is a public health emergency (PHE) involving to a novel coronavirus named SARS-CoV-2 that causes Coronavirus Disease 2019 (COVID-19). On March 27, 2020, the Secretary of HHS issued a Notice of Emergency Use Authorization (EUA)
+Declaration pursuant to Section 564 of the Federal Food, Drug, and Cosmetic Act (the FD&C
+Act or the Act).
+www.fda.gov
+
+BLA ST 125742/0 BioNTech/Pfizer COVID-19 Vaccine, mRNA (COMIRNATY)
+Page 2 of 4
+In response to the PHE, BIMO reviewers proactively performed a review of the sponsor's investigational new drug application (IND 19736) and issued the necessary BIMO inspections to review the study conduct of Protocol C4591001, "A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-COV-2 RNA Vaccine Candidates Against COVID-19 in Healthy Individuals."
+Protocol C4591001 was a multi-center study conducted at a total of 153 clinical sites: 131 study sites in the United States and 22 sites outside of the United States. Due to the COVID-19 pandemic travel restrictions, only the domestic sites were considered for an on-site BIMO inspection. Initially, six (6) study sites were inspected, before FDA issued the original Emergency Use Authorization for individuals 16 years of age and older. Subsequently, three
+(3) additional sites were inspected before FDA authorized use of the vaccine in those 12 and older. All of the study sites were selected based on subiect enrollment, previous inspectional history, and other information submitted in IND 19736.
+The inspections were conducted in accordance with FDA's Compliance Program 7348.811, Inspection Program for Clinical Investigators, focusing primarily on the study conduct, human subject protection and compliance with related FDA regulations. The data integrity and verification portion of the BIMO inspections were limited because the study was ongoing, and the data required for verification and comparison were not vet available to the IND. The table below summarizes the domestic study site information and the outcome of each BIMO inspection:
+Site ID
+1007
+1009
+1044
+1056
+1109
+1118
+1125
+1133
+1149
+Site Location
+Cincinnati Children's Hospital Medical Center
+Cincinnati Center for Clinical Research
+Cincinnati, OH
+J. Lewis Research Inc./ Foothill Family Clinic
+South, Salt Lake City, UT
+Virginia Research Center, LLC.
+Midlothian, VA
+Indago Research and Health Center, Inc.
+Hialeah, FL
+Deland Clinical Research Unit
+DeLand, FL
+Meridian Clinical Research, LLC.
+Binghamton, NY
+Meridian Clinical Research, LLC
+Norfolk, NE
+Research Centers of America
+Hollywood, FL
+Collaborative Neuroscience Research, LLC at two locations: Long Beach & Garden
+Grove, CA
+Form FDA
+483 Issued
+No
+No
+No
+No
+No
+No
+No
+No
+Final
+Classification
+No Action Indicated
+(NAI)
+NAI
+NAI
+NAI
+NAI
+NAI
+NAI
+NAI
+No
+NAI
+
+BLA ST 125742/0 BioNTech/Pfizer COVID-19 Vaccine, mRNA (COMIRNATY)
+Page 3 of 4
+SIGNIFICANT INSPECTIONAL FINDINGS
+No significant inspectional findings were noted.
+SPONSOR/MONITORING ISSUES
+No significant sponsor or monitoring issues were noted at the sites that were inspected.
+FINANCIAL DISCLOSURE
+The Clinical Investigator Compliance Program directs the FDA investigator to ask the clinical investigator if and when he/she disclosed information about his/her financial interests to the sponsor and/or interests of any sub-investigators, spouses) and dependent children, and if and when the information was updated. The information submitted to the BLA was verified for each of the inspected clinical sites.
+ADMINISTRATIVE FOLLOW-UP
+Should you have any questions or comments about the contents of this memo or any aspect of Bioresearch Monitoring, please contact me at 240-402-8038.
+Haecin Chun
+Consumer Safety Officer
+

docs/CBER Sentinel Program Sufficiency Memo - COMIRNATY.txt

@@ -0,0 +1,219 @@
+CBER Sentinel Program Sufficiency Memo: BNT162b2 (COVID- 19 Vaccine)/STN 125742
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+Department of Health and Human Services
+Food and Drug Administration
+Center for Biologics Evaluation and Research
+CBER SENTINEL PROGRAM SUFFICIENCY MEMORANDUM
+From:
+Through:
+Subiect:
+Product:
+Sponsor:
+STN:
+Proposed
+Indication:
+Joyce Obidi
+Health Scientist, CBER Surveillance Program
+Office of Biostatistics and Epidemiology (OBE)
+Hui-Lee Wong
+Associate Director, CBER Surveillance Program, OBE
+CBER Sentinel Program Sufficiency Assessment
+COMIRNATY; BNT162b2 (Pfizer-BioNTech COVID-19 Vaccine)
+Pfizer
+125742/0
+Active immunization to prevent COVID-19 disease caused by SARS-
+CoV-2 in individuals >16 years of age.
+Approval Type:
+A Priority
+" Standard review
+Submission Date: May 18, 2021
+Action Due Date:
+January 16, 2022
+Last Updated on January 29, 2019
+1
+
+CBER Sentinel Program Sufficiency Memo: BNT16262 (COVID-19 Vaccine/STN 125742
+1.
+2.
+Objectives/Scope:
+This memo reviews the capability and sufficiency of the CBER active post-market risk identification and analysis system referred to as the CBER Sentinel Program to evaluate the serious risk for myocarditis and pericarditis following receipt of BNT1622, a COVID-19 Vaccine indicated for active immunization to prevent COVID-19 disease caused by SARS-CoV-2 in individuals >16 years of age in lieu of a safety post-market requirement (PMR) study under FDAAA'. The CBER Sentinel Program covers activities conducted through the contract with the Harvard Pilgrim Health Care Institute, the current and future contracts through the Biologics Effectiveness and Safety (BEST)
+Initiative, and the interagency agreement with the Centers for Medicare and Medicaid (CMS). Please see the STN 125742/0 OBE/Division of Epidemiology (DE) review of the Pharmacovigilance Plan (PVP) for background on the serious risks of myocarditis and pericarditis, and subclinical myocarditis. Post-authorization safety data identified serious risks for myocarditis and pericarditis after COMIRNATY, with increased risk in males under 30 years of age, particularly following the second dose, and onset of symptoms within 7 days following vaccination. At the end of May 2021 CDC issued clinical considerations regarding myocarditis and pericarditis after receipt of mRNA COVID-19 vaccines among adolescents and young adults (https://www.cdc.gov/vaccines/covid-19/clinical-considerations/myocarditis.html). The topic was presented and discussed at the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting on June 10, 2021 and the Advisory Committee for Immunization Practices (ACIP) meeting on June 23, 2021. The Emergency Use Authorization (EUA) Fact Sheet was revised on June 25, 2021 to add a Warning for myocarditis and pericarditis. A postmarketing observational safety study (ies) is needed to assess myocarditis and pericarditis following administration of COMIRNATY (BNT16262) to:
+a. Quantify the magnitude of risk by age, sex, and dose
+b. Follow up cases for recovery status and long-term sequelae
+c. Characterize subclinical cases of myocarditis
+CBER Sentinel Program Sufficiency Assessment:
+Determination of the sufficiency of the CBER Sentinel Program to further characterize the serious risk of myocarditis and pericarditis with BNT16262 was based on the following factors:
+' Under section 901 of the Food and Drug Administration Amendments Act (FDAAA), "The Secretary may not require the responsible person to conduct a study under this paragraph, unless the Secretary makes a determination that the reports under subsection (k)(1) and the active postmarket risk identification and analvsis system as available under subsection (k)(3) will not be sufficient to meet the purposes set forth in subparagraph (B)."NOTE: The active post-market risk identification and analysis system under subsection (k)(3) refers to the Sentinel program.
+2 ISBT 128 is a global standard for the safe identification, accurate labeling, and efficient information transfer of medical products of human origin (including blood, cells, tissues, milk, and organ products) across disparate national and international health care systems. https://www.iccbba.org/isbt-128-basics
+Last Updated on January 29, 2019
+2
+
+CBER Sentinel Program Sufficiency Memo: BNT162b2 (COVID- 19 Vaccine)/STN 125742
+2.1
+2.1 Identification of exposure to BNT1622
+2.2 Identification of the appropriate study population: Patients > 16 years of age
+2.3 Characterization of occurrence of myocarditis and pericarditis, and subclinical myocarditis, with BNT16262
+2.4 Identification of exposure to comparator product (when applicable)
+Assessment for identification of exposure to BNT162b2
+2.1.1. Is the CBER Sentinel Program able to identify the product (exposure) of interest?
+Please answer each question i - xi, including sub-questions.
+Is this the first or the only FDA-approved product for the indication?
+Can the exposure be identified using a billing or reimbursement coding system? If yes, check all that apply: & CPT & HCPCS &
+& NDC DICD • Other: [Coding system]
+iii.
+Is the ISBT 128 coding system? needed for the product identification?
+Can the reimbursement code of the product identify the brand
+iv.
+name?
+Is a history of uptake for previously approved products for the
+V. same indication needed? If ves, list all products:
+Is medical chart review needed to identify or validate the
+vi.
+identification of this product?
+vii.
+Are claims data sources needed for exposure identification?
+Are electronic health record (HR) data sources needed for
+viii.
+exposure identification?
+Are any other health record type data sources needed for
+ix.
+exposure identification? If yes, all health record types needed:
+[e.g., Registries, any other health records]
+X.
+Is product lot number needed for identification of this product? O Is there a care setting of interest required for identification of this product? If yes, check all that apply:
+Yes No
+xi.
+• Inpatient I Outpatient I Emergency Room I Other:
+Hospitalization
+2.1.2. Summary for product exposure identification
+[
+区
+区
+区
+Last Updated on January 29, 2019
+3
+
+CBER Sentinel Program Sufficiency Memo: BNT16262 (COVID-19 Vaccine/STN 125742
+2.2.
+& Available data sources in the CBER Sentinel Program are sufficient to identify the exposure of the product BNT162b2 due to reasons identified in 2.1.1.i. Billing codes for BNT16262 allows for clear ascertainment of exposure to the product.
+• Available data sources in the CBER Sentinel Program are NOT sufficient to identify the exposure of the product [name] due to reasons identified in [list all bullets from
+2.1.1.i. 2.1.1.xi. that support insufficiency].
+Assessment for identification of the appropriate study population: Patients ≥ 16 years of age
+2.2.1. Is the CBER Sentinel Program able to identify the study population of interest?
+Please provide an answer for each question i - vi, including sub-
+Yes No
+questions.
+Does age need to be identified? If yes, list the inclusion and exclusion criteria.. Check all that apply for the level of granularity in I Days O Months Years
+Does sex need to be identified? If yes, list the inclusion [List ii. the sex to be included] and exclusion criteria [List the sex to
+be excluded].
+Does race need to be identified? If yes, list the inclusion [List iii. race to be included] and exclusion criteria [List race to be
+excluded]
+Can the study population be identified in the data sources iv. required for the exposure and outcome identification?
+Was this population previously identified within the CBER
+V. Sentinel Program activities? vi.
+Is there a requirement for linking mothers to their newborns in
+the data sources?
+2.2.2. Summary for identification of study population
+区
+& Available data sources in the CBER Sentinel Program are sufficient to identify the study population of interest, patients > 16 years of age, due to reasons identified in
+2.2.1. - 2.2.1.vi. This study population of interest has been identified in the data sources required of exposure (BNT162b2) and outcome (myocarditis/pericarditis).
+• Available data sources in the CBER Sentinel Program are NOT sufficient to identify the study population of interest due to reasons identified in list all bullets fron
+2.2.1.i. -2.2.1.vi. that support insufficiency]
+Last Updated on January 29, 2019
+4
+
+CBER Sentinel Program Sufficiency Memo: BNT16262 (COVID-19 Vaccine/STN 125742
+2.3
+Assessment for characterization of occurrence of myocarditis and pericarditis, and subclinical mvocarditis
+2.3.1 Is the CBER Sentinel Program able to identify the outcome(s) of interest?
+Please provide an answer for each question i - xi, including sub-
+Yes No
+questions.
+Can the outcome of interest be identified using a billing or
+i. reimbursement coding system? If yes, check all that apply: dICD X DCPT L Other: Medical Record Review
+Are there surrogate data elements or biomarkers that can assist to identify the outcome of interest? If yes, check all that apply:
+ii.
+E Laboratory Test Results L Prescription drug I Order oflab o test L Order of other diagnostic modalities L Other: [Data
+element/Biomarker]
+Are there specific care settings in which this outcome is
+iii.
+identified? If yes, check all that apply: Inpatient I Outpatient A Emergency Room L Other: Hospitalization
+Was this outcome previously identified within the CBER Sentinel Program activities? If yes, in what population was it used? It was
+iv.
+used in a similar population of Medicare beneficiaries 65y and older.
+Is there a validated and acceptable algorithm available in the
+V. literature to identify the outcome of interest? If yes, list the PP [PPV and describe the population in which it was validated:
+Is a minimum follow-up time needed to identify the outcome of
+vi.
+interest? Ifyes, what is the required follow-up period? 3-6 months
+Is medical chart review required to identify or validate the
+vii.
+identification of the outcome?
+Is the prevalence of the outcome known? If yes, list background
+viii. ix.
+rates. 0.95-2/16 per 100,000 PY in Gubernot 2021
+Are claims data sources needed for outcome characterization?
+Are electronic health record (EH) data sources needed for
+X. outcome characterization?
+Are any other health record type data sources needed for outcome
+xi.
+characterization? If yes, all health record types needed: Registries
+Г
+Г
+2.3.2 Summary of outcome characterization
+Last Updated on January 29, 2019
+5
+
+CBER Sentinel Program Sufficiency Memo: BNT16262 (COVID-19 Vaccine/STN 125742
+& Available data sources in the CBER Sentinel Program are NOT sufficient to identify the outcomes of myocarditis and pericarditis due to reasons identified in 2.3.1.vi. -2.3.1.viii.
+Based on the prevalence of background rates estimated in the CBER Sentinel data sources and the number of observed myocarditis/pericarditis events in the CBER Sentinel Program ongoing near-real time surveillance, the CBER Sentinel data sources are currently not sufficiently powered to assess the magnitude of risk for the 12-30 years old that has been reported in VAERS in an epidemiology study (e.g., self-controlled analyses). CBER Sentinel will continue to monitor these safety outcomes. In order to follow up cases for recovery status and long-term sequelae, a minimum follow up time of 3-6 months is required. CBER Sentinel data sources do not have sufficient longitudinal data on patients to conduct this type of analysis. Additionally, a study of subclinical myocarditis using CBER Sentinel data sources is not feasible because of the absence of a definition of subclinical myocarditis and unknown background incidence of troponin abnormalities.
+2.4. Assessment for identification of exposure to comparator product (when applicable):
+NOT APPLICABLE
+2.4.1. Is the CBER Sentinel Program able to identify the required comparator product?
+Respond to the questions below, if applicable.
+Please provide an answer for each question i - xi, including sub-
+Yes No
+questions
+iv.
+V.
+vi.
+vii.
+viii.
+Is a comparator product needed for the assessment? If no, skip to section III for Recommendation. If yes, list all products:
+Can the comparator product be identified using a billing reimbursement code? If yes, check all that apply: DCPT DHCPCS ONDC DICD DOther: [Billing reimbursement code]
+Can the comparator product be exclusively identified using the billing reimbursement codes?
+Is the ISBT 128 coding system? needed for the comparator product identification?
+Can the reimbursement code of the comparator product identify the brand name?
+Is medical chart review needed to identify or validate the identification of this comparator product?
+Are claims data sources needed for exposure identification of the comparator product?
+Are electronic health record (EHR) data sources needed for exposure identification of the comparator product?
+[
+Г
+Last Updated on January 29, 2019
+6
+
+CBER Sentinel Program Sufficiency Memo: BNT162b2 (COVID- 19 Vaccine)/STN 125742
+Please provide an answer for each question i - xi, including sub-questions
+ix.
+X.
+xi.
+Are any other health record type data sources needed for exposure identification of the comparator product? If yes, list all health record types needed: [e.g., Registries, any other health records]
+Is product lot number needed for identification of this comparator product?
+Is there a care setting of interest for identification of this comparator product? If yes, check all that apply: D Inpatient I Outpatient L Emergency Room L Other:
+Hospitalization
+Yes No
+L
+[
+[
+[
+2.4.2. Summary for comparator exposure identification
+• Available data sources in the CBER Sentinel Program are sufficient to identify the comparator product due to reasons identified in list all bullets from 2.4.1.i._-2.4.1.xi. that support sufficiency].
+" Available data sources in the CBER Sentinel Program are NOT sufficient to identify
+the comparator product due to reasons identified in [list all bullets from
+2.4.1.i. 2.4. 1.xi. that support insufficiency].
+3. Recommendation:
+• The CBER Sentinel Program is sufficient to assess the serious risk of [describe] associated with [product] at this time. [Summarize all bullets 2. 1. -2.4. that support sufficiency]
+The CBER Sentinel Program is NOT sufficient to assess the serious risks of myocarditis and pericarditis, and subclinical myocarditis associated with COMIRNATY (BNT16262) in lieu of PMR safety studies under FDAAA. At the time of BLA approval, the data sources in the CBER Sentinel Program are not sufficient to identify the outcomes due to lack of sufficient power to assess the magnitude of risk in patients 12-30 years of age. In addition, CBER Sentinel Program is not sufficient to follow up cases for recovery status and long-term sequelae, or for identification and characterization of subclinical myocarditis cases.
+Last Updated on January 29, 2019
+

docs/CMC Review Memo, August 21, 2021 - COMIRNATY.txt

@@ -0,0 +1,1285 @@
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+CMC REVIEW MEMORANDUM
+Date:
+AUGUST 21, 2021
+To:
+The Biologics License Application (BLA) File ST 125742
+From:
+Xiao Wang, OVRR/DVP, CMC Product Reviewer
+Through: Anissa Cheung, OVRR/DVP
+Keith Peden, Lab Chief, OVRR/DVP
+Robin Levis, Deputy Director, OVRR/DVP
+Jerry Weir, Director, OVRR/DVP
+СС:
+Ramachandra Naik, Chair, OVRR/DVRPA
+Capt. Michael Smith, RPM, OVRR/DVRPA
+Laura Gottschalk, RPM, OVRR/DVRPA
+Applicant: BioNTech Manufacturing GmbH (in partnership with Pfizer Inc.)
+Subiect:
+CMC Review of Original BLA STN 125742.0;
+Product:
+Pfizer-BioNTech COVID-19 Vaccine; Human Coronavirus RNA Vaccine for the Prevention of Coronavirus Disease 2019 (COVID-19)
+
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+The following abbreviations are used throughout the memorandum:
+AMTE
+ATM
+BLA
+BNT (b) (4)
+CMC
+COA
+СРР
+CQA
+СТМ
+dLIA
+DS
+DP
+EUA (b) (4)
+FC
+GMP
+IM
+IPT-C
+IPT-M
+IR (b) (4)
+(b) (4)
+(b) (4)
+LNP
+LPQ
+MCB
+modRNA
+NHP
+PAI
+PPQ
+RBD
+RH
+RPH (b) (4)
+(b) (4)
+WCB
+Analytical Method Transfer Exercise
+Animal Trial Material
+Biologics License Application
+BioNTech Manufacturing GmbH
+Chemistry, Manufacturing, and Control Certificate of Analysis Critical Process Parameter Critical Quality Attribute Clinical Trial Material (b) (4)
+Direct Luminex Assay
+Drug Substance
+Drug Product
+Emergency Use Authorization
+Final Container
+Good Manufacturing Practice
+Intramuscular
+In-process Tests for Control In-process Tests for Monitoring
+Information Request
+Lipid Nanoparticle
+Laboratory Process Qualification
+Master Cell Bank
+Nucleoside-modified Messenger RNA
+Nonhuman Primate
+Pre-approval Inspection
+Process Performance Qualification
+Receptor Binding Domain
+Relative Humidity
+Relative Process History
+Working Cell Bank
+
+Table of Contents
+1. Product Name/Proprietary Name/Product Type..
+1
+2. Submissions reviewed......
+3. Executive Summary and Recommendation
+2
+4. BNT162b2 Drug Substance...........
+4.1 General Description ...................
+4.2 Manufacturers.
+4.3 Control of Materials...
+4.4 Description of Drug Substance Manufacturing Process and Process Controls... 11
+4.5 Process Validation for Drug Substance Manufacturing..
+4.6 DS Manufacturing Process Development ....
+4.7 Impurity Profile of the Drug Substance.
+4.8 Adventitious Agents Safety Evaluation
+4.9 Characterization Studies on Drug Substance
+4.10 Control of Drug Substance.......
+4.11 Analytical Procedures for Drug Substance.
+4.12 Validation of Analytical Procedures....
+4.13 Reference Standards
+4.14 Summary of Batch Analysis ......
+4.15 Container-Closure System.......
+4.16 Stability of Drug Substance......
+5. BNT162b2 Drug Product....
+5.1 General Description and Composition.
+5.2 Manufacturers.
+5.3 Control of Excipients .......
+5.4 Description of Drug Product Manufacturing Process and Process Controls .......59
+5.5 Process Validation .....
+5.6 DP Manufacturing Process Development
+5.7 Impurity Profile of the Drug Product.
+5.8 Characterization Studies on Drug Product
+5.9 Control of Drug Product
+5.10 Analytical Procedures for Drug Product
+..5
+..... 5
+.....5
+....6
+......... 15
+...... 23
+....26
+....28
+........ 28
+....30
+.....33
+...... 35
+...42
+....43
+.....43
+....44
+...49
+.............. 49
+............. 50
+.............. 51
+...... 65
+............... 80
+.....83
+....84
+...84
+...90
+
+5.11 Validation of Analytical Procedures.
+....... 93
+5.12 Reference Standards
+........ 100
+5.13 Summary of Batch Analysis ......
+......... 101
+5.14 Container-Closure System of the Final Container..
+......... 101
+5.15 Stability of Drug Product ..
+...... 102
+6. Other CMC-related Information Not Covered in Module 3
+............ 108
+7. Follow-up on Ongoing Issues Identified at the Time of EUA Request.................... 109
+8. Pre-Approval Inspection
+...112
+9. Nonclinical Studies
+....112
+9.1 Nonclinical Pharmacology Studies.....
+......... 112
+9.2 Nonclinical Pharmacokinetics (PK) Evaluation.
+.....115
+10. Clinical Assays ....
+........... 116
+10.1 Diagnostic Assays Used to Support Clinical Efficacy Endpoints
+….... 116
+10.2 Immunogenicity Assays Used for Exploratory Immunogenicity Endpoints...
+.... 118
+iv
+
+1. Product Name/Proprietary Name/Product Type
+Product: Pfizer-BioNTech COVID-19 Vaccine
+Proprietary name: COMIRNATY
+Nonproprietary name: COVID-19 Vaccine, mRNA
+Product Type: Human Coronavirus mRNA vaccine expressing SARS-CoV-2 spike glycoprotein (BioNTech code number BNT162b2, Pfizer code number PF-07302048); the mRNA (variant RBP020.2) is formulated with lipids ALC-0315, ALC-0159, DSPC, and cholesterol to form lipid nanoparticles (LNPs).
+2. Submissions reviewed
+Date Received
+Submission
+May 6, 2021
+STN 125742/0
+Contents/Comments
+BLA Roll 1 submission including nonclinical pharmacology and pharmacokinetics studies and clinical assays
+May 18, 2021
+ST 125742/0.1
+BLA Roll 2 submission encompassing all quality-related information in Module 3
+July 9, 2021
+ST 125742/0.10 Lot-release protocol template for the drug product
+including the assay performed and acceptance criteria
+July 15, 2021
+ST 125742/0.11 Request for an exception to the 21 CFR 610.15(a) for
+the vaccine as a preservative-free presentation
+July 23, 2021
+ST 125742/0.16 Response to DVP/DBSQC IR regarding the validation of RNA (b) (4) testing by (b) (4)
+July 28, 2021
+ST 125742/0.19 Response to DVP IR regarding multiple CMC-related
+issues (DS and DP manufacturing process and testing, and clinical assays) and the categorical exclusion for an environment analvsis
+August 2, 2021 ST 125742/0.27 CMC-related information described in the draft package insert
+August 5, 2021 ST 125742/0.31 Response to DVP/Statistical IR regarding the validation studies for the (b) (4)
+direct Luminex assay (dLIA)
+for laG antibod quantification in human sera
+August 6, 2021 ST 125742/0.33 Response to DVP IR regarding manufacturing process validation issues
+August 6, 2021 ST 125742/0.34 Response to DVP/Statistical IR regarding the validation
+report (VAL 100147509) for (b) (4)
+of the
+vaccine DP by (b) (4)
+August 9, 2021 STN 125742/0.35 Response to DBSQC/DVP IR regarding validation of
+the assav methods and lot release
+August 9, 2021 ST 125742/0.36 Response to DMPQ IR regarding the saline diluent
+August 10, 2021 ST 125742/0.39 Response to DVP IR regarding a (b) (4)
+step executed during the (b) (4) process at Pfizer Puurs
+August 13, 2021 ST 125742/0.47 Response to DMPQ IR regarding the saline diluent
+
+Date Received
+Submission
+Contents/Comments
+August 17, 2021 ST 125742/0.55 Stability data to support a shelf-life extension of the
+undiluted DP up to 9 months when stored at the intended long-term storage condition
+August 19, 2021 STN 125742/0.61 Response to DVP IR regarding the final commercial
+shelf life of the BNT162b2 DP and date of manufacture
+August 19, 2021 STN 125742/0.62 Response to DVP IR regarding the final (b) (4)
+3. Executive Summary and Recommendation
+The BNT162b2 COVID-19 vaccine, developed under a collaborative agreement between Pfizer and BioNTech (BNT), is a nucleoside-modified messenger RNA (modRNA)-based vaccine candidate indicated for active immunization for the prevention of coronavirus disease 2019 (COVID-19). The single-stranded mRNA encodes the SARS-CoV-2 full-length spike (S) glycoprotein, which is codon-optimized and modified to express the P2 mutant, a pre-fusion S protein (P2 S; version 9). The modRNA is stabilized by formulation with lipids consisting of DSPC, cholesterol, ALC-0315, and ALC-0159 to generate lipid nanoparticles (LNPs). Other ingredients in the BNT162b2 vaccine include potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose.
+The final vaccine product is a white to off-white, sterile, preservative-free, multi-dose frozen suspension to be diluted with 0.9% sodium chloride injection, US, for intramuscular (IM) injection. The vaccine is filled in a 2 mL clear glass vial with a rubber stopper (not made of natural rubber latex) as a multi-dose concentrate (after dilution each vial contains 6 doses of 0.3 mL) and is administered as a series of two IM immunizations with each dose containing 30 g of modRNA. The second dose is administered 21 days after the first dose. The undiluted vaccine vials should be stored frozen between -90°C to -60°C and they may be stored at -25°C to -15°C for up to two weeks. To facilitate storage and administration of the BNT162b2 vaccine at the point of use, the thawed vials can be stored between 2°C to 8°C for up to 1 month (31 days) prior to dilution; the diluted vaccine must be stored between 2°C to 25°C and used within 6 hours from the time of dilution. The vaccine is indicated for use in individuals 16 years of age or older.
+The manufacturing process for the BNT162b2 drug substance (DS) consists of two major steps: (b) (4)
+. Two manufacturing
+facilities (Pfizer ACMF and Pfizer Suite ®) located in Andover, MA are involved in the commercial production of the BNT162b2 DS. The DS manufacturing process was validated at both facilities by process-performance qualification (PPQ) studies ( and PPQ lots manufactured at Pfizer ACMF and at Pfizer Suite , respectively). Consistency of the DS manufacturing process was demonstrated by maintaining process parameters within defined ranges and obtaining satisfactory in-process and release testing results.
+Additionally, data obtained from the analytical comparability assessment for the ACMF
+2
+
+and Suite # DS batches further support the DS manufacturing process for the consistent production of the BNT162b2 DS with acceptable quality.
+The manufacturing process for the BNT1622 drug product (DP) involves (b) (4) the modRNA DS with lipid excipients during LP formulation followed by fill and finish. The two facilities proposed for the manufacture of the BNT1622 DP are Pfizer Puurs (located in Puurs, Belgium) and Pfizer Kalamazoo (located in Kalamazoo, Michigan, USA), both of which have been authorized for the manufacture of the BNT1622 D under the Emergency Use Authorization (EUA 27034). Validation of the DP manufacturing process took place in two Phases. The Phase I network PPQ study, which involved multiple authorized DP manufacturing facilities under the EUA, was executed to demonstrate that the manufacturing process consistently produces DP lots of acceptable quality across multiple supply nodes. The Phase II process validation occurred at the proposed commercial facilities with (b) (4) batches at (b) (4) and (5) (4) batches at (b) (4) batch sizes being manufactured at Pfizer Puurs and (b) (4) batches at (b) (4) and (b) (4) batches at (5) (4) batch sizes being manufactured at Pfizer Kalamazoo. Both Phase I and Phase Il process-validation studies were executed successfully according to pre-established protocols, thereby demonstrating that the D manufacturing process is consistent and well-controlled. Additionally, a (5) (4) batch size for the manufacture of BNT162b2 DP was validated at the Pfizer Purs site. Analytical comparison of the process-validation batches to clinical and emergency supply lot data further demonstrated comparable product quality from clinical through commercial supply of the BNT162b2 DP. Overall, the process validation data support the capability of the commercial manufacturing process to produce a consistent DP with acceptable quality at the proposed commercial manufacturing facilities.
+Stability studies have been generated for both the DS and DP lots to support the licensure of the BNT1622 vaccine. All available stability data generated to date support the initial commercial shelf life of (b) (4) for the BNT1622 DS when stored at the intended storage condition of (b) (4) For DP shelf-life determination, up to ( months of stability data are available for one clinical batch at the intended storage condition of -70 ‡ 10°C and up to 9 months of stability data are available for (b) 4) emergency supply DP lots when stored at the intended storage condition of -90 to - 60°C. As comparable product quality has been demonstrated from clinical through commercial supply of the BNT162b2 DP, the stability data from both the clinical trial materials (CTMs) and the emergency supply lots are considered supportive of the proposed shelf life of 9 months for the commercial BNT1622 DP. The final commercial shelf life of the BNT162b2 DP is intended to be (** months when stored at the intended storage condition of -90 to -60°C; stability studies are ongoing. The available stability data from the emergency supply/PPQ DP lots will be submitted post licensure at intervals (9, (b) (4)
+months) as data become available to support future shelf-life
+extensions.
+The analvtical procedures developed and used for the release and stability monitoring of BNT162b2 DS and DP include tests to ensure their identity, purity, quality, and
+3
+
+potency. The assay methods are appropriately established and performed routinely according to the established standard operating procedures (SOPs). Validation of each assay method was performed at all the proposed testing sites (either through validation/co-validation or by analytical method transfer exercise) and the results have demonstrated that the assay methods are accurate, specific, robust, and precise over the specified range, indicating that they are suitable for the intended use.
+Two notable issues were identified during the previous EUA 27034 review and were resolved. The first issue involves the occurrence of (b) (4)
+in
+DP lots produced for emergency use, and the second issue involves the occasional observation of visible intrinsic particles detected during visual inspection of filled DP vials. Investigation of the (b) (4)
+identified that the b) (4)
+are
+only associated with the b) (4)
+batches that were manufactured with a (b) (4)
+operation at (b) (4) (a supplier of the (b) (4)
+). Since the
+implementation of a (b) (4)
+process at (b) (4), the resulting DP lots
+have been consistently demonstrating b) (4)
+Regarding the
+intrinsic particles, the frequency of occurrence is low and DP vials containing intrinsic particles can be detected and discarded through 100% automated/manual visual inspection. The intrinsic particles consist of (b) (4) components used for (b) (4) (b) (4) (i.e., they are not foreign particles) and the available data suggest that they have minimal potential to impact product safety and quality.
+Two clinical diagnostic assays (Cepheid Xpert Xpress RT-PCR assay for the detection of SARS-CoV-2 in clinical specimens and Roche Elecsys Anti-SARS-CoV-2 assay for the evaluation of serostatus to SARS-CoV-2) were used to assess clinical endpoints.
+Both assays have received FDA authorization under EUA. Validation of both assays has been performed at Pfizer's testing facility (Pfizer Vaccine Research and Development;
+Pearl River, NY), and the results support the suitability of both assays for their intended use in clinical studies.
+Final Recommendation:
+I recommend approval of this BLA.
+4
+
+4. BNT162b2 Drug Substance
+4.1 General Description
+The BNT162b2 drug substance (DS) is a single-stranded, 5'-capped mRNA encoding the full-length SARS-CoV-2 spike glycoprotein (S1S2 protein) derived from the Wuhan-Hu-1 isolate (GenBank MN908947.3 and GenBank QHD43416.1). The antigen-coding
+RNA sequence is codon-optimized and contains two proline mutations (b) (4)
+), which ensure expression of an antigenically optimal trimerized pre-fusion confirmation (P2 S). The RNA also contains common structural elements, including 5'-cap, 5'-UTR, 3'-UTR, and poly(A) tail, all of which are designed for mediating high RNA stability and translation efficiency. (b) (4) is replaced with the b) (4)
+during the RNA transcription. This nucleoside substitution has
+been demonstrated to enhance translation of in vitro transcribed mRNA while reducing its reactogenicity.
+The final BNT162b2 DS is a clear to b) (4) and is formulated at a target concentration of (b) (4)
+in DS (b) (4)
+4.2 Manufacturers
+Facilities and manufacturing sites involved in the commercial DS manufacturing and testing are presented in Table 1.
+Table 1. Sites and Responsibilities for Manufacture and Testing of BNT162b2 DS
+Site
+FEI/DUNS Numbers
+(Pfizer, Andover, ACMF) (Pfizer,
+FEI: 1222181
+Andover Building (b) (4)
+DUNS: 174350868
+and Building & ) Wyeth BioPharma
+Division of Wyeth Pharmaceuticals,
+Responsibility
+ACMF/Suite ® : Manufacture of drug substance
+Bldg. (b) (4): Release and
+Stability Testing
+LICa
+1 Burtt Road
+Andover, MA 01810
+United States
+Pfizer Inc
+875 Chesterfield Parkway West
+FEI: 1940118
+DUNS: 004954111
+Release and Stability
+Testing
+Chesterfield, MO 63017
+United States
+a. The legal entity name was changed at the acquisition by Pfizer in 2009; since then, the Wyeth Pharmaceuticals manufacturing site in Andover, Massachusetts belongs to Pfizer's production sites and is embedded in Pfizer's GMP svstem.
+Reviewer's Comments:
+Two manufacturing nodes were employed for DS manufacture under the initial EUA
+27034 request: (1) Pfizer, Andover, ACMF and (2) BioNTech, Mainz, and (b) (4)
+Germany. Pfizer, Andover, Suite was introduced as an
+additional DS manufacturing site under the EUA 27034. Both Andover ACMF and Suite manufacturing facilities are included in the BLA submission. The
+5
+
+BNT/b) (4)
+commercial DS.
+manufacturing node is not intended for the manufacture of
+4.3 Control of Materials
+Control of Non-Compendial Starting Materials and Raw Materials
+Raw materials used in the DS manufacturing process are purchased from approved suppliers and are tested and released upon receipt in accordance with the applicant's internal quality control program.
+The current acceptance criteria for non-compendial starting materials and raw materials used during the manufacture of the BNT162b2 DS are presented in Table 2 below. Note that starting materials are defined as a reagent or material used during the manufacture of the BNT162b2 vaccine product that is intended to be part of the final product, such as (b) (4)
+(b) (4)
+6
+
+21 pages have been determined to be not releasable: (b)(4)
+
+4.8 Adventitious Agents Safety Evaluation
+The adventitious agent control program includes the engineering systems of the facility and vessels, the control of raw materials, various filtration steps to control microbial burden in buffers and the process stream, and in-process and environmental testing to monitor the level of adventitious agents in and around the process stream.
+All raw materials used in the production of DS are evaluated as part of a comprehensive program to identify and manage transmissible spongiform encephalopathy (TSE) / bovine spongiform encephalopathy (BSE) risks. The only raw material of direct animal origin was identified to be b) (4)
+Based on the comprehensive adventitious-agent control
+program, all raw materials were found to be compliant with the EMA Note for Guidance (EMA/410/01 rev.3) and associated with minimal risk for TSE/BSE.
+Other materials of animal origin may be used in the production of polymer for filters, manifolds, containers, and/or filter components. These equipment components may contain traces of animal tallow derivatives. The tallow is processed under rigorous conditions and is considered compliant with the TSE note for guidance (EMA/410/01).
+4.9 Characterization Studies on Drug Substance (b) (4)
+(b) (4)
+28
+
+20 pages have been determined to be not releasable: (b)(4)
+
+5. BNT162b2 Drug Product
+5.1 General Description and Composition
+The BNT162b2 DP is a sterile dispersion of RNA-containing lipid nanoparticles (LNPs) in aqueous cryoprotectant buffer. It is filled into multi-dose vials containing 0.45 mL of the DP at (b) (4) . After dilution with 1.8 mL of sterile 0.9% sodium chloride solution, each vial contains a total of six 0.3 mL doses, with each dose containing 30 g of RNA.
+The composition of DP, including the BNT162b2 DS, lipid excipients, buffer, and cryoprotectant, are listed in Table 22 below. The concentration and amount of each component per DP container, and the corresponding amount per dose are also listed.
+Table 22. Composition of BNT162b2 Drug Product, Multi-dose Vial Name of Ingredients Reference to
+Function
+Concentration Amount Amount
+Standard
+(mg/mL)
+per vial per dose
+BNT162b2 DS
+In-house
+Active ingredient
+0.5
+225 Mg
+30 ug
+specification
+ALC-0315
+In-house
+Functional lipid
+7.17
+3.23 mg 0.43 mg
+specification
+ALC-0159
+In-house
+Functional lipid
+0.89
+0.4 mg
+0.05 mg
+specification
+DSPC
+In-house
+Structural livid
+1 56
+0.7 mg 0.09 mg
+specification
+Cholesterol
+Ph. Eur. and /or
+Structural lipid
+3.1
+1.4 mg
+0.2 mg
+USP-NE
+Sucrose
+USP-NF, Ph. Eur.
+Cryoprotectant
+103
+46 mg
+6 mg
+Sodium chloride
+USP-NF, Ph. Eur. Buffer component
+6
+2.7 mg 0.36 mg°
+Potassium chloride
+USP-NF, Ph. Eur.a Buffer component
+0.15
+0.07 mg 0.01 mg
+Dibasic sodium
+USP-NF, Ph. Eur. Buffer component
+1.08
+0.49 mg 0.07 mg
+phosphate. dihvdrate
+Monobasic potassium USP-NF, Ph. Eur.a Buffer component
+0 15
+0.07 mg 0.01 mg
+phosphate
+Water for iniection
+USP-NF, Ph. Eur. Solvent/vehicle
+g.s b
+9.s b
+q.s.b
+a. Supplier Certificate of Analysis confirms compliance to both USP-NF and Ph. Eur.; however, incoming testing may be performed only in accordance with a site's local compendia.
+b. q.s. = quantum satis (as much as may suffice)
+c. The diluent (0.9% sodium chloride Injection) contributes an additional 2.16 mg per dose
+The four lipids used to encase the modRNA include:
+• ALC-0315: ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate)
+• ALC-0159: 2-[(polyethylene glycol)-2000]-N,N-ditetradeclacetamide
+• DSPC: 1,2-distearoyl-sn-glycero-3-phosphocholine
+• Cholesterol
+Diluent vials of sterile 0.9% Sodium Chloride Injection, US are provided but shipped separately by the applicant. The provided diluent is supplied as either a 10 mL or a 2 mL single-use vial. Alternate brand of sterile 0.9% sodium Chloride Injection, US may be used as the diluent and also for single use. The diluent vials should be discarded after 1.8 mL is withdrawn.
+49
+
+5.2 Manufacturers
+Facilities and manufacturing sites involved in the commercial BNT162b2 D manufacturing and testing are presented in Table 23 below.
+Table 23. Sites and Responsibilities for BNT162b2 Drug Product Manufacture
+Site
+FEI/DUNS Numbers
+Responsibility
+Pharmacia & Upjohn Company LLCC FEI: 1810189
+LNP production/bulk DP formulation
+7000 Portage Road
+DUNS: 618054084
+Fill and finish
+Kalamazoo, MI 49001
+Primary packaging
+United States
+Secondary packaging
+Release and stability testing
+Pfizer Manufacturing Belgium NV
+FEI: 1000654629
+LNP production/bulk DP formulation
+Riksweg 12
+DUNS: 370156507
+Fill and finish
+Puurs, 2870
+Primary packaging
+Belgium
+Secondary packaging
+Release and stability testing
+Wyeth BioPharma Division of Wyeth FEI: 1222181
+Release and stability testing
+Pharmaceuticals LLCa
+DUNS: 17430868
+1 Burtt road
+Andover, MA 01810
+United States
+Pfizer Inc.
+FEI: 1940118
+Release and stability testing
+875 Chesterfield Parkway West
+DUNS: 004954111
+Chesterfield, MO 63017
+United States
+Pfizer Ireland Pharmaceuticals
+FEl: 3004145594
+Release and stability testing
+Grange Castle
+DUNS: 985586408
+Grange Castle Business Park
+Clondalkin, Dublin 22
+Ireland
+FEI: (b) (4)
+DUNS:(b) (4)
+Release testing (Sterility)
+(b) (4)
+FEI: (b) (4)
+DUNS: (b) (4)
+Release testing (Sterility)
+a. The legal entity name change from Wyeth BioPharma Division of Wyeth Pharmaceuticals was changed at the acquisition by Pfizer in 2009, since then the Wyeth Pharmaceuticals manufacturing site in Andover, Massachusetts belongs to Pfizer's production sites and is embedded in Pfizer's GMP svstem. Pfizer will be utilized throughout the CTD
+b. (b) (4) is a wholly owned subsidiary of Pfizer Inc.
+c. Pharmacia & Upjohn Company LLC is a wholly owned subsidiary of Pfizer Inc.
+Reviewer's Comments:
+Four manufacturing nodes were employed for BNT162b2 DP manufacture at the time of the initial EUA request: (1) Pfizer Puurs, (2) Pfizer Kalamazoo, (3) (b) (4) for LNP formation/bulk DP formulation followed by fill and finish at Pfizer Puurs, and (4) (b) (4)
+for LNP formation/bulk DP formulation followed by fill and finish
+50
+
+at Pfizer Puurs. Additional DP manufacturing sites were introduced for emergency supply production under EUA 27034, including Pfizer (b) (4) for DP fill and finish and (b) (4) for LNP formation and bulk DP formulation.
+For commercial BNT162b2 D production, the Pfizer Puurs and Pfizer Kalamazoo manufacturing facilities are included in the BLA submission. The Pfizer (b) (4) site for the fill and finish will be added as a supplement after BLA approval.
+Facilities and manufacturing sites for the production and testing/release of 0.9% sodium chloride, US diluent and their specified functions are listed in Table 24 below.
+Table 24. Sites and Responsibilities for 0.9% Sodium Chloride, US Manufacture
+Site
+FEI/DUNS
+Responsibility
+Numbers
+Fresenius-Kabi USA, LLC (b) (4)
+FEI# (b) (4)
+DUNS# (b) (4)
+Hospira, Inc (b) (4)
+FEI# (b) (4)
+DUNS# (b) (4)
+Manufacture, testing and release (of 2 mL size diluent vials)
+Manufacture, testing and release (of 10 mL size diluent vials)
+Hospira is a wholly owned subsidiary of Pfizer Inc.
+Reviewer's Comments:
+The saline diluent will be supplied as either a 10 mL single-use vial manufactured by Hospira, Inc. (NDC 0409488810) or a 2 mL single-use vial manufactured by Fresenium Kabi USA, LLC (NDC 6332318602). In amendment 47 submission (submitted on August 13, 2021), the applicant listed an additional manufacturing facility, Pfizer (b) (4)
+, for the production of the saline diluent. However, due to the
+Warning Letter (reference WL(b) (4)
+issued on (b) (4)
+) and Official Action
+Indicated status, the agency will not approve the facility as the saline diluent supplier as part of this BLA. The applicant acknowledged the request and removed Pfizer (b) (4)
+from the Diluent Manufacturers table in a follow-up
+submission (amendment 56 submitted on August 17, 2021).
+5.3 Control of Excipients
+The compendial excipients used in the manufacture of BNT162b2 DP and their quality standards are provided in Table 25 below.
+Table 25. Specifications for Compendial Excipients
+Excipient
+Cholesterol
+Sucrose
+Sodium chloride
+Potassium chloride
+Dibasic sodium phosphate, dihydrate
+Reference to Standard
+USP-NF and/or Ph. Eur.
+USP-NF and Ph. Eur.
+USP-NF and Ph. Eur.
+USP-NF and/or Ph. Eur.
+USP-NF and Ph. Eur.
+51
+
+Excipient
+Reference to Standard
+Monobasic potassium phosphate
+USP-NF and/or Ph. Eur.
+Water for Iniection
+USP-NF and Ph. Eur.
+a. Specification also includes test for microbial contamination per USP<61> (Ph. Eur. 2.6.12)
+Among the four lipid components used in the BNT162b2 LNP production, cholesterol is a compendial excipient, and the other three lipids, ALC-0159, ALC-0315, and DSPC, are non-compendial excipients. The supplier's release specifications for all four lipids include testing for (b) (4)
+To ensure the quality of the lipids and
+the resulting BNT162b2 DP, in-house control tests are performed for all four lipid excipients including (b) (4)
+prior to
+release of the LNP DP. For cholesterol, an additional in-house test for (b) (4)
+is also performed.
+Table 26 below summarizes the source of the lipid excipients used for clinical study, emergency supply, and commercial BNT162b2 DP.
+Table 26. List of Lipid Manufacturers with Phase of Use
+Lipid
+Clinical Trial
+Emergency Supply
+Commercial Supply
+Material
+ALC-0315
+ALC-0159
+(b) (4)
+Pfizer Groton,
+(b) (4). Pfizer Kalamazoo.
+Pfizer Groton
+DSPC
+Cholesterol
+(b) (4)
+(b) (4)
+Manufacturers' full names: (b) (4)
+Pfizer, Groton, CT USA (Pfizer Groton); (b) (4)
+Pharmacia & Upjohn Company LLC, Kalamazoo, MI USA (Pfizer Kalamazoo); (b) (4)
+(b) (4)
+Pfizer
+Kalamazoo (b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+52
+
+6 pages have been determined to be not releasable: (b)(4)
+
+5.4 Description of Drug Product Manufacturing Process and Process Controls
+Flow diagrams for the DP manufacturing process and process controls are illustrated in Appendices C and D for LNP production/bulk DP formulation and fill/finish operations, respectively. For emergency supply/commercial DP manufacture, a scale-out approach was used to increase capacity of the LNP-(b) (4 process with up to b) (4) used
+(b) (4) . The process scale approximates b) (4)
+RNA per (b) (4), such that ®
+can be used to process as much as b) (4)
+RNA corresponding
+to a bulk DP batch (b) (4) of approximately (b) (4). The current batch size ranges at the two commercial DP manufacturing sites are set to be b) (4) at Pfizer Kalamazoo and
+(b) (4) at Pfizer Puurs.
+The manufacturing process for the BNT162b2 DP includes the following major steps:
+(b) (4)
+59
+
+(b) (4)
+Steps (b) (4)
+- Fill and Finish
+For DP filling, (b) (4)
+sterile
+bulk DP is aseptically filled into glass vials. At the end of filling, each vial is stoppered, capped, and crimped. During filling, an in-process (b) (4) is performed at routine intervals for (b) (4)
+..All non-conforming vials are rejected.
+Filled vials are 100% inspected for defects either through automated visual inspection or manual visual inspection. Vials passing inspection are statistically sampled for meeting Acceptance Quality Limit (AQL) testing.
+The labeling and packaging of the vaccine vials for commercial distribution is performed on a fully automated or semi-automated packaging line. After labeling, the vials are placed into trayboxes, and the boxes are manually closed and labeled.
+Packaged BNT162b2 vials are frozen and stored in a freezer at -90°C to -60°C.
+Critical-Process Parameters and In-Process Controls
+To ensure DP manufacturing process consistency and the quality of the BNT162b2 DP, relevant process parameters and IPT-Cs with acceptable ranges/acceptance criteria have been established (Table 31). The critical process parameters (CPPs) were conservatively identified using Cause and Effect (C&E) Risk Assessment based on product and process understanding, scientific rationale, and manufacturing experience and available data. IPT-Cs are used during the manufacturing process to control a quality attribute/critical quality attribute within a specified range. In addition, IPT-Ms are
+60
+
+implemented throughout the process to ensure a continuous state of control and to enable forward processing.
+Table 31. Process Controls for the Manufacture of BNT162b2 D
+Unit Operation
+Process Control/parameter
+Acceptance Range/ Category
+Acceptance Criteria
+Kalamazoo
+Puurs
+(b) (4)
+61
+
+One page has been determined to be not releasable: (b)(4)
+
+Reviewer's Comment:
+Following further review of the (b) (4) parameters evaluated during process validation at Pfizer Puurs, the following two process parameters were tightened as submitted in BLA125742/0 amendment 19 on July 28, 2021:
+b) (4)
+The control limits applied for (b) (4)
+capping were reviewed by the facility reviewer.
+testing and the process controls for
+Hold Times During DP Manufacturing Process
+The hold times of the DP in-process materials during (b) (4)
+are provided in Tables 32 and 33,
+respectively.
+(b) (4)
+63
+
+(b) (4)
+Reviewer's Comment:
+Hold time for (b) (4) step was tightened from (b) (4)
+with up to (4)
+of this time allowed at up to (b) (4)
+with up to (b) (4)
+of this time allowed up to (b) (4). This change was made to ensure that the revised (0) (4)
+-acceptance criterion for DP can be met. The process hold time change
+has been validated via cumulative hold-time PPQ execution.
+Hold Time Out of Freezing for the BNT162b2 DP
+The Table 34 below summarizes the allowable times out of intended storage condition of -90 to -60°C during manufacture, packaging and transport.
+Table 34. Time Out of Storage Condition for BNT1622 Drug Product
+(b) (4)
+64
+
+(b) (4)
+Hold Time for the Diluted BNT162b2 Vaccine Prior to Administration
+The BNT162b2 final vaccine product is a concentrated suspension prepared in a multidose vial free of preservatives. Following dilution with saline, the in-use hold period and storage condition for the vaccine product is set to be up to 6 hours at 2°C to 25°C.
+To support this hold condition, an in-vial dilution hold-time study was conducted in which the physicochemical stability of the BNT1622 DP, held in glass vials and diluted with saline as intended, was evaluated at 2-8°C, 25°C, and b) * C. The results indicate that the diluted vaccine can be stored at ambient temperature (25°C) for ™ hours and can be exposed to elevated ambient temperature (b) (4)) for (™ hours with no impact on product quality. In addition, a microbial challenge with selected model diluents and surrogate DP solutions as well as a BNT162b2-specific microbial challenge were conducted to evaluate the potential for microbial growth in a matrix representative of saline-diluted vaccine. In both studies, (b) (4)
+microorganisms listed in (b) (4) and growth of
+the microorganisms was monitored. The results demonstrate that at (b) (4) , which is
+(b) (4) the proposed in-use time, no increase in growth was observed for any of the organisms with the spiked test samples stored at 20-25°C.
+Reviewer's Comments:
+The result was close to the acceptance criterion of (o) (4)
+at the " - hour time point ((b) (4)
+increase from To for ®
+). Overall,
+the results support the proposed in-use period of 6 hours at ambient temperature after dilution with saline.
+5.5 Process Validation
+A global approach to development has been undertaken across multiple manufacturing facilities in order to maximize BNT162b2 vaccine production and availability. The process-validation approach for all DP supply nodes included within the emergency/commercial supply network is composed of two phases. The Phase I validation covers the overall DP manufacturing network by performing minimally one (1) process validation (P) run of each manufacturing supply node. The Phase II validation covers the full validation of each of the supply nodes with separate protocols at each site. Note that for the BLA submission, only Pfizer Puurs and Pfizer Kalamazoo are the proposed DP manufacturing sites for licensure.
+Phase I Network PPQ Validation
+65
+
+13 pages have been determined to be not releasable: (b)(4)
+
+Hold Time for Packing, Shipping and Point of Use (b) (4)
+DP Shipping Conditions of -90 to -15°C with an Allowance for a Maximum Cumulative
+Time of (b) (4) at (b) (4)
+The shipping condition of -90 to -15°C with an allowance for a maximum cumulative time of (b) (4) at (b) (4)
+is supported by the following:
+79
+
+5.6 DP Manufacturing Process Development
+Introduction of a Scaled-up Process for the Production of LPs (b) (4)
+80
+
+2 pages have been determined to be not releasable: (b)(4)
+
+(b) (4)
+5.7 Impurity Profile of the Drug Product
+Possible process-related impurities include b) (4)
+, introduced from
+the DP manufacturing process, and (b) (4)
+, which are part of the (b) (4)
+may be present in the final vaccine container. All these impurities are present in low amounts and are further reduced during the DP manufacturing process by b) (4)
+Part of the process validation included evaluation of consistent removal of process-related impurities throughout the manufacturing process. Results from the BNT162b2
+DP process validation lots have demonstrated robust and consistent removal of (b) (4)
+for all PPQ lots made at Pfizer Purs and Pfizer Kalamazoo,
+which is well below the safety concern limit of (b) (4)
+.For (b) (4)
+, a comprehensive safety risk assessment has
+been performed to compare the theoretical worst case concentration of impurities that could be introduced into the final DP assuming no impurity clearance during the manufacturing process. The evaluation results as shown in Table 42 below demonstrate that none of the impurities pose a safety concern. Additionally, removal of (b) (4) was further demonstrated during process validation (quantification limit of (b) (4) in all PPQ
+BNT162b2 DP lots, which is equivalent to (b) (4)
+).
+(b) (4)
+Overall, based on the demonstration of consistent removal and the safety-based risk assessment, all the process-related impurities from the DP manufacturing process do not necessitate testing as part of BNT162b2 DP release.
+83
+
+5.8 Characterization Studies on Drug Product
+The DP characterization assays were developed to further describe and demonstrate the structure and physicochemical properties of the DP. The enhanced analytical characterization assays employed for the BNT162b2 DP and the testing results are briefly described as follows:
+b) (4)
+5.9 Control of Drug Product
+Specifications
+The specifications for BNT1622 DP at release and throughput shelf life are shown in
+Table 43 below.
+Table 43. BNT162b2 Drug Product Specifications
+84
+
+Quality Attribute
+Appearance
+Appearance (Visible
+Particulates)
+(b) (4)
+Analytical Procedure
+Appearance (Visual)
+Appearance (Particles)
+(b) (4)
+Acceptance Criteria
+White to off-white suspension
+May contain white to off-white opaque, amorphous particles
+(b) (4)
+b) (4)
+(b) (4)
+LNP (b) (4)
+LNP (b) (4)
+RNA (b) (4)
+RNA Content
+ALC-0315 Content
+ALC-0159 Content
+DSPC Content
+Cholesterol Content
+Vial Content (Volume)
+Lipid Identities
+Identity of Encoded RNA
+Sequence
+[(b) (4)
+RNA (b) (4)
+Bacterial Endotoxin
+Endotoxin (b) (4)
+(b) (4)
+| (b) (4)
+Sterility
+Sterility®
+No growth detected
+(b) (4)
+Container-Closure Integrity (b) (4)
+Pass
+a. All assays performed on stability unless otherwise noted
+b. In accordance with b) (4)
+, with minor difference in instrument calibration
+c. Assay not performed on stability
+d. Acceptance criteria values reflect (b) (4) correction
+e. (b) (4) sterility test, which is performed in accordance with the (b) (4) with the exception of (b) (4)
+method, may also be used
+f.
+Tested at release and on stability for stability batches only
+The acceptance criteria used for stability during shelf life will be predominantly the same as the acceptance criteria used for lot release, with the exception of the LP (b) (4) and RNA (b) (4) attributes, for both of which a separate stability acceptance criterion has been established to enable alternative storage at -20°C and 2-8°C at the point of administration.
+85
+
+Reviewer's Comment:
+• The proposed commercial acceptance criteria for the following attributes at release and during stability have been tightened for the commercial BNT1622 D compared with the DP product under the EUA. The changes were made based on the capability of the manufacturing process, historical release data for the emergency supply/commercial lots, as well as considerations of the assay variability.
+(b) (4)
+Justification of Specifications
+The acceptance criteria in the DP specification reflect the current understanding of criticality of quality attributes, their impact on product performance, and the quality of the product used in clinical trials to ensure consistent manufacture of DP. The lots used in the establishment of the commercial specification include nonclinical toxicology lot (° ), clinical lots manufactured from process 1 DS (5) (4)), and commercial-scale emergency supply DP lots manufactured from process 2 DS (* 4
+* lots manufactured
+between August 2020 and January 2021, including
+(W PPQ lots with ® manufactured at
+the Pfizer. Kalamazoo facility and ® manufactured at the Pfizer, Purs site). Statistical analysis was applied to the release data for the ( commercial-scale DP lots. The
+86
+
+mean, standard deviation and mean ‡ k*SD (k is the factor) for the release data set were calculated for each quality attribute, if applicable. Based on the statistical analysis results, the acceptance criteria were further adjusted and justified. For those attributes not subjected to statistical analysis, acceptance criteria were determined based on understanding of formulation robustness, compendial requirements, clinical experience and/or literature references.
+Table 44. Justification of Specifications for BNT1622 Drug Product
+(b) (4)
+87
+
+2 pages have been determined to be not releasable: (b)(4)
+
+(b) (4)
+(b) (4)
+(b) (4)
+5.10 Analytical Procedures for Drug Product
+The testing sites that are involved in assay performance and validation activities are listed in Table 46 below.
+Table 46. BNT162b2 Commercial DP Testing Sites
+Analvtical Procedure
+Testing Site
+Appearance (Visual)
+ARD, PGS-Puurs, PGS-KZO
+Release, Stability Release, Stability
+Appearance (Particles)
+(b) (4)
+Ґ(b) (4)
+Ґ(b) (4)
+(b) (4)
+(b) (4)
+Container Content (b) (4)
+(b) (4)
+(0 (4)
+Endotoxin (b) (4)
+Sterility
+(b) (4) Sterility
+ARD. PGS-GC. PGS-KZO ARD, PGS-Puurs, PGS-KZO ARD, PGS-Purs, PGS-KZO ARD, PGS-Puurs, PGS-KZO ARD, PGS-Puurs, PGS-KZO ARD, PGS-Puurs, PGS-KZO ARD, PGS-Puurs, PGS-KZO ARD, PGS-AND, PGS-GC ARD, PGS-AND, PGS-GC ARD, PGS-Puurs, PGS-KZO
+PGS-Puurs, PGS-KZO
+PGS-Puurs, PGS-KZO
+PGS-Purs, PGS-KZO
+90
+Release. Stability Release, Stabilit Release Release, Stability Release. Stability Release, Stability Release Release Release, Stability Release, Stability Release, Stability Release. Stabilit Release. Stability
+
+• Pfizer Analytical Research and Development (ARD) Laboratories at Chesterfield, MO (ARD-STL) and at Andover, MA (ARD-AND)
+• Pfizer Global Supply, Andover, MA (PGS-AND)
+• Pfizer Global Supply, Grange Castle, Ireland (PGS-GC)
+• Pfizer Global Supply, Kalamazoo, MI (PGS-KZO)
+• Pfizer Global Supply, Purs, Belgium (PGS-Puurs)
+Appropriate analytical procedures were established to monitor and assess the BNT162b2 DP as detailed below.
+(b) (4)
+91
+
+One page has been determined to be not releasable: (b)(4)
+
+(b) (4)
+5.11 Validation of Analytical Procedures
+Compendial procedures were qualified for use in accordance with the applicable pharmacopeias, excluding endotoxin and sterility. Endotoxin, in alignment with (b) (4)
+, and sterility in alignment with (b) (4)
+, were validated in the course of release testing of the b) (4) CTM batches. The validation of bacterial endotoxins and sterility tests are reviewed by DBSQC reviewers.
+All the analytical procedures used for the BNT162b2 DP have been validated. The assay may be originally validated or co-validated in selected testing sites. Upon transfer to additional testing location, reproducibility is evaluated in the validation or transfer.
+A summary of the parameters evaluated for each analytical assay, the acceptance criteria and the results are described in the following tables.
+(b) (4)
+(b) (4)
+93
+
+7 pages have been determined to be not releasable: (b)(4)
+
+5.13 Summary of Batch Analysis
+The BNT162b2 DP lots included in the section were used for nonclinical toxicology, clinical trials, process performance qualification (PPQ), emergency supply, and stability.
+The batch analysis data are presented for the DP lots manufactured across multiple manufacturing sites, including from sites that are not being licensed under the BLA submission. All batches met the specification at the time of release. Overall, the results demonstrate the capabilities of the manufacturing process for consistent production of quality DP.
+The PPQ batch range data at Pfizer Purs and at Pfizer Kalamazoo are shown in the Table 38.
+5.14 Container-Closure System of the Final Container
+The primary container-closure system for the BNT162b2 vaccine consists of the vial components listed in Table 47.
+Table 47. List of Components in Container Closure System
+Component
+Description
+Vial
+2 mL Type I borosilicate glass vial, 13 mm finish
+Vial Stopper
+13 mm vial stopper composed of gray (b) (4)
+elastomer
+(bromobutyl rubber) coated with (b) (4)
+a
+Vial Seal
+13 mm aluminum vial seal with tamper-evident polypropylene flip off cap
+a. b) (4) lubricant complies with (b) (4)
+requirements for b) (4)
+requirements for (b) (4)
+. requirements for (b) (4)
+Used as a Lubricant, (b) (4)
+Extractables for the DP Container-Closure System
+Controlled extraction studies were performed on the product contact bromobutyl rubber stopper material ((b) (4)
+) using model solvents, including (b) (4)
+• In one extraction study,
+stoppers were extracted (b) (4)
+. In a second extraction study, stoppers were
+(b) (4)
+. For both extraction studies, volatile,
+semi-volatile, non volatile and elemental extractables were analyzed.
+A Safety-Concern Threshold (SCT) was initially defined as (b) (4)
+total daily intake
+(TDI) for each compound, a level at which unidentified or identified leachable compound presents negligible safety concern to patients. The putative hazard of each potential leachable compound was further assessed and the SCT adjusted accordingly based on the presence or absence of a mutagenic concern. Potential leachable compounds without a mutagenic concern are assigned a SCT of (b) (4) TDI. Based on the results from the extraction studies, the following compounds and elements were selected and monitored as potential leachables: (b) (4)
+101
+
+Leachables for the DP Container-Closure System
+Leachable studies are in progress to support the BNT162b2 commercial container closure system with representative DP lots b) (4)
+Vials stored at -90°C to -60°C are being tested using methods
+validated for the potential leachables (identified in the extractables studies as well as unexpected compounds) at the initial timepoint, 6 months, (b) (4)
+. Currently available leachables information, including detection limits for validated methods and initial time point results from (' DP lots, demonstrated that all leachable compounds are below the SCT of (b) (4)
+TDI. Among the tested potential
+leachables, only (b) (4)
+were detected at (b) (4)
+, respectively. In addition, no unidentified leachable
+compounds have been detected. Based on a comprehensive review of available safety data, the presence of elements at or below the method quantitation limits in BNT162b2 DP pose negligible risk to patients. The rest of the leachable data will be reviewed in the next GMP inspection.
+5.15 Stability of Drug Product
+At Pfizer Kalamazoo, the date of manufacture for the final drug product is defined as the date of the final sterile filtration operation. At Pfizer Puurs, however, the date of manufacture is defined as the date of (b) (4)
+.In either case, the date
+of manufacture is no later than the date of final sterile filtration.
+The proposed initial commercial shelf life of the BNT162b2 DP is 9 months when stored at the intended storage condition of -90°C to -60°C. The initial shelf life is determined based on up to 9 months of currently available stability data on (4) emergency supply lots, and up to (4) months of stability data on clinical and non-clinical lots. The stability data generated to date on the emergency supply and PPQ lots also support an additional storage condition at -20 ‡ 5°C for up to 2 weeks, as well as short-term storage at 5 ‡ 3°C for up to one month (within the ®
+"month shelf life).
+The final commercial shelf life of the BNT162b2 DP is intended to be ™* months when stored at the intended storage condition of -90°C to -60°C. The applicant commits to submitting stability data to support extension of the DP shelf life beyond the 9-month period at intervals (b) (4)
+months) when supporting data are available.
+Materials used for the DP stability studies include emergency supply and PPQ lots manufactured by Pfizer Puurs ((b) (4)), Pfizer Kalamazoo ((b) (4)), (b) (4) (with fill/finish at Pfizer Purs, (b) (4)), and (b) (4) (with fill/finish at Pfizer Puurs, (b) (4)), and (b) (4) clinical and b) (4) non-clinical DP manufactured by b) (4)
+The stability protocols for emergency supply/PPQ lots are described in Table 48 for the long-term -90°C to -60°C and the accelerated -20 ‡ 5°C and 5 ‡ 3°C conditions.
+Table 48. Stability Protocol for BNT162b2 Drug Product
+102
+
+Analytical Procedure
+Appearance (Visible)
+-90 to -60°C
+(long-term)a
+0, 1W°, 2W, 1M, 2M, 3M, 6M, 9M, () (4)
+Appearance Visible Particulates)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+(b) (4)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+[(b) (4)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+'(b) (4)
+0, 1W°, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+[(b) (4)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+[(Ь) (4)
+[(b) (4)
+(ALC-0315 Content)
+(b) (4)
+(ALC-0159 Content)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+(b) (4)
+(DSPC Content)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+†(b) (4)
+(Cholesterol Content) 0, 1Wd, 2W, 1M, 2M,
+3M, 6M, 9M, (b) (4)
+[(6) (4)
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+[(b) (4)
+(RNA (b) (4) )
+0, 1Wd, 2W, 1M, 2M, 3M, 6M, 9M, (b) (4)
+†(b) (4)
+Container Closure Integrity Test
+Endotoxin
+Sterility
+0, 3M°, 6M, (b) (4)
+0, (b) (4)
+O. (b) (4)
+0, (b) (4)
+Test Intervals
+-20 ‡ 5°C
+5 ‡ 3°C
+(Accelerated) (Accelerated)9
+0, 1W, 2W, 0, 1W, 2W, (b) (4)
+1M, (b) (4)
+0, 1V, 2W,
+(b) (4)
+0, 1W, 2W,
+(b) (4)
+0, 1W, 2W.
+(b) (4)
+0, 1W, 2W
+(b) (4)
+0.1W.2W.
+16) 4
+0. 1W,2W,
+(b) (4)
+0, 1W, 2W
+(b) (4)
+0, 1W, 2W, (b) (4)
+0, 1W, 2W
+(b) (4)
+O, 1W, 2W, (b) (4)
+[0, 1W. 2W, (b) (4)
+0, 1W, 2W
+(b) (4)
+0, (0) (4)
+Not Tested
+Not Tested
+Not Tested
+0, 1W, 2W,
+1M, (b) (4)
+0, 1W, 2W
+1M,(b) (4)
+0, 1W, 2W
+1M, (b) (4)
+0, 1W, 2W, 1M, (b) (4)
+0, 1W, 2W, 1M, (b) (4)
+0, 1W, 2W,
+1M, (b) (4)
+0, 1W, 2W, 1M. (b) (4)
+0, 1W, 2V,
+1M, (b) (4)
+| 0, 1W, 2W, 1M,(b) (4)
+0, 1W. 2W
+1M, (b) (4)
+0, 1W, 2W, 1M, (b) (4)
+0, 1W, 2W,
+1M, (b) (4)
+O, (0) (4)
+Not Tested
+Not Tested
+Not Tested
+103
+
+a. Testing not performed at the 1W, 2W, or 2M time point for lots (b) (4)
+; Testing not performed at the 2M point for lots (b) (4)
+Testing not performed at the 1W or 2W time point for lot (b) (4)
+b. Being performed at 3M and 6M time points for lots (b) (4)
+c. Being performed at 3M time point for lots (b) (4)
+d. 1W testing performed on lots (b) (4)
+e. 1W testing performed on lot (b) (4) only; Testing not performed at the 1W, 2W, or () 4 time point for lots (b) (4)
+; Testing
+not performed at the 1W or 2W time point for lots b) (4)
+. Testing not performed on lots (b) (4)
+g. 1W testing performed on lots (b) (4)
+testing performed on lots (b) (4)
+testing not performed on lots (b) (4)
+; 1M, (b) (4) (b) (4)
+F1M and ()(4) testing
+performed on lots (b) (4)
+ends at (b) (4) time point
+h. Testing not performed on lots (b) (4)
+W = Week. M = Month
+For emergency supply/PPQ lots, the updated stability results include the following:
+• Lots (b) (4)
+: up to 9 months of stability data at the intended storage
+condition of -60 to -90°C, up to (b) (4) of data at the accelerated condition of -20 ‡ 5°C, and up to months of data at the accelerated condition of 5 ‡ 3°C. For Lot
+(b) (4), up to (b) (4) of data are available at the stress conditions of (b) (4) and (b) (4)
+• Lots (b) (4)
+: up to b) (4) of
+stability data at the intended storage condition and the accelerated conditions of -20
+‡ 5°C, up to b) (4) of data at the accelerated condition of 5 ‡ 3°C, as well as up to b) (4) of data at the stress condition (b) (4)
+• Lots (b) (4)
+up to (b) (4) of stability data at
+all three tested storage conditions (-60 to -90°C, -20 ‡ 5°C and 5 ‡ 3°C)
+• Lots b) (4)
+up to b) (4) of stability data at all three
+tested storage conditions (-60 to -90°C, -20 ‡ 5°C and 5 ‡ 3°C), For lots (b) (4), up to (b) (4) of stability data are available at the stress conditions of (b) (4)
+• Lots (b) (4)
+up to (b) (4) of stability data at all three
+tested storage conditions (-60 to -90°C, -20 # 5°C and 5 ‡ 3°C).
+For clinical and non-clinical DP lots, the updated stability results include the following:
+• Lots EE3818, ED3938, BCV40720-C, BCV40720-A, BCV40620-E, and BCV40620-
+A: up to 6 months of stability data at -70 ‡ 10°C and up to (b) (4) of stability data at 5 + 3°C
+• Lot BCV40420-A: up to ** months of stability data at -70 + 10°C and up to (b) (4) of stability data at 5 ‡ 3°C
+• Non-clinical lot (b) (4)
+up to b) (4) of stability data at -70 ‡ 10°C and
+5 ‡ 3°C.
+Summary of Stability Data
+Long-term storage stability
+104
+
+For emergency supply and PPQ lots stored at -90°C to -60°C and for clinical and non-clinical lots stored at -70 # 10°C, all results, generated to date, met the acceptance criteria at the time of testing. Stability data from (b) (4)
+up to 4
+months of data available) and (b) (4) emergency lots ((b) (4)
+, up to 9
+months of data available) support the proposed shelf-life of 9 months at the intended storage conditions of -90°C to -60°C. Additionally, trending on critical stability-indicating quality attributes (LNP (6) (4) , LNP (b) (4)
+, RNA content, RNA (b) (4)
+, lipid
+content, RNA (b) (4)
+) has been analyzed for stability lots and the data show
+that there are no significant trends that would impact the shelf life of the DP through the
+9-month time point when stored at the long-term condition of -90°C to -60°C.
+Accelerated (b) (4) stability (b) (4)
+Accelerated (b) (4)
+(b) (4)
+stability
+Accelerated - 20 ‡ 5°C stability
+All (b) (4) PPQ and eight emergency supply lots have been placed on formal stability at the accelerated -20 ‡ 5°C storage condition. All data generated to date were within the stated specifications through at least the (b) (4) time point. Out of the specification results were were observed for LNP (b) (4) from multiple PPQ/emergency supply lots beginning from the b) (4) time point.
+Reviewer's Comments:
+Even though all stability data generated through the b) (4) time point for DP lots stored at -20 ‡ 5°C are within the specifications, trending for LP (b) (4) is observed.
+The available (b) (4) stability data showed that, except for b) (4)
+, all
+other lots (n = (4) demonstrated an (b) (4) in LP (b) (4) by (b) (4)
+At the
+time points, the trending is more evident, with the LP (b) (4) ranging
+from (b) (4)
+, which represents an average(b) (4)
+when
+compared with the LNP (b) (4) at release that ranges from (b) (4)
+105
+
+Accelerated 5 ‡ 3°C stability
+For emergency supply and PPQ lots, all data generated to date are within the specifications through at least the 1-month time point, with the exception of (b) (4)
+both of which did not meet the specification of RNA b) (4) (2-week time point
+for (b) (4) and 1-month time point for (b) (4)). Both lots (b) (4)
+were
+manufactured using a (b) (4) lot of ALC-0315 made from the original lipid manufacturing process. The (b) (4) process was later updated by b) (4)
+, and since the change, the resulting BNT1622 DP all met the specification of RNA (b) (4) when stored at 5 ‡ 3°C at all timepoints tested to date, which are 1 month for some lots and months for other lots.
+For clinical DP lots, out-of-specification results were observed for RNA (b) (4) beginning from the -month time point, and for LNP (b) (4) and LNP (b) (4) beginning from the -month time point. It is not unexpected to see trends under the accelerated storage condition and the results have no impact to the overall stability study.
+Thermal Stress (b) (4) stability (b) (4)
+Reviewer's Comments:
+As all the emergency supply BNT162b2 DP lots included in the stability protocol were made using the commercial process, their stability data are being used to support the commercial use DP expiry of 9 months when stored at the intended storage condition of -90 to -60°C. Additionally, the stability data generated to date support the DP shelf life of up to two weeks at -20 ‡ 5°C and up to 1 month (31 days) at 5 ‡ 3°C.
+Additional Stability Studies for the BNT1622 D (b) (4)
+stability
+106
+
+(b) (4)
+studies have been initiated for the emergency supply and PPQ lots to
+provide support to the in-use period for the DP. The design of the thermal cycling studies includes the following:
+(b) (4)
+Photostability (b) (4)
+was subjected to the (b) (4) photostability condition ((b) (4)).
+DP vials were exposed to a light source providing an overall illumination of not less than (b) (4)
+Post Approval Stability Protocol and Commitment
+Upon completion of the stability protocol, post-approval, a minimum of (b) (4) of BNT162b2 DP manufactured will be enrolled in the commercial stability program at the long-term storage condition of -90°C to -60°C each year. The post-approval commercial stability protocol for the BNT162b2 DP is described below in Table 49.
+Table 49. Post-Approval Commercial Stability Protocol for DP Stored at -90 to -60°C
+Analytical Procedure/Quality Attribute
+Test Intervals (Months)a
+Appearance (Visible)
+1, 6, (b) (4)
+Appearance (Visible Particulates)
+1, 6, (b) (4)
+(b) (4)
+1, 6, (b) (4)
+107
+
+Analytical Procedure/Quality Attribute
+(b) (4)
+Test Intervals (Months)@
+1, 6, (b) (4
+[LNP (b) (4)
+LNP (b) (4)
+[RNA (b) (4)
+RNA Content
+ALC-0315 Content
+ALC-0159 Content
+DSPC Content
+Cholesterol Content (b) (4)
+RNA (b) (4)
+1, 6
+1, 6,
+1, 6,
+1, 6,
+1,6,
+1, 6,
+1, 6,
+1, 6,
+1, 6,
+1, 6.
+Container Closure Integrity Test
+Sterility
+Endotoxin
+Annually through end of shelf life
+0, End of shelf life
+O, End of shelf life
+a. Additional test intervals may be included for the purpose of extending expiry.
+6. Other CMC-related Information Not Covered in Module 3
+Environmental Assessment or Claim of Categorical Exclusion
+The applicant states that the pharmacologically active moiety or DS in COMIRNATY is messenger RNA (mRNA), which is recognized as naturally occurring. Therapeutic use of the vaccine product will not significantly alter the concentration or distribution of mRNA, its metabolites, or degradation products in the environment.
+The vaccine contains four pharmacologically inactive lipid excipients. The phospholipid (DSPC) and the sterol lipid (cholesterol) are both recognized as naturally occurring membrane lipids, therefore, the use of the vaccine product will not alter significantly the concentration or distribution of these lipids, their metabolites, or degradation products in the environment. The other two novel lipids ALC-0315 and ALC-0159 are not recognized as naturally occurring. However, the presence of both ALC-0315 and CLA-0159 lipids is not expected to have an impact on the environment based on the conservatively estimated concentrations of each lipid at the point of entry into the aquatic environment (expected introduction concentration of (b) (4) for ALC-0315 and (b) (4) for ALC-0159).
+Exception to the 21 CFR 610.15(a) Requirement for a Preservative
+Under 21 CFR 610. 15(a), a vaccine product in multiple-dose containers should contain a preservative. On July 15, 2021, the applicant submitted to ST 125742/0 in amendment 11, a request for exception to the 21 CFR 610.15(a) requirement. The justification for the unpreserved multi-dose presentation of the BNT162b2 vaccine product includes the following:
+• (b) (4)
+, the multi-dose preservative-free vial
+presentation remain an important tool to enable sufficient global supply to deal with the COVID-19 emergency.
+108
+
+• The BNT162b2 vaccine product is frozen at -90 to -60°C for storage and distribution with provisions for short-term storage for up to two weeks at -20 ‡ 5°C and up to 1 month at 2 - 8°C until administration. On the day of administration, sterile saline diluent is added into the thawed vial to provide 6 doses of the vaccine. Any unused vaccine must be discarded 6 hours after dilution.
+• The risks of this multi-dose preservative-free approach have been assessed by taking into consideration of formulation factors, including (b) (4)
+, DP storage temperature, and solution properties, which may impact the
+ability of the finished DP to support or inhibit microbial growth. Dilution and administration risks have also been evaluated from prior extensive experience with other products and data from platform formulations and commonly used b) (4) studies. The microbial challenge assessment using the panel of microbes described in (b (4) support the in-use period of 6 hours to ensure adequate time to prepare and administer 6 doses of the vaccine.
+• Successful distribution of more than b) (4)
+doses of vaccine in this multi-
+dose, non-preserved presentation under the US EUA 27034 and other global authorizations.
+Reviewer's Comments:
+The request for an exception to the 21 CFR 610.15(a) for the BNT162b2 vaccine as a multi-dose preservative-free presentation is considered acceptable.
+UNII code designations
+The UNIl code designations were reviewed and they appear to be acceptable.
+7. Follow-up on Ongoing Issues Identified at the Time of EUA Request
+RNA (b) (4) of BNT16262 Drug Product - (b) (4)
+(b) (4)
+109
+
+One page has been determined to be not releasable: (b)(4)
+
+(b) (4)
+Intrinsic Particles During Visual Inspection
+At the time of the EUA request, the sponsor reported that during the visual inspection step of the DP manufacturing process, white-colored particles have been observed to a varying degree across many lots spanning multiple manufacturing sites, including (b) (4)
+and two fill/finish sites and across different (b) (4) sources (vendors
+and batches). Upon investigation by (b) (4)
+, the
+visible particles were identified to be composed of (b) (4)
+, and thus intrinsic to the product. Based on these observations, the specification for appearance (visible particulates) was updated from "essentially free from visible particulates" for clinical lots to "may contain white to off-white opaque, amorphous particles" for emergency supply/commercial lots.
+Vials containing particles will be rejected and discarded during the 100% automated or manual inspection and Acceptable Quality Limit (AQL) sampling procedure for the inspected vials are further conducted to assess the robustness of the inspection method. The percentage of vials rejected due to particles during visual inspection has been low, ranging from (b) (4)
+. Additionally, visible particles are rarely observed
+in vials during routine release or stability testing, indicating a low propensity for particle formation post-inspection. Further evaluation of samples from DP lot b) (4) with and without visible particles demonstrated that product quality (RNA content and b) (4)
+) was not impacted by the presence of visible particles.
+Although visible particles may occasionally be observed in undiluted vials, following dilution with sterile 0.9% sodium chloride and mixing, the dosing solutions are expected to be free from visible particles. Any vials with visible particles observed after dilution should not be administered and should be discarded.
+Reviewer's Comments:
+The impact of visible intrinsic particles appears to be minimal due to the following reasons: (1) the particles are intrinsic to the product (i.e., they are not foreign particles); (2) the frequency of occurrence is low; (3) the rare vials with intrinsic
+111
+
+particles can be identified during 100% visual inspection and discarded; (4) the vials with intrinsic particles are not associated with changes in RNA content or b) (4)
+; (5) the intrinsic particles are dispersible upon dilution with saline; and
+(%) given that the particulates are composed of the (b) (4), the toxicity of which has been characterized in non-clinical repeat-dose toxicity studies, and their presence as visible particulates would not be associated with any unique chemical toxicological concern. In addition, as a precautionary measure, the instruction for the preparation of vaccine directs the healthcare provider to withhold administration if visible particles are observed after dilution with saline.
+8. Pre-Approval Inspection
+The pre-approval inspection (PAI) for the Pfizer Puurs facility was conducted from June 24, 2021 through July 2, 2021. No 483 items were issued. The facility is considered capable of consistently manufacturing the BNT1622 DP with acceptable quality.
+The PAI for the Pfizer Kalamazoo facility was waived. In May 2021, ORA/OBO performed a Level I surveillance inspection with focus on the production of the BNT162b2 DP. A form 483 was issued; the observations were deemed Voluntary Action Indicated (VAI) based on the adequacy of the firm's responses.
+The PAl for the Pfizer Andover site was performed from July 19, 2021 through July 23,
+2021. A form 483 with thirteen (13) observations was issued. On August 2, 2021, the applicant submitted the response to ST 126742/0.25 to address all the 483 issues identified during the Pfizer Andover PAI. The inspection was classified as VAI based on the adequacy of the firm's response to the Form 483.
+During the PAI at Pfizer Andover, a recurring issue of b) (4) out-of-specification (OOS) in DS batches was noticed. An expedited investigation effort was made by the firm focusing on evaluating raw materials, operation parameters, and stability data. The investigation was still ongoing and no definite root cause was yet identified during the inspection. (b) (5), (b) (7)(E)
+9. Nonclinical Studies
+This review focuses on selected studies relevant to nonclinical pharmacology and pharmacokinetics. Nonclinical toxicity studies and results were reviewed by the toxicology reviewer.
+9.1 Nonclinical Pharmacology Studies
+Two variants of BNT162b2, "variant 8" and "variant 9" (V8 and V9, respectively) were tested in nonclinical studies. The V8 and V9 variants differ only in their codon optimization sequences but have the same amino acid sequence. Immunogenicity of BNT162b2 (V9) was evaluated in mice, rats, and nonhuman primates. Immunogenicity
+112
+
+of BNT162b2 (V8) was evaluated in rats. However, only BNT162b2 (V9) has been evaluated in the clinic and therefore is the subject of this marketing application.
+Immunological assays used in nonclinical pharmacology studies include the following:
+• S1 and receptor-binding domain(RBD)-binding IgG ELISA in mouse and rat studies
+• SARS-CoV-2 pseudovirus-based neutralization assay (pVNT) in mouse and rat
+studies
+• Direct Luminex-based immunoassay (dLIA) for S1-binding IgG in nonhuman primate (NHP) studies
+• Authentic SARS-CoV-2 neutralization assay in HP studies
+• Interferon y (IFNy)-specific ELISpot in mouse and NHP studies
+• Intracellular cytokine staining flow cytometry in mouse and NHP studies
+Immunogenicity in Mice (Study Report: R-20-0085)
+Four groups of eight female BALB/c mice (at least 6 weeks of age) were immunized once on day 0 with 0.2, 1, and 5 g of BNT162b2 or with buffer (control group), by IM injection. Blood was collected on days 7, 14, 21, and 28 after immunization, and antibody immune responses were analyzed by ELISA and pVNT. On day 28, spleens were collected for splenocyte isolation and analysis of T-cell responses using IN ELISpot assays. In addition, Luminex assays and intracellular cytokine staining (ICS) were performed to assess cytokine responses.
+The results demonstrated that BNT162b2 was highly immunogenic in mice with strong antigen-binding IgG and high-titer neutralizing antibody responses together with a Th1-phenotype CD4+ response as well as an IN+, IL-2+, CD8+ T-cell response after a single immunization. Total IgG ELISA showed that the vaccine induced a strong, dose-dependent IgG response that recognizes both S1 and RBD. First detection of IgG antibodies was possible 7 days after immunization for all animals throughout the groups with an increase of total antibody amount until day 28. All mice developed functional neutralizing antibodies starting at 14 days after immunization, and the titer increased until the final study day. In addition, by profiling the IgG subtypes, a balanced IgG2a/IgG1 response was detected for the two higher doses (1 and 5 Ng), while the low dose induced a response with higher IgG1 than IgG2 levels (0.2 g). Stimulation of fresh splenocytes with an S protein-specific overlapping peptide pool demonstrated robust CD4+ and CD8+ T-cell IN responses, and a Th1-dominant profile was demonstrated in quantification of cytokines (IL-2 and IFNy) in the corresponding culture supernatants.
+Immunogenicity in Rats (Study Reports: 38166 and 20GR142)
+Male and female Wistar Han rats received three weekly IM doses of 100 ug of BNT162b2 (V8) in study 38166 or 30 g of BNT162b2 (V9) in study 20GR142. For both studies, serum samples were collected on day 17, two days after the 3rd administration, and on day 38, the end of the study. For study 38166, the sera were analyzed by ELISA for IgG that bound S1 and RBD as well as for SARS-CoV-2-S pseudovirus neutralizing
+113
+
+antibodies. For study 20G142, sera were only analyzed for SARS-CoV-2 neutralization activities. After immunization with BNT162b2 (V8), animals developed high titers of antigen-specific antibodies as well as neutralization titers. BNT162b2 (V9) also elicited SARS-CoV-2 neutralizing antibody responses in both male and female rats at the end of the dosing and recovery phases of the study. SARS-CoV-2 neutralizing-antibody responses were not observed in animals prior to vaccine administration or in saline-administered control animals.
+Immunogenicity and SARS-CoV-2 Challenge in Nonhuman Primates (Study Report:
+VR-VTR-10671)
+BNT162b2 was assessed for immunogenicity and for protection against an infectious SARS-CoV-2 challenge in rhesus macaques. Groups of 2-4-year-old male rhesus macaques were immunized IM with 30 or 100 ug of BNT162b2 or saline control on days O and 21. In the study, a panel of 38 SARS-CoV-2 human convalescent sera (HCS) was included as a currently assessable benchmark to evaluate the quality of the humoral immune response to the vaccine. S1-binding IgG and SARS-CoV-2 neutralizing antibodies (determined by NT50 titers) were readily detectable as early as 14 days after a single immunization, and levels substantially increased further following the second immunization. On day 28, seven days after dose 2, at the 30-ug dose level, the neutralizing geometric mean titer (GMT) reached 8-fold the GMT of the 38 member panel of HCS; at the 100 g dose level, the neutralizing GMT was 18-fold the HCS GMT. The HCS were drawn from SARS-CoV-2 infected individuals 18 to 83 years of age, at least 14 days after PCR-confirmed diagnosis and at a time when individuals were asymptomatic. A decline of both S1-binding IgG levels and neutralizing titers was observed at the latest measured time point (day 56) but remained above the neutralizing GMT and the S1-binding geometric mean concentration (GMC) of the HCS.
+As seen following mouse immunization, strong S-specific Th1-dominant INF* but minimal IL-4 T-cell responses were detected in all immunized rhesus macaques after the the second 30 or 100 g dose of the BNT162b2. By intracellular cytokine staining analysis, there was a dose-dependent increase in S-specific CD4* T-cell response with a strong Th1-bias evidenced by a high frequency of INFy*, IL-2*, or TNF-at cells.
+Notably, CD8* T-cell responses were also detectable in BNT-162b2-immunized animals.
+Groups of 2-4 year old male rhesus macaques that had received two IM immunizations with 100 Ng BNT162b2 V9 (n=6) or saline (Control; n=3) 21 days apart were challenged 55 days after the second immunization with 1.05×10 plaque-forming units of SARS-CoV-2 (strain USA-WA1/2020), which were split equally between the intranasal (IN) and intratracheal (IT) routes. The presence of SARS-CoV-2 RNA was then measured by RT-QPCR in bronchoalveolar lavage fluid, nasal swabs, and oropharyngeal (OP) swabs.
+Viral RNA was detected in BAL fluid in all three control-immunized animals (2 on Day 3 and 1 on Day 6); however, no viral RNA was detected in BNT162b2-immunized and SARS-CoV-2-challenged animals. For nasal and OP swabs, viral RNA can be detected in most of the control-immunized animals at all tested time points (Days 1, 3, and 6),
+114
+
+whereas it was only detected in BNT162b2-immunized macaques on Day 1 after challenge and became undetected on Day 3 and onward. None of the challenged animals showed clinical signs of significant illness, indicating that the 2-4-year-old male rhesus challenge model is primarily an infection model for SARS-CoV-2 and not a COVID-19 disease model. No radiographic evidence of vaccine-elicited enhanced disease was observed.
+9.2 Nonclinical Pharmacokinetics (PK) Evaluation
+Assessment included evaluating the PK and metabolism of two novel lipid excipients
+(ALC-0315 and ALC-0159) in the LNP and potential biodistribution of BNT162b2.
+The biodistribution of BNT162b2 was evaluated using (b) (4) expression as a surrogate reporter in b) (4) mice. (b) (4) expressing modRNA was formulated like BNT162b2 with the identical lipid composition to generate LNPs. Mice were injected intramuscularly with a total dose of 2 g/animal of LNP, and (b) (4) expression was measured in vivo following (b) (4) application at 6 h, 24 h, 48 h, 72 h, 6 d, and 9 d after injection. (b) (4) expression was identified at the injection site at 6 hours after injection and was not detected after 9 days. Expression in the liver was also present to a lesser extent at 6 hours after injection and was not detected by 48 hours after injection. A tissue distribution study was also performed in (b) (4)
+Rats using (8) (4)
+LNPs, which similarly comprised of a proprietary mixture of BNT162b2 lipid components and b) (4) -encoding mRNA. The test item also contains trace amounts of radiolabeled (b) (4) , a non-exchangeable, non-metabolizable lipid marker in order to monitor the disposition of the LP. The tested animals (21 male and 21 female) each received a single intramuscular dose of (b) (4)
+at a target mRNA total dose of
+50 Mg/animal. Whole blood and tissue samples were collected at 0.25, 1, 2, 4, 8, 24 and
+48 hours post-dose (three animals/sex/timepoint). The study results showed that following intramuscular injection, the concentration of (b) (4)
+was greatest in
+the injection site at all time points. Outside the injection site, levels of radioactivity peaked in the plasma by 1-4 hours post-dose and distributed mainly into liver, adrenal glands, spleen and ovaries over 48 hours. Total recovery of radioactivity outside of the injection site was greatest in the liver, with much lower total recovery in spleen and very little recovery in adrenals glands and ovaries. The mean concentrations and tissue distribution pattern were broadly similar between the sexes.
+An b) (4)
+rat PK study, using the (b) (4) -encoding modRNA formulated in
+an identical lipid composition as BNT1622, was performed to evaluate pharmacokinetics of both ALC-0315 and ALC-0159 lipids. In this study, plasma samples were collected up to 336 hours following a single ® administration to male b) (4)
+Rats at a dose of 1 mg/kg. The results demonstrated that ALC-0315 and ALC-0159 distribute from the plasma to the liver. Plasma concentrations of ALC-0315 and ALC-0159 decreased rapidly, with initial t12 of 1.62 and 1.72 h, respectively. ALC-0315 and ALC-0159 were then cleared from plasma, resulting in terminal elimination t12 of 139 and 72.7 h, respectively. The estimated percent of dose distributed to the liver was ~ 60% for ALC-0315 and ~20% for ALC-0159. While there was no detectable excretion of
+115
+
+either lipid in the urine, the percent of lipids excreted unchanged in feces was ~1% for ALC-0315 and ~50% for ALC-0159.
+The in vitro metabolism of ALC-0315 and ALC-0159 was evaluated in blood, liver microsomes, S9 fractions, and hepatocytes from mice, rats, monkeys, and humans. The in vivo metabolism was examined in rat plasma, urine, feces, and liver samples from the PK study. Metabolism of ALC-0315 and ALC-0159 appears to occur slowly in vitro and in vivo. ALC-0315 and ALC-0159 are metabolized by hydrolytic metabolism of the ester and amide functionalities, respectively, and this hydrolytic metabolism is observed across the species evaluated.
+Reviewer's Comments
+Based on current hypotheses regarding the etiology of vaccine-associated enhanced disease, the provided data are reassuring due to: (1) the robust induction of functional (i.e., neutralizing) antibodies in mice, rats and rhesus macaques; (2) the Th1-bias in T-cell responses; and (3) the lack of disease in vaccinated rhesus macaques challenged with SARS-CoV-2. The nonclinical ADME studies indicate that the LNP mainly localizes to the site of injection and, to a lesser extent, distributes to the liver. Approximately 50% of ALC-0159 is excreted unchanged in feces, while metabolism appears to play a role in the elimination of ALC-0315.
+10. Clinical Assays
+10.1 Diagnostic Assays Used to Support Clinical Efficacy Endpoints
+Two diagnostic assays (Cepheid Xpert Xpress RT-PCR assay for the detection of SARS-CoV-2 in clinical specimens and Roche Elecsys Anti-SARS-CoV-2 assay for the evaluation of serostatus to SARS-CoV-2) are described below.
+Cepheid Xpert Xpress RT-PCR Assay
+The Cepheid Xpert Xpress SARS-CoV-2 assay, which has received FDA authorization under an EUA, is a rapid, automated in vitro diagnostic test for the qualitative detection of the nucleocapsid (N) and envelope (E) gene sequences from nasopharyngeal, nasal, or mid-turbinate swab and/or nasal wash/ aspirate specimens collected from patients suspected of having COVID-19 disease. The Cepheid Xpert assay was used to assess viral infection before vaccination and to confirm COVID-19 disease cases during study follow-up. Detection of RNA sequences for the N and E genes are carried out by realtime (b) (4) RT-PCR following a single-step sample processing protocol.
+Report VR-MVR-10080 describes the method validation for the Cepheid Xpert Xpress
+PC Assay conducted at Pfizer Pearl River. The validation results are summarized below
+Detection limits: Based on simulated samples (generated by spiking with the commercially available AccuPlex SARS-CoV-2 reference material or a live SARS-CoV-2 reporter virus), the detection limits was established to be (b) (4)
+and (b) (4)
+116
+
+Accuracy: The assay's clinical accuracy was evaluated using simulated samples, patient samples as well as pre-COVID-19 samples.
+(b) (4)
+Taken together, the validation results for the Cepheid Xpert press SARS-CoV-2 assay support its intended use to test samples from Pfizer's clinical efficacy trial of the SARS-CoV-2 vaccine candidate and other epidemiological studies.
+Roche Elecsys Anti-SARS-CoV-2 Assay
+The Roche Elecsys Anti-SARS-CoV-2 assay, which has received FDA authorization under an EUA, is a rapid, automated in vitro diagnostic test for detecting the presence of antibodies to nucleocapsid (N) protein of SARS-CoV-2 (antigen not present in the BNT162b2 vaccine candidate) in serum or plasma samples. This is a qualitative assay marketed as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, which would indicate a recent or prior infection. The Elecsys Anti-SARS-CoV-2 assay will be used to assess serostatus before vaccination. Detection of N protein antibodies to SARS-CoV-2 is carried out by a two-step immunoassay method in which biotin- and ruthenium-conjugates of N protein are incubated with human serum or plasma. Streptavidin-coated paramagnetic beads are then added to isolate N protein/antibody complexes and chemiluminescent emissions are measured by a photomultiplier. Results are presented in qualitative "Positive" or "Negative" based on N-specific antibody levels above or below a predetermined cutoff index (COl) value.
+The specificity of the assay was evaluated using (b) (4)
+117
+
+(b) (4)
+The sensitivity of the Elecsys Anti-SARS-CoV-2 assay was evaluated (5) (4)
+Reviewer's Comments:
+The submitted data are supportive of both the Cepheid Xpert Xpress assay and the Roche Elecsys Anti-SARS-CoV-2 assay being suitable for their intended use in Phase 2/3 clinical studies to evaluate the efficacy of the BNT162b2 vaccine performed at Pfizer's testing facility (Pfizer Vaccine Research and Development;
+Pearl River, NY). It is important to note that the validation studies relied on available information generated by the assay kit manufacturers (Cepheid and Roche) in support of assay EU as well as academic studies assessing assay performance published in peer-reviewed publications; the validation results generated by the applicant were in general agreement with information from these external sources.
+10.2 Immunogenicity Assays Used for Exploratory Immunogenicity Endpoints Two immunogenicity assays, SARS-CoV-2 mNeonGreen virus microneutralization assay and b) (4) direct Luminex assay (dLIA) for IgG quantification, are used for evaluating the immune responses from clinical trial samples.
+SARS-CoV-2 mNeonGreen Virus Microneutralization Assay (SARS-CoV-2 mG NT)
+The SARS-CoV-2 mNG NT is a biofunctional assay that measures neutralizing antibodies against SARS-CoV-2. The SARS-CoV-2 mG virus is derived from the USA WA1/2020 strain that had been engineered to contain an mNeonGreen (mNG) reporter gene in open reading frame 7 of the viral genome. The recombinant virus is rescued by reverse genetics and upon productive infection of cells, green fluorescence is produced. This reporter virus generates similar plaque morphologies and indistinguishable growth curves from wild-type virus.
+b) (4)
+118
+
+(b) (4)
+Report VR-MVR-10083 describes the method validation for the SARS-CoV-2 mG NT assay conducted at Pfizer Hackensack. The validation results are summarized below:
+(b) (4)
+Reviewer's Comments
+Assay specificity was assessed in the evaluation of the limit of detection. This validation study at Pfizer Hackensack involved assessing (b) (4)
+119
+
+(b) (4)
+Direct Luminex Assay (dLIA)
+The (b) (4)
+S1 IgG dLIA measures IgG antibody levels to the subunit 1 (S1) of the
+SARS-CoV-2 spike protein in human serum samples. (b) (4)
+Report VR-MQR-10211 summarizes qualification results for the (b) (4) S1 IgG dLIA. The qualification results are also summarized below:
+b) (4)
+120
+
+(b) (4)
+Reviewer's Comments
+The qualification study reports for the S1 IgG dLIA and RBD IgG dLIA were submitted to the original BLA. Upon request for the validation reports for both assays, the applicant submitted to STN125742/0 amendment 19, the dLIA validation report (VR-MVR-10077) for quantification of IgG antibodies to SARS-CoV-2 full-length S protein.
+Additional IR was issued on August 2, 2021 to obtain clarification on which immunogenicity assay was used in the clinical studies. The applicant provided the response to amendment 31 on August 5, 2021, stating that the S1 IgG dLIA was used for immunogenicity assessments in Phase I (C4591001 sentinel cohort) and Phase 2 (C4591001 Phase 2 immunogenicity cohort) studies. The validated full-length S-binding IgG dLIA will be used for the lot consistency study and is not part of the original BLA filing.
+The qualification study report for the S1 IgG dLIA assay is considered acceptable for this BLA submission with the reasons as follows: 1) the vaccine efficacy is determined by the clinical endpoints and the dLIA assay was used for the exploratory immunogenicity endpoint; and 2) appropriate assay parameters were evaluated during the qualification study, including precision, (b) (4) linearity, lower limit of detection/quantification, range, reference standard bias, and assay run performance.
+121
+
+The qualification results for the S1 IgG dLIA assay support its intended use for the quantification of anti-S1 IgG antibodies in human sera.
+122
+
+5 pages have been determined to be not releasable: (b)(4)
+

docs/December 16, 2021 Approval Letter - Comirnaty.txt

@@ -0,0 +1,50 @@
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+Our ST: BL 125742/36
+SUPPLEMENT APPROVAL
+BioNTech Manufacturing GmbH
+Attention: Amit Patel
+Pfizer Inc.
+235 East 42nd Street
+New York, NY 10017
+December 16, 2021
+Dear Mr. Patel:
+We have approved your request submitted and received on November 18, 2021, to supplement your Biologics License Application (BLA) under section 351(a) of the Public Health Service Act for COVID-19 Vaccine, mRNA (COMIRNATY), to include a new 30 microgram dose formulation (Tris/Sucrose) of COMIRNATY manufactured at the Pfizer Manufacturing Belgium NV, Puurs, Belgium (Pfizer, Puurs) facility.
+LABELING
+We hereby approve the draft content of labeling including the Package Inserts submitted under amendment 10, dated December 13, 2021, and the draft carton and container labels submitted under amendment 6, dated December 9, 2021.
+CONTENT OF LABELING
+As soon as possible, but no later than 14 days from the date of this letter, please submit the final content of labeling (21 CFR 601.14) in Structured Product Labeling (SPL) format via the FDA automated drug registration and listing system, (ELIST) as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ default.htm. Content of labeling must be identical to the Package Inserts submitted on December 13, 2021. Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida nces/UCM072392.pdf.
+The SPL will be accessible via publicly available labeling repositories.
+CARTON AND CONTAINER LABELS
+Please electronically submit final printed carton and container labels identical to the carton and container labels submitted on December 9, 2021, according to the guidance for industry Providing Regulatory Submissions in Electronic Format - Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-regulatory-submissions-electronic-format-certain-human-pharmaceutical-product-applications.
+U.S. Food & Drug Administration
+10903 New Hampshire Avenue
+Silver Spring, MD 20993
+www.fda.gov
+
+Page 2 - STN BL 125742/36 - Amit Patel
+All final labeling should be submitted as Product Correspondence to this BLA, ST BL 125742, at the time of use and include implementation information on Form FDA 356h.
+ADVERTISING AND PROMOTIONAL LABELING
+You may submit two draft copies of the proposed introductory advertising and promotional labeling with Form FDA 2253 to the Advertising and Promotional Labeling
+Branch at the following address:
+Food and Drug Administration
+Center for Biologics Evaluation and Research
+Document Control Center
+10903 New Hampshire Ave.
+WO71-G112
+Silver Spring, MD 20993-0002
+You must submit copies of your final advertising and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).
+All promotional claims must be consistent with and not contrary to approved labeling.
+You should not make a comparative promotional claim or claim of superiority over other products unless vou have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).
+Please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that includes this change.
+We will include information contained in the above-referenced supplement in your BLA
+file.
+Sincerely,
+Jerry P. Weir, Ph.D.
+Director
+Division of Viral Products
+Office of Vaccines
+Research and Review
+Center for Biologics
+Evaluation and Research
+

docs/Employee-Officer List Memo, August 22, 2021 - COMIRNATY.txt

@@ -0,0 +1,63 @@
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+EMPLOYEE/OFFICER LIST MEMO
+To:
+Date:
+BLA:
+Sponsor:
+Product:
+The File
+August 22, 2021
+STN 125742/0
+BioNTech Manufacturing GmbH
+COVID-19 Vaccine, mRNA (COMIRNATY)
+From:
+Laura Gottschalk, PhD (RPM)
+Through:
+Ramachandra Naik, PhD (Chair)
+The following officers or employees of FDA participated in the decision to approve this application and consented to be identified on this list.
+• Maria Allende, MD
+• Esmeralda Alvarado, PhD
+• Dennis Cato
+• Anil Choudhary, PhD
+• Maryna Eichelberger, PhD
+• CAPT Oluchi Elekwachi, PharmD, MPH
+• CDR Debra M. Emerson, RPh, MS
+• CDR Donald Ertel, MS
+• Doran Fink, MD, PhD
+• Laura Fontan, PhD Richard Forshee, PhD
+• Patrick Funk, PhD Karla Garcia, MS
+• Alifiya H. Ghadiali, PhD
+• Laura Gottschalk, PhD
+• Cheryl Hulme
+• Dana Jones
+• CDR James Kenney, DSc
+• Shiowjen Lee, PhD
+• Robin Levis, PhD
+• Nicole Li, MS
+• Tsai-Lien Lin, PhD
+• Yun Lu, PhD
+• Christian D. Lynch
+• Carrie Mampilly, MPH
+• Ramachandra Naik, PhD
+• Narayan Nair, MD
+• Timothy Nelle, PhD
+• Tao Pan, PhD
+• Keith Peden, PhD
+• Kirk Prutzman, PhD
+• Joseph Quander, III
+• Robert Sausville
+• CDR David Schwab, MSIS
+• CAPT Ann T. Schwartz, MD
+• John Scott, PhD
+• Muhammad Shahabuddin, PhD
+• CAPT Michael Smith, PhE
+• Daphne Stewart
+• Lisa L. Stockbridge, PhD
+• Xinyu Tang, PhD
+• Hsiaoling Wang, PhD
+• Jerry P. Weir, PhD Susan Wollersheim, MD
+• Zhongren Wu, PhD Ye Yang, PhD Emnet Yitbarek, PhD
+• Iryna Zubkova, PhD
+1
+

docs/July-8-2022-Approval-Letter-COMIRNATY.txt

@@ -0,0 +1,59 @@
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+Our ST: BL 125742/45
+SUPPLEMENT APPROVAL
+PMR FULFILLED
+July 8, 2022
+BioNTech Manufacturing GmbH
+Attention: Gosia Mineo, M.S.
+Pfizer, Inc.
+1 Pfizer Way 190/004/4405
+Pearl River, NY 10965
+Dear Ms. Mineo:
+We have approved your request received on December 16, 2021, to supplement your Biologics License Application (BLA) submitted under section 351(a) of the Public Health Service Act for COVID-19 Vaccine, mRNA (COMIRNATY), manufactured at the Pfizer Manufacturing Belgium NV, Purs, Belgium (Pfizer, Puurs), Pharmacia & Upjohn Company LLC, Kalamazoo, Michigan (Pfizer, Kalamazoo) and Hospira, Inc., McPherson, Kansas (Pfizer, McPherson) facilities, to include use in adolescents 12 through 15 years of age for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
+The review of this supplement was associated with the following National Clinical Trial number: 04368728.
+LABELING
+We hereby approve the draft content of Package Insert labeling, submitted under amendment 13, dated July 1, 2022.
+CONTENT OF LABELING
+As soon as possible, but no later than 14 days from the date of this letter, please submit the final content of labeling (21 CFR 601.14) in Structured Product Labeling (SPL) format via the FDA automated drug registration and listing system (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ default.htm. Content of labeling must be identical to the Package Insert submitted on July 1, 2022. Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida nces/UCM072392.pdf.
+The SPL will be accessible via publicly available labeling repositories.
+U.S. Food & Drug Administration
+10903 New Hampshire Avenue
+Silver Spring, MD 20993
+www.fda.gov
+
+Page 2 - STN BL 125742/45 - Gosia Mineo, M.S.
+All final labeling should be submitted as Product Correspondence to this BLA, ST 125742, at the time of use and include implementation information on Form FDA 356h.
+ADVERTISING AND PROMOTIONAL LABELING
+You may submit two draft copies of the proposed introductory advertising and promotional labeling with Form FDA 2253 to the Advertising and Promotional Labeling
+Branch at the following address:
+Food and Drug Administration
+Center for Biologics Evaluation and Research
+Document Control Center
+10903 New Hampshire Ave.
+WO71-G112
+Silver Spring, MD 20993-0002
+You must submit copies of your final advertising and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).
+All promotional claims must be consistent with and not contrary to approved labeling.
+You should not make a comparative promotional claim or claim of superiorit over other products unless you have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).
+Please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that includes these changes.
+FULFILLED POSTMARKETING REQUIREMENT
+This submission fulfills your postmarketing requirement #1 identified in the August 23, 2021, approval letter for BLA ST 125742/0 for COVID-19 Vaccine, mRNA.
+The requirement addressed in this submission is as follows:
+1. Deferred pediatric Study C4591001 to evaluate the safety and effectiveness of
+COMIRNATY in children 12 years through 15 years of age.
+Final Protocol Submission: October 7, 2020
+Study Completion: May 31, 2023
+Final Report Submission: October 31, 2023
+
+Page 3 - STN BL 125742/45 - Gosia Mineo, M.S.
+PEDIATRIC REQUIREMENTS
+Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.
+We note that you have fulfilled the pediatric study requirement for ages 12 through 15 vears for this application.
+We will include information contained in the above-referenced supplement in your BLA file.
+Sincerely,
+Doran Fink, M.D., Ph.D.
+Acting Deputy Director
+Office of Vaccines Research and Review
+Center for Biologics Evaluation and Research
+

docs/November 8, 2021 Summary Basis for Regulatory Action - Comirnaty.txt

@@ -0,0 +1,1008 @@
+Date:
+From:
+Summary Basis for Regulatory Action
+11/8/2021
+Ramachandra Naik, PhD, Review Committee Chair,
+DVRPA/OVRR
+BLA STN:
+Applicant:
+125742/0
+BioNTech Manufacturing GmbH (in partnership with
+Pfizer, Inc.)
+Submission Receipt
+Date:
+May 18, 2021
+PDUFA Action Due Date: January 16, 2022
+Proper Name:
+COVID-19 Vaccine, mRNA
+Proprietary Name:
+COMIRNATY
+Active immunization to prevent coronavirus disease
+2019 (COVID-19) caused by severe acute respiratory
+Indication:
+syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older
+Recommended Action: The Review Committee recommends approval of this product.
+Director, Office of Vaccines Research and Review
+Director, Office of Compliance and Biologics Quality
+
+Discipline Reviews
+CMC
+• CMC Product (OVRR)
+• Facilities Review (OCBQ/DMPQ)
+• Facilities Inspection (OCBQ/DMPQ and
+OVRR/DVP)
+• Lot Release, QC, Test Methods, Product
+Quality (OCBQ/DBSQC)
+Clinical
+• Clinical (OVRR)
+• Postmarketing Safety, Epidemiological
+Review (OBE/DE)
+• Real World Evidence
+• Benefit-Risk Assessment
+• BIMO
+Statistical
+• Clinical Data (OBE/DB)
+• Nonclinical Data
+Nonclinical/Pharmacology/Toxicology
+• Toxicology (OVRR)
+• Developmental Toxicology (OVRR)
+Labeling
+• Promotional (OCBQ/APLB)
+• Carton and Container Labels
+• Labeling Review
+• Consults (CDISC, Datasets)
+• Documentation Review
+Advisory Committee Summary
+Reviewer / Consultant - Office/Division
+Xiao Wang, PhD, OVRR/DVP
+Anissa Cheung, MSc, OVRR/DVP
+Kathleen Jones, PhD, OCBQ/DMPQ
+Laura Fontan, PhD, OCBQ/DMPQ
+Gregory Price, PhD, OCBQ/DMPQ
+CDR Donald Ertel, MS, OCBQ/DMPQ
+Nicole Li, MS, OCBQ/DMPQ
+Christian Lynch, OCBQ/DMPQ
+Alifiya Ghadiali, OCBQ/DMPQ
+Zhongren Wu, PhD, OCBQ/DMPQ
+Ekaterina Allen, PhD, OCBQ/DMPQ
+Hsiaoling Wang, PhD, OCBQ/DBSQC
+Emnet Yitbarek, PhD, OCBQ/DBSQC
+Karla Garcia, MS, OCBQ/DBSQC
+Anil Choudhary, PhD, MBA, OCBQ/DBSQC
+Esmeralda Alvarado Facundo, PhD, OCBQ/DBSQC
+Marie Anderson, PhD, OCBQ/DBSQC
+Cheryl Hulme, OCBQ/DMPQ
+Susan Wollersheim, MD, OVRR/DVRPA
+CAPT Ann T. Schwartz, MD, OVRR/DVRPA
+Lucia Lee, MD, OVRR/DVRPA
+Deborah Thompson, MD, MSPH, OBE/DE
+Yun Lu, PhD, OBE
+Hong Yang, PhD, OBE
+Osman Yogurtcu, PhD, OBE
+Patrick Funk, PhD, OBE
+Haecin Chun, MT (ASCP) SSB, MS, OCBQ/DIS
+Lei Huang, PhD, OBE/DB
+Ye Yang, PhD, OBE/DB
+Xinyu Tang, PhD, OBE/DB
+Nabil Al-Humadi, PhD, OVRR/DVRPA
+CAPT Oluchi Elekwachi, PharmD, MPH,
+OCBQ/APLB
+Daphne Stewart, OVRR/DVRPA
+Laura Gottschalk, PhD, OVRR/DVRPA
+Brenda Baldwin, PhD, OVRR/DVRPA
+CAPT Michael Smith, PhD, OVRR/DVRPA
+No Advisory Committee meeting held
+2
+
+Table of Contents
+1. Introduction......
+2. Background .....
+3. Chemistry, Manufacturing and Controls (CMC) a.
+Product Quality.
+b.
+Testing Specifications......
+......3
+....4
+.....6
+...6
+.. 10
+C. CBER Lot Release.
+11
+d.
+Facilities Review / Inspection
+1 1
+e.
+Container/Closure System.
+f. Environmental Assessment.
+4. Nonclinical Pharmacology/Toxicology
+5. Clinical Pharmacology .....
+6. Clinical/Statistical..
+a.
+Clinical Program
+b.
+Bioresearch Monitoring (BIMO) - Clinical/Statistical/Pharmacovigilance ... 22
+7. Safety and Pharmacovigilance ......
+8. Labeling.....
+9. Advisory Committee Meetings ......
+10. Other Relevant Regulatory Issues.
+11. Recommendations and Benefit/Risk Assessment
+а.
+b.
+C.
+Recommended Regulatory Action.......
+Benefit/Risk Assessment..............
+Recommendation for Postmarketing Activities
+14
+14
+..14
+....... 15
+.......15
+..... 15
+......22
+.....25
+.....26
+....27
+..27
+..... 27
+............ 28
+. 28
+1. Introduction
+BioNTech Manufacturing GmbH (in partnership with Pfizer Inc.) submitted a Biologics License Application (BLA) ST BL 125742 for licensure of COVID-19 Vaccine, mRNA.
+The proprietary name of the vaccine is COMIRNATY. COMIRNATY is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. The vaccine is administered intramuscularly (IM) as a series of two 30 g doses (0.3 mL each) 3 weeks apart.
+COMIRNATY (also referred to as BNT162b2 in this document) contains a nucleoside-modified messenger RNA (mRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2 that is formulated in lipids including ((4-hydroxybutyl)azanediyl)bishexane-6,1-diyl)bis(2-hexyldecanoate), 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol.
+3
+
+COMIRNATY is supplied as a concentrated multi-dose liquid formulation (0.45 mL
+volume) stored frozen at -90°C to -60°C in a 2 mL Type 1 glass vial. A sterile diluent, 0.9% Sodium Chloride Injection, US, is supplied separately in 2 mL glass vials manufactured by Fresenius Kabi LLC and in 10 mL vials manufactured by Hospira, Inc.
+The diluent is stored at 20°C to 25°C and will be shipped in parallel with shipments of
+COMIRNATY, with arrivals synchronized so that the diluent is delivered before the vaccine is delivered. Healthcare providers may also use other sources of sterile 0.9% Sodium Chloride Injection, US as a diluent for COMIRNATY, if necessary.
+The COMIRNATY Multiple Dose Vial is thawed in a refrigerator (2°C to 8°C) for 2 to 3 hours or at room temperature (up to 25°C) for 30 minutes. The vial must be warmed to room temperature for dilution. Once at room temperature, the COMIRNATY Multiple Dose Vial is diluted with 1.8 mL of the diluent. After dilution, each vial of COMIRNATY contain six doses of 0.3 mL of vaccine. Each 0.3 mL dose of COMIRNATY contains 30 ug of mRNA encoding the spike glycoprotein of SARS-CoV-2 and the following ingredients: lipids (0.43 mg ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis (2-hexyldecanoate), 0.05 mg 2-(polyethylene glycol 2000)-N, N-ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.2 mg cholesterol), 0.01 mg potassium chloride, 0.01 mg monobasic potassium phosphate, 2.52 mg sodium chloride, 0.07 mg dibasic sodium phosphate dihydrate, and 6 mg sucrose. After dilution, the vials are stored at 2°C to 25°C and must be used within 6 hours from the time of dilution.
+COMIRNATY is preservative-free.
+The expiry dating period for COMIRNATY Multiple Dose Vial is 9 months from the date of manufacture when stored at -90°C to -60°C. The date of manufacture shall be no later than the date of final sterile filtration of the formulated drug product (at Pharmacia & Upjohn Company LLC in Kalamazoo, Michigan, the date of manufacture is defined as the date of sterile filtration for the final drug product; at Pfizer-Manufacturing Belgium NV in Purs, Belgium, it is defined as the date of the b) (4)
+2. Background
+SARS-CoV-2 is a novel, zoonotic coronavirus that emerged in late 2019 and was identified in patients with pneumonia of unknown cause. The virus was named SARS-
+Cov-2 because of its similaritv to the coronavirus responsible for severe acute respiratory syndrome (SARS-CoV, a lineage B betacoronavirus). SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus sharing more than 70% of its sequence with SARS-CoV, and ~50% with the coronavirus responsible for Middle Eastern respiratory syndrome (MERS-CoV). SARS-CoV-2 is the causative agent of COVID-19, an infectious disease with respiratory and systemic manifestations. Disease symptoms vary, with many persons presenting with asymptomatic or mild disease and some progressing to severe respiratory tract disease including pneumonia and acute respiratory distress syndrome (ARDS), leading to multiorgan failure and death.
+The SARS-CoV-2 pandemic continues to present a challenge to global health and, as of August 2021, has caused approximately 208 million cases of COVID-19, including 4.3 million deaths worldwide. In the United States (U.S.), more than 37 million cases have
+4
+
+been reported to the Centers for Disease Control and Prevention (CDC), of which 90% have occurred in individuals 16 years of age or older. While the pandemic has caused morbidity and mortality on an individual level, the continuing spread of SARS-CoV-2 and emerging variants has caused significant challenges and disruptions in worldwide healthcare systems, economies, and many aspects of human activity (travel, employment, education).
+In the U.S., there are no licensed vaccines or anti-viral drugs for the prevention of
+COVID-19. In December 2020, the FDA issued emergency use authorizations (EUs) for two mRNA vaccines which encode the SARS-CoV-2 spike glycoprotein: Pfizer-BioNTech
+COVID-19 Vaccine (manufactured by Pfizer, Inc. in partnership with BioNTech manufacturing GmbH) for use in individuals 16 years of age and older, and Moderna COVID-19 Vaccine (manufactured by ModernaTX, Inc.) for use in individuals 18 years of age and older. In February 2021, the FDA issued an EUA for a replication-incompetent adenovirus tvpe 26 (Ad26)-vectored vaccine encoding a stabilized variant of the SARS-CoV-2 spike glycoprotein, manufactured by Jansen Biotech, Inc. (Jansen COVID-19
+Vaccine) for use in individuals 18 years of age and older. In May 2021, the FDA expanded the emergency use authorization for the Pfizer-BioNTech COVID-19 Vaccine to include adolescents 12 through 15 years of age. On October 22, 2020, FDA approved remdesivir for use in adult and pediatric patients 12 years of age and older and weighing at least 40 kilograms (about 88 pounds) for the treatment of COVID-19 requiring hospitalization. Several other therapies are currently available under emergency use.
+Table 1. Regulatory History
+Regulatory Events / Milestones
+1. Pre-IND meeting (Written Responses)
+2. IND submission
+3. Fast Track designation granted
+4. Submission of EUA request for individuals ≥16 years of age
+5. Issuance of EUA for individuals ≥16 years
+6. Submission of EUA request for individuals 12-15 years of age
+7. Issuance of EUA for individuals 12-15 years of age
+8. Pre-BLA meeting (Written Responses)
+9. BLA ST 125742/0 received
+10 BLA filed
+11. Mid-Cycle communication
+12. Late-Cycle meeting
+13. Action Due Date
+Date
+April 6, 2020 (Part 1)
+April 10, 2020 (Part 2)
+April 22, 2020
+July 7, 2020
+November 20, 2020
+December 11, 2020
+April 9, 2021
+May 10, 2021
+Clinical: March 9, 2021
+CMC: March 31, 2021
+May 18, 2021
+July 15, 2021
+The Applicant canceled
+The Applicant canceled
+January 16, 2022
+5
+
+3. Chemistry, Manufacturing and Controls (CMC)
+a. Product Quality
+COMIRNATY Manufacturing Overview
+COMIRNATY contains a nucleoside-modified messenger RNA (mRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2 that is formulated in lipids including (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate),2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol. COMIRNATY is supplied as a frozen suspension to be diluted with a diluent, 0.9% Sodium Chloride Injection, US, that is supplied separately or can be acquired elsewhere, if necessary. Manufacture of the mRNA drug substance will take place in Andover, MA, USA. The final formulated drug product will be manufactured, filled, finished, labeled and packaged in Purs, Belgium or in Kalamazoo, MI, USA. The 0.9% Sodium Chloride Injection, US diluent will be manufactured by Fresenius-Kabi
+USA, LLC ((b) (4)
+) and Hospira, Inc. ((b) (4)
+).
+The mRNA in COMIRNATY is a single-stranded, 5'-capped mRNA encoding the full-length SARS-CoV-2 spike glycoprotein derived from the Wuhan-Hu-1 isolate (GenBank MN908947.3 and GenBank QHD43416.1). The antigen-coding RNA sequence is codon-optimized and contains two proline mutations (b) (4)
+87P), which ensures an
+antigenically optimal trimerized pre-fusion confirmation (S-2P). The RNA also contains common structural elements, including 5'-cap, 5'-UTR, 3'-UTR, and poly(A) tail, all of which are designed for mediating high RNA stability and translation efficiency. During
+RNA transcription, (b) (4) is replaced with the (b) (4)
+.This
+nucleoside substitution has been demonstrated to enhance translation of in vitro transcribed mRNA while reducing its reactogenicity.
+Drug Substance (DS)
+The manufacture of mRNA DS is divided into (b) (4) major manufacturing process stages:
+(b) (4)
+6
+
+Drug Product (DP)
+The manufacturing process of the DP is divided into the following critical steps:
+• Preparation of the DS: (b) (4)
+• Formation of LNP: In this step, (b) (4)
+• Formulation of the bulk DP: The bulk DP is formulated by b) (4)
+• Filling: The bulk DP is sterile filtered and aseptically filled into 2 mL Type I borosilicate glass vials manufactured by b) (4)
+• Labeling and storage: The filled vials are visually inspected, labeled, and frozen at
+-90°C to -60°C.
+Composition
+The composition of the formulation of COMIRNATY and the function of the ingredients are provided in Table 2.
+Table 2. Composition of COMIRNATY Multiple Dose Vial
+Ingredients
+Amount per vial Function
+SARS-CoV-2 spike glycoprotein mRNA
+(UNII: 5085ZFP6SJ)
+ALC-0315 [4-hydroxybutyl)azanediyl)bis (hexane-6, 1-diyl)bis(2-hexyldecanoate)
+(UNIl: AVX8DX713V)
+ALC-0159 [2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide]
+(UNIl: PJH39UMU6H)
+DSPC [1,2-distearoyl-sn-glycero-3-phosphocholine]
+(UNIt: 0431P12MOK)
+Cholesterol
+(UNII: 97C5T2UQ7J)
+Potassium chloride
+(UNIl: 660YQ98110)
+Monobasic potassium phosphate
+(UNI: 4J9FJOHL51)
+Sodium Chloride
+225 ug
+Active Ingredient
+3.23 mg
+Lipid component
+0.4 mg
+Lipid component
+0.7 mg
+Lipid component
+1.4 mg
+Lipid component
+0.07 mg
+Excipient
+0.07 mg
+2.7 mg
+Excipient
+Excipient
+
+Ingredients
+Amount per vial Function
+(UNIl: 451W471Q8X)
+Dibasic sodium phosphate dihydrate
+(UNII: GR686LBA74)
+Sucrose
+(UNII: C151H8M554)
+Water for Injection
+(UNII: 059QFOKOOR)
+UNII: Unique Ingredient Identifier
+q.s. = quantum satis (as much as may suffice)
+0.49 mg
+46.0 mg
+q.S.
+Excipient
+Excipient
+Excipient
+Stability of COMIRNATY in Multiple Dose Vial
+For the long-term storage condition study, parameters monitored are Appearance,
+(o) (4) by
+(b) (4)
+, LNP (b) (4)
+, RNA content
+and (b) (4)
+Assay, Lipid (ALC-0315, ALC-0159, DSPC, and
+Cholesterol) Content by (b) (4)
+, Endotoxin content by b) (4)
+, Container closure integrity test by (b) (4)
+,and Sterility.
+The stability data provided in the submission support a dating period of 9 months from the date of manufacture when stored at -90°C to -60°C for the COMIRNATY DP filled in 2 mL Tve I borosilicate glass vials. Stabilit data on emergency use and process performance qualification lots also support storage at -20°C ‡ 5°C for up to 2 weeks as well as short term storage at 5°C + 3°C for up to one month (within the 9-month expiry dating period.
+The Diluent for COMIRNATY
+The contents of the vaccine vial are diluted with sterile 0.9% Sodium Chloride Injection, USP. Vials of sterile 0.9% Sodium Chloride Injection, US are provided but shipped separately. The provided diluent or another sterile 0.9% Sodium Chloride Injection, USP should be used as the diluent.
+The provided 0.9% Sodium Chloride Injection, USP diluent will be supplied either as cartons of 10 mL single-use vials manufactured by Hospira, Inc (NDC 0409-4888-10), or 2 mL single-use vials manufactured by Fresenius Kabi USA, LLC (NDC 63323-186-02).
+The composition of the saline diluent and the function of the ingredients are provided in
+Table 3.
+Table 3. Composition of the Diluent
+Ingredients
+SODIUM CHLORIDE
+(UNIl: 451W471Q8X)
+Quantity
+(per 0.3 mL dose)
+2.16 mg
+Water for Injection
+0.3 ml
+(UNIt: 059QFOKOOR)
+UNII: Unique Ingredient Identifier
+Function
+Excipient
+Excipient
+8
+
+COMIRNATY
+Product Composition
+COMIRNATY Multiple Dose Vial is supplied as a frozen suspension that is diluted at the time of use with 1.8 mL of saline diluent. A single dose of COMIRNATY contains 30 ug mRNA in a volume of 0.3 mL, and it does not contain preservative. [See section 10.b regarding exception to the 21 CFR 610.15(a) requirement for a preservative.]
+Stability of COMIRNATY
+The Applicant conducted in-use stability studies to support the maximum temperature and time period that COMIRNATY can retain its physicochemical properties. Based on the data generated, COMIRNATY retains its quality attributes for up to 6 hours when stored between 2°C to 25°C (35°F to 77°F).
+The carton labels and the Package Insert (PI) state that after dilution, vials should be stored between 2°C to 25°C (35°F to 77°F) and used within 6 hours from the time of dilution. During storage, exposure to room light should be minimized, and direct exposure to sunlight and ultraviolet light should be avoided. Any vaccine remaining in vials must be discarded after 6 hours and cannot be refrozen.
+Assavs used in clinical studies
+Diagnostic Assays Used to Support Clinical Efficacy Endpoints
+Two clinical diagnostic assays (Cepheid Xpert Xpress RT-PCR assay for the detection of SARS-CoV-2 in clinical specimens and Roche Elecsys Anti-SARS-CoV-2 assay for the evaluation of serostatus to SARS-CoV-2) were used to assess clinical endpoints. Both assavs have received FDA authorization under EUA.
+The Cepheid Xpert Xpress RT-PCR assay is a rapid, automated in vitro diagnostic test for the qualitative detection of the N and E gene sequences from nasopharyngeal, nasal, or mid-turbinate swab and/or nasal wash/aspirate specimens collected from patients suspected of having COVID-19. This assay is used to assess viral infection of the participants before vaccination and to confirm COVID-19 cases during study follow-up.
+The Roche Elecsys Anti-SARS-CoV-2 assay is a rapid, automated in vitro diagnostic test for detecting the presence of antibodies to nucleocapsid (N) protein of SARS-CoV-2 (antigen not present in COMIRNATY) in serum or plasma samples. This is a qualitative assay marketed as an aid in identifving individuals with an adaptive immune response to SARS-CoV-2, which would indicate a recent or prior infection. This assay is used to assess serostatus of the participants before vaccination.
+Data were submitted to support the suitability of both the Cepheid Xpert Xpress assay and the Roche Elecss Anti-SARS-CoV-2 assay for their intended uses in Phase 2/3 clinical studies when performed at Pfizer's testing facility (Pfizer Vaccine Research and Development; Pearl River, NY).
+Immunogenicity Assays Used for Exploratory Immunogenicity Endpoints
+Two immunogenicity assays (SARS-CoV-2 mNeonGreen (mNG) virus microneutralization assay and (b) (4)
+direct Luminex assay (dLIA) for IgG
+9
+
+quantification) were used for evaluating the immune responses from clinical trial samples.
+The SARS-CoV-2 mNG microneutralization assay measures neutralizing antibodies (50% inhibition tiers) against SARS-CoV-2 using Vero cell monolayers in a 96-well plate format. The SARS-CoV-2 mNG virus is derived from the USA WA1/2020 strain that had been rescued by reverse genetics and engineered to express a fluorescent reporter gene (mNeonGreen) upon productive infection of cells. The validation protocol (that includes evaluation of dilutional linearity, precision, limits of quantification, and limit of detection) and the results of the validation study, executed at Pfizer Hackensack Meridian Health Center (Nutley, New Jersey), were submitted to support the suitability of the assay for testing of clinical trial immunogenicity samples.
+The (b) (4) S1 IgG dLIA measures IgG antibody levels to the subunit 1 (S1) of the SARS-CoV-2 spike protein in human serum samples. Qualification data provided in the submission support the b) (4) dLIA for quantification of human IgG antibodies that bind to the S1 protein of SARS-CoV-2 and confirm that the assay is suitable for its intended use.
+b. Testing Specifications
+Specifications and Methods
+The tests and specifications applied for routine release of COMIRNATY are shown in
+Table 4.
+Table 4. Control of COMIRNATY: Tests and Specifications
+Quality Attribute
+Analytical Procedure
+Appearance
+Appearance (Visual)
+Appearance
+(Visible
+Particulates)
+Appearance (Particles)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+INP (b) (4)
+(b) (4)
+| LNP (b) (4)
+(b) (4)
+RNA b) (4)
+(b) (4)
+RNA content
+(b) (4)
+assay
+assay
+ALC-0315 content (b) (4)
+ALC-0159 content (b) (4)
+DSPC content
+(b) (4)
+Cholesterol content (b) (4)
+Vial content (volume) Container content
+Lipid identities
+(b) (4)
+Acceptance Criteria
+White to off-white suspension
+May contain white to off-white opaque, amorphous particles
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+(b) (4)
+Not less than (b) (4)
+(b) (4)
+(ALC-0315, ALC-
+0159, Cholesterol, DSPC)
+10
+
+Quality Attribute
+Identitv of encoded RNA (b) (4)
+(b) (4)
+(b) (4)
+RNA (b) (4)
+(b) (4)
+Endotoxin ((b) (4))
+Bacterial Endotoxin (b) (4)
+Sterility
+Sterility ((b) (4)
+Container
+(b) (4)
+Closure Integrity
+Abbreviations: LNP = Lipid nanoparticles; (b) (4)
+Analytical Procedure
+Acceptance Criteria
+Identitv confirmed
+(b) (4)
+(b) (4)
+(b) (4)
+No Growth Detected
+Pass
+The analytical methods and their validations and/or qualifications for the COMIRNATY DS and DP were found to be adequate for their intended use.
+C. CBER Lot Release
+The lot release protocol template was submitted to CBER for review and found to be acceptable after revisions. A lot release testing plan was developed by CBER and will be used for routine lot release.
+d. Facilities Review / Inspection
+Facility information and data provided in the BLA were reviewed by CBER and found to be sufficient and acceptable. The facilities involved in the manufacture of COMIRNATY are listed in Table 5 below. The activities performed and inspectional histories are also noted in Table 5 and are further described in the paragraphs that follow.
+11
+
+Table 5. Facilities involved in the manufacture of COMIRNATY
+FEI
+Name/address
+Number
+DUNS number
+Inspection/ waiver
+Pfizer Inc.
+875 Chesterfield Parkway
+West
+Chesterfield, MO 63017 (b) (4)
+Manufacture
+Drug Substance
+Release and stability testing
+Drug Product
+Release and stability testing
+Wyeth BioPharma Division of Wyeth Pharmaceuticals
+LLC
+1 Burtt Road
+Andover, MA 01810
+Drug Substance
+Manufacture, release and stability testing
+Drug Product
+Release and stability testing
+Pharmacia & Upjohn
+Company LLC
+7000 Portage Road
+Kalamazoo, MI 49001
+Drug Product
+LNP production, bulk drug product formulation, fill and finish, primary packaging, secondary packaging, release and stability testing
+Pfizer Manufacturing
+Belgium NV
+Rijksweg 12
+Puurs, 2870
+Belgium
+Drug Product
+LNP production, bulk drug product formulation, fill and finish, primary packaging, secondary packaging, release and stability testing
+1940118
+1222181
+1810189
+1000654629
+004954111
+174350868
+618054084
+370156507
+Waiver
+Pre-License
+Inspection
+Waiver
+Pre-license inspection
+Results/ Justification
+ORA
+Surveillance
+August 19-20, 2019
+NAI
+CBER
+Pre-license inspection
+July 19-23, 2021
+VAI
+ORA/OBPO
+Surveillance
+May 11-20, 2021
+VAI
+CBER
+Pre-license inspection
+June 24-July 2, 2021
+NAI
+12
+
+Name/address
+Pfizer Ireland
+Pharmaceuticals
+Grange Castle Business
+Park
+Clondalkin, Dublin 22 reland
+Drug Product
+Release and stability testing
+(b) (4)
+FEI
+Number
+DUNS number
+Inspection/ waiver
+Results/ Justification
+3004145594
+985586408
+Waiver
+ORA Surveillance
+November 4-12, 2019
+VAI
+(b) (4)
+(b) (4)
+Waiver
+CDER
+Pre-approval inspection
+(b) (4)
+Drug Product
+Release testing (sterility (b) (4)
+VAI
+(b) (4)
+(b) (4)
+Waiver
+ORA
+Surveillance (b) (4)
+Drug Product
+Release testing (sterility)
+VAI
+ORA conducted a surveillance inspection of Pfizer Inc., Chesterfield, MO, from August
+19 - 20, 2019. No Form FDA 483 was issued, and the inspection was classified as No Action Indicated (NAI).
+CBER conducted a pre-license inspection (PLI) of Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC from July 19 - 23, 2021. All inspectional issues were resolved, and the inspection was classified as Voluntary Action Indicated (VAI).
+ORA conducted a surveillance inspection of Pharmacia & Upjohn Company LLC from May 11 - 20, 2021. All inspectional issues were resolved, and the inspection was classified as VAI.
+CBER conducted a PLI of Pfizer Manufacturing Belgium NV from June 24 - July 2, 2021.
+No Form FDA 483 was issued, and the inspection was classified as NAI.
+ORA conducted a surveillance inspection of Pfizer Ireland Pharmaceuticals from
+November 4 - 12, 2019. All inspectional issues were resolved, and the inspection was classified as VAI.
+CDER conducted a pre-approval inspection of (b) (4)
+from b) (4)
+All inspectional issues were resolved, and the inspection was classified as VAI.
+ORA conducted a surveillance inspection of (b) (4)
+from b) (4)
+. All inspectional issues were resolved, and the inspection was classified as VAl.
+13
+
+e. Container/Closure System
+The COMIRNATY drug product is filled and stored at -90°C to -60°C in a 2 mL glass vial sealed with a bromobutyl rubber stopper and an aluminum seal with flip-off plastic cap.
+The glass vials are supplied by (b) (4)
+The stopper and caps are supplied by (b) (4)
+, respectively.
+Pfizer performed container closure integrity testing (CCIT) on the filled 2 mL glass vials using a b) (4)
+test method. All acceptance criteria were met.
+f. Environmental Assessment
+The BLA included a request for categorical exclusion from an Environmental Assessment under 21 CF 25.31. The FDA concluded that this request is justified, and no extraordinary circumstances exist that would require an environmental assessment.
+4. Nonclinical Pharmacology/Toxicology
+Nonclinical Toxicology
+For the nonclinical safety evaluation, COMIRNATY was evaluated in two repeat dose toxicity studies in Wistar Han rats and a Combined Fertility and Developmental Study (Including Teratogenicity and Postnatal Investigations) in Wistar Han rats.
+The repeat dose toxicitv evaluations were conducted on COMIRNATY and a similar vaccine termed BNT162b2 (V8). COMIRNATY and BNT162b2 (V8) have identical amino acid sequences of the encoded antigens but COMIRNATY includes the presence of optimized codons to improve antigen expression. The IM route of exposure was selected as it is the route of clinical administration. Generation of an immune response to COMIRNATY was confirmed in rats in both repeat-dose toxicity studies. In both repeat-dose toxicity studies, administration of COMIRNATY by IM injection to male and female rats once every week for a total of 3 doses was tolerated without evidence of systemic toxicity. Edema and erythema at the injection sites, transient elevation in body temperature, elevations in white blood cells and acute phase reactants and decreased albumin:globulin ratios were observed. Iniection site reactions were common in all vaccine-administered animals and were greater after boost immunizations.
+For the Combined Fertility and Developmental Study, COMIRNATY was administered to female rats twice before the start of mating and twice during gestation at the human clinical dose (30 ug RNA/dosing day). There were some effects (change in body weight and food consumption and effects localized to the iniection site observed in rats in these studies following administration of COMIRNATY that were not considered adverse and a relationship to COMIRNATY was not established. There were no effects on mating performance, fertility, or any ovarian or uterine parameters nor on embryo fetal or postnatal survival, growth, or development in the offspring. An immune response was observed in female rats following administration of each vaccine candidate and these responses were also detectable in the offspring (fetuses and pups).
+14
+
+Nonclinical Pharmacology and Pharmacokinetics
+COMIRNATY was evaluated in nonclinical pharmacology studies using animal models of mice, rats and nonhuman primates (NHP). The data from these studies indicate: (1) strong antigen-binding IgG and high titer neutralizing antibodies in mice, rat and rhesus macaques; (2) Th1-biased CD4+ T-cell response and IFNy+, CD8+ T-cell response to BNT162b2 in both mouse and NHP studies; and (3) protection of rhesus macaques from an infectious SARS-Cov-2 challenge, with reduced detection of viral RNA in the BNT162b2-immunized animals as compared with the control-immunized macaques.
+Nonclinical pharmacokinetics (PK) evaluation included (1) biodistribution of COMIRNATY using (b) (4)
+expressing RNA as a surrogate reporter in (b) (4) mice and in rats, and
+(2) the biodistribution and metabolism of the two novel lipids (ALC-0315 and ALC-0159) contained in COMIRNATY in in vitro studies and in a PK study in rats following administration of (b) (4) expressing RNA encapsulated in LPs made with radiolabeled lipid markers. The study results indicate that following IM injection, the RNA encapsulated in LP mainly localizes to the site of injection and, to a lesser extent, distributes to the liver. The metabolism of ALC-0315 and ALC-0159 was evaluated in vitro using blood, liver microsomes, S9 fractions, and hepatocytes from mice, rats, monkeys and humans and in vivo by examining the plasma, urine, feces, and liver samples from the PK study in rats. Approximately 50% of ALC-0159 is excreted unchanged in feces, while metabolism appears to play a role in the elimination of ALC-0315.
+5. Clinical Pharmacology
+Pharmacodynamic data, comprised of humoral immune responses to COMIRNATY, were obtained in the clinical studies. The data demonstrated that COMIRNATY induces a humoral immune response against the SARS-CoV-2 spike protein. The exact immunologic mechanism that confers protection against SARS-CoV-2 is unknown.
+6. Clinical/Statistical
+a. Clinical Program
+Overview
+The Applicant included data from two clinical studies in the BLA. The clinical studies which will be discussed in this BRA are shown in Table 6.
+Table 6. Overview of Clinical Studies
+Study ID
+C4591001
+NCT ID
+04368728
+Phase
+1/2/3
+Countries
+Argentina, Brazil, Germany, South Africa, Turkey, U.S.
+Phase 1: 30 participants
+Enrollment
+Age
+Phase 2/3: 43.847 participants
+16 - 85 YOA
+Evaluate VE for prevention of
+Purpose
+COVID-19 (pivotal clinical endpoint study)
+BNT162-01
+04380701
+1/2
+Germany
+24
+18 - 85 YOA
+Evaluate safety and immunogenicity
+15
+
+Study ID
+Control
+C4591001
+Saline Placebo
+Phase 2/3: 2 groups, randomized
+Groups
+1:1 to receive COMIRNATY or
+Placebo IM
+Schedule
+DO, D21
+Total follow-up
+6 Months (follow-up ongoing)
+YOA: years of age; VE: vaccine efficacy; IM: intramuscular; D: day
+BNT162-01
+None
+1 group, randomized received
+COMIRNATY IM
+DO. D21
+6 Months (follow-up ongoing)
+Study C4591001
+Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blind Phase 1/2/3 study being conducted in the U.S., Argentina, Brazil, Germany, South Africa and Turkey. Initially the study was designed as a Phase 1/2 study in healthy adults in the U.S. for vaccine candidate and dosage selection, as well as evaluation of immunogenicity and preliminary efficacy. The protocol was expanded to include a Phase 2/3 portion of the study to evaluate clinical disease efficacy endpoint in individuals 12 years of age and older in the U.S. and additional sites outside of the U.S.
+The Phase 1 portion of the study was designed to identify a preferred vaccine candidate, vaccine dose, and administration schedule for further development based on the vaccine's safety, tolerability, and immunogenicity. To this end, two age groups were evaluated in separate cohorts, younger adults 18 through 55 years of age (N=45) and older adults 65 through 85 years of age (N=45). The study population included healthy men and women and excluded participants at high risk of SARS-CoV-2 infection or with serological evidence of prior or current SARS-CoV-2 infection. Two different vaccine candidates were evaluated, and younger participants received increasing dose levels (10, 20 and 30 mg) with progression to higher dose levels in a stepwise manner.
+Evaluation of increasing doses in the older age group (65 through 85 years) was based on recommendations from an internal review committee that reviewed safety and immunogenicity data derived from adults 18 through 55 years of age. For each vaccine candidate and dose, participants were randomized 4:1, such that 12 participants received the vaccine candidate and 3 participants received placebo. Review of the safety and immunogenicity from the Phase 1 portion of Study C4591001, in combination with data from Study BNT162-01, supported the final vaccine candidate, dose and dosing regimen (BNT162b2 administered at 30 Mg, given 3 weeks apart) to proceed to the Phase 2/3 portion of Study C4591001.
+In Phase 2/3, participants were enrolled with stratification by age (younger adults: 18 through 55 years of age; older adults: over 55 years of age) with the goal for the older age strata to consist of 40% of the entire study population. Adolescents were added to the protocol, based on review of safety data in younger adults enrolled in the ongoing study; thus, the age strata were revised as follows: 16 through 55 years of age, and 56 years of age and older. The study population for Phase 2/3 includes participants at higher risk for acquiring COVID-19 and at higher risk of severe COVID-19, such as participants working in the healthcare field, participants with autoimmune disease, and participants with chronic but stable medical conditions such as hypertension, asthma, diabetes, and infection with HIV, hepatitis B or hepatitis C. Participants were randomized
+1:1 to receive 2 doses of either COMIRNATY or placebo, 3 weeks apart. The Phase 2
+portion of the study evaluated reactogenicity and immunogenicity of the vaccine in 360
+16
+
+participants in the early stage of Phase 2/3, and these participants also contribute to the overall efficacy and safety data in the Phase 3 portion.
+The ongoing Phase 3 portion of the study is evaluating the safety and efficacy of
+COMIRNATY for the prevention of COVID-19 occurring at least 7 days after the second dose of vaccine. Efficacy is being assessed throughout a participant's blinded follow-up in the study through surveillance for potential cases of COVID-19. If, at any time, a participant develops acute respiratory illness, an illness visit occurs. Assessments for illness visits include a nasal (mid-turbinate) swab, which is tested at a central laboratory using a reverse transcription-polymerase chain reaction (RT-PCR) test (i.e., Cepheid;
+FDA- authorized under EUA), or other sufficiently validated nucleic acid amplification-based test (NAAT), to detect SARS-CoV-2. The central laboratory NAAT result is used for the case definition, unless it was not possible to test the sample at the central laboratory. In that case, the following NAAT results are acceptable: Cepheid Xpert Xpress SARS-CoV-2, Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001), and Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001).
+The study design included a planned interim analysis of the first primary efficacy endpoint (the efficacy of BNT162b2 against confirmed COVID-19 occurring from 7 days after Dose 2 in participants without evidence of SARS-CoV-2 infection before vaccination) at pre-specified numbers of COVID-19 cases (at least 62, 92, and 120 cases). All primary and secondary efficacy endpoints were analyzed in the final efficacy analysis after at least 164 COVID-19 cases were accrued. Participants are expected to participate for a maximum of approximately 26 months.
+Per protocol, since December 14, 2020, following issuance of the emergency use authorization for the Pfizer-BioNTech COVID-19 Vaccine, study participants 16 years of age and older have been progressively unblinded to their treatment assignment (when eligible per local recommendations) and offered BNT162b2 vaccination if they were randomized to placebo.
+The study was unblinded in stages as all ongoing participants were either individually unblinded (when eligible per local recommendations) or the subject had concluded their
+6-month post-Dose 2 study visit. Participants 16 years of age and older who participated in the Phase 2/3 study were given the opportunity to receive COMIRNATY no later than the 6-month timepoint after the second study vaccination. Participants who originally received placebo but received COMIRNATY were moved to a new visit schedule to receive both doses of COMIRNATY, 3 weeks apart.
+The primary safety and efficacy endpoints were:
+1. Primary safety endpoint (descriptive): Solicited local adverse reactions (injection site pain, redness, swelling), solicited systemic adverse events (AE) (fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain), unsolicited AEs, serious adverse events (SAEs).
+17
+
+2. First primary efficacy endpoint: COVID-19 incidence per 1000 person-years of follow-up based on laboratory-confirmed NAAT in participants with no serological or virological evidence (up to 7 days after Dose 2) of past SARS-CoV-2 infection.
+3. Second primary efficacy endpoint: COVID-19 incidence per 1000 person-years of follow-up based on laboratory-confirmed NAAT in participants with and without serological or virological evidence (up to 7 days after Dose 2) of past SARS-CoV-2 infection.
+The pertinent secondary endpoint was:
+1. Severe COVID-19 incidence per 1000 person-years of follow-up.
+Study C4591001 results
+The population in the protocol-specified, event-driven final primary efficacy analysis included all participants 12 years of age and older who had been enrolled from July 27, 2020 and followed for the development of COVID-19 through November 14, 2020. For participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, VE against confirmed COVID-19 occurring at least 7 days after Dose 2 was 95.0% (95% credible interval: 90.0, 97.9), which met the pre-specified success criterion. The case split was 8 COVID-19 cases in the BNT162b2 group compared to 162 COVID-19 cases in the placebo group. This protocol-specified, event-driven final primary efficacy analysis was the basis for issuance of the emergency use authorization for the Pfizer-BioNTech COVID-19 Vaccine on December 11, 2020.
+Therefore, the primary study objective of VE against COVID-19 was met as the point estimate was above 50% and the lower bound of the 95% Cl of the point estimate of VE was above 30%.
+The population for the updated vaccine efficacy analvsis per protocol included participants 16 years of age and older who had been enrolled from July 27, 2020, and followed for the development of COVID-19 during blinded placebo-controlled follow-up through March 13, 2021, representing up to ~6 months of follow-up after Dose 2. Overall, 60.8% of participants in the COMIRNATY group and 58.7% of participants in the placebo group had ≥4 months of follow-up time after Dose 2 in the blinded placebo-controlled follow-up period. The overall VE against COVID-19 in participants without evidence of prior SARS-CoV-2 infection was 91.1% (95% CI: 88.8 to 93.1). The overall VE against COVID-19 in participants with or without evidence of prior SARS-CoV-2 infection was 90.9% (95% CI: 88.5 to 92.8).
+Subgroup analvses of vaccine efficacy (although limited by small numbers of cases in some subgroups) did not suggest meaningful differences in efficacy across genders, ethnic groups, geographies, or for participants with obesity or medical comorbidities associated with high risk of severe COVID-19.
+The updated vaccine efficacy information is presented in Tables 7a and 7b.
+18
+
+Table 7a: First COVID-19 occurrence from 7 days after Dose 2 in participants without evidence of prior SARS-CoV-2 infection - Evaluable Efficacy (7 Days)
+Population During the Placebo-Controlled Follow-up Period *
+COMIRNATY
+Placebo
+Na=19,993
+Na=20,118
+Cases
+Cases
+n1b
+nib
+Surveillance Time
+Surveillance Time
+Vaccine Efficacy %
+Subgroup
+(n2d)
+(n2d)
+(95% CIe)
+77
+833
+91.1
+All participants
+6.092 (19,711)
+5.857 (19,741)
+(88.8, 93.1)
+70
+709
+90.5
+16 through 64 years
+4.859 (15,519)
+4.654 (15,515)
+(87.9, 92.7)
+7
+124
+94.5
+65 years and older
+1.233 (4192)
+1.202 (4226)
+(88.3, 97.8)
+* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis a.
+N = Number of participants in the specified group.
+b. n1 = Number of participants meeting the endpoint definition.
+C.
+Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d. e.
+n2 = Number of participants at risk for the endpoint.
+Two-sided confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adiusted to the surveillance time.
+Table 7b: First COVID-19 occurrence from 7 days after Dose 2 in participants with or without* evidence of prior SARS-CoV-2 infection - Evaluable Efficacy (7 Days)
+Population During the Placebo-Controlled Follow-up Period *
+Placebo
+COMIRNATY
+Na=21.210
+Na=21,047
+Cases
+Cases
+n1b
+Vaccine Efficacy
+nib
+Surveillance Time
+%
+Subgroup
+Surveillance Time (n2d)
+(n2d)
+(95% CI°
+81
+854
+90.9
+All participants
+6.340 (20.533)
+6.110 (20,595)
+(88.5. 92.8)
+74
+726
+90.2
+16 through 64 years
+5.073 (16,218)
+4.879 (16,269)
+(87.5, 92.4)
+7
+128
+94.7
+65 vears and older
+1.267 (4315)
+1.232 (4326)
+(88.7. 97.9)
+Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat; diarrhea; vomiting).
+* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+a.
+N = Number of participants in the specified group.
+n1 = Number of participants meeting the endpoint definition.
+C.
+Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d.
+е.
+n2 = Number of participants at risk for the endpoint.
+Two-sided confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time.
+19
+
+Efficacy Against Severe COVID-19
+Vaccine efficacy against severe COVID-19 for participants with or without prior SARS-
+CoV-2 infection is shown in Tables 8a and 8b. The VE against severe COVID-19 in participants with or without evidence of prior SARS-CoV-2 infection was 95.3% (95% CI:
+71.0 to 99.9) using the protocol definition of severe COVID-19 and 100.0% (95% CI: 87.6 to 100.0) based on the CDC definition of severe COVID-19.
+Table 8a: Vaccine Efficacy - First Severe COVID-19 Occurrence in Participants 16
+Years of Age and Older With or Without* Prior SARS-CoV-2 Infection Based on
+Protocol Definition From 7 Days After Dose 2 - Evaluable Efficacy (7 Days)
+Population During the Placebo-Controlled Follow-up
+COMIRNATY
+Placebo
+Cases
+Cases
+n1a
+n1a
+Surveillance Time
+Surveillance Time
+(n29)
+(n29)
+7 days after Dose 26
+21
+6.353 (20.540)
+6.237 (20,629)
+Vaccine Efficacy
+%
+(95% CId)
+95.3
+(70.9, 99.9)
+Table 8b: Vaccine Efficacy - First Severe COVID-19 Occurrence in Participants 16
+Years of Age and Older With or Without* Prior SARS-CoV-2 Infection Based on Centers for Disease Control and Prevention (CDC) Definition From 7 Days After Dose 2 - Evaluable Efficacy (7 Days) Population During the Placebo-Controlled
+Follow-up
+COMIRNATY
+Cases n1a
+Surveillance Timeb (n26)
+Placebo
+Cases n1a
+Vaccine Efficacy
+Surveillance Timeb
+%
+(n26)
+(95% CId)
+7 davs after Dose 2d
+31
+100
+6.345 (20,513)
+6.225 (20,593)
+(87.6, 100.0)
+Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat; diarrhea; vomiting).
+Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT (nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+† Severe illness from COVID-19 is defined in the protocol as confirmed COVID-19 and presence of at least 1 of the following:
+• Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 breaths per minute, heart rate ≥125 beats per minute, saturation of oxygen <93% on room air at sea level, or ratio of arterial oxygen partial pressure to fractional inspired oxygen <300 mm Hg);
+• Respiratory failure defined as needing highflow oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation (ECMO)];
+•
+•
+•
+•
+Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or requiring vasopressors);
+Significant acute renal, hepatic, or neurologic dysfunction;
+Admission to an Intensive Care Unit:
+Death.
+‡Severe illness from COVID-19 as defined by CDC is confirmed COVID-19 and presence of at least 1 of the following:
+Hospitalization;
+Admission to the Intensive Care Unit:
+Intubation or mechanical ventilation;
+Death.
+a. n1 = Number of participants meeting the endpoint definition.
+Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period
+C. n2 = Number of participants at risk for the endpoint.
+20
+
+d.
+Two-side confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time
+Study BNT162-01
+Study BNT162-01 is an ongoing Phase 1/2, open-label, dose-finding study to evaluate the safety and immunogenicity of several candidate vaccines, including BNT162b2 (1, 3, 10, 20, and 30 Mg), conducted in Germany in healthy and immunocompromised adults.
+Only safety and immunogenicity data in individuals 16 years of age and older, the population for the intended use and who received the final vaccine formulation (30 g BNT162b2) are used to support this application. The 30 g dosage of BNT162b2 was administered to 12 adults 18 to 55 years of age and 12 adults 56 to 85 years of age.
+The primary objective was to evaluate the safety of the BNT162 candidate vaccines.
+Secondary and exploratory objectives were to describe humoral and cellular immune responses following vaccination, measured at baseline and various time points after vaccination, specifically 7 days post Dose 2. Adverse event monitoring was the same as the safety monitoring in study C4591001.
+The study started April 23, 2020. The BLA contains safety data (reactogenicity and AE analyses) up to 1 month after Dose 2 (data cutoff date: October 23, 2020), neutralizing antibody data up to ~2 months after Dose 2 (data cutoff date: October 23, 2020), and T-cell data up to ~6 months after Dose 2 (data cutoff date: March 2, 2021).
+Study BNT162-01 Results
+Disposition of 30 ug BNT162b2 group:
+- Safety: Of a total of 24 participants, 12 participants 18 to 55 years of age and 12 participants 56 to 85 years of age completed the visit at 1- month post-Dose 2.
+- Immunogenicity: Of the 12 participants, serum neutralizing antibody and T-cell responses were available for 10 and 12 participants, respectively.
+Safety: The safety profiles for adult participants 18-55 and 56-85 years of age receiving
+30 Mg BNT162b2 in this study were similar to age-matched participants in study
+C4591001.
+Immunogenicity: Dose-dependent increases were noted 42 days after Dose 2, compared to SARS-CoV-2 neutralizing GMT at baseline (pre-Dose 1), and most pronounced at the 30 ug dose level. The Th1 polarization of the T-helper response was indicated by IN and IL-2 production, and only minimal IL-4 production upon antigen-specific (SARS-CoV-2 S protein peptide pools) re-stimulation.
+Review of the safety and immunogenicity from Phase 1 part of Study C4591001, in combination with data from Study BNT162-01, supported selection of the final vaccine candidate and dose level (BNT162b2 at 30 g, given as two doses 3 weeks apart) to proceed into Phase 2/3 part of Study C4591001.
+Lot Consistency
+Consistency of process performance qualification (PPQ) batches manufactured at both Pfizer Purs and Pfizer Kalamazoo was demonstrated by verifing process parameters and in-process testing results as well as DP release testing. Data obtained from the analvtical comparability assessments on the PPQ batches manufactured at both sites
+21
+
+provide evidence of reproducible and consistent manufacture of COMIRNATY D of acceptable product quality across all supply nodes.
+b. Bioresearch Monitoring (BIMO) - Clinical/Statistical/Pharmacovigilance
+BIMO inspection assignments were issued for a total of nine (9) clinical study sites that participated in the conduct of study Protocol C4591001. Three (3) of these inspection assignments focused on clinical study sites that enrolled the pediatric population and six
+(6) of the study sites enrolled the adult population. The inspections did not reveal findings that impact the BLA.
+c. Pediatrics
+The Applicant's Pediatric Plan was presented to the FDA Pediatric Review Committee (PeRC) on August 3, 2021. The committee agreed with the Applicant's request for a deferral for studies in participants 0 to <16 years of age because the biological product is ready for approval for use in individuals 16 years of age and older before pediatric studies in participants 0 to <16 years of age are completed (Section 505B(a)(3)(A)(i) of PREA).
+The PREA-required studies specified in the approval letter and agreed upon with the Applicant are as follows:
+1. Study C4591001 to evaluate the safety and effectiveness of COMIRNATY in children 12 years through 15 years of age
+2. Study C4591007 to evaluate the safety and effectiveness of COMIRNATY in children 6 months to <12 ears of age
+3. Study C4591023 to evaluate the safety and effectiveness of COMIRNATY in infants <6 months of age
+7. Safety and Pharmacovigilance
+The most commonly reported (≥10%) solicited adverse reactions in COMIRNATY recipients 16 through 55 years of age following any dose were pain at the injection site (88.6%), fatigue (70.1%), headache (64.9%), muscle pain (45.5%), chills (41.5%), joint pain (27.5%), fever (17.8%), and injection site swelling (10.6%). The most commonly reported (≥10%) solicited adverse reactions in COMIRNATY recipients 56 years of age and older following any dose were pain at the injection site (78.2%), fatigue (56.9%), headache, (45.9%), muscle pain (32.5%), chills (24.8%), joint pain (21.5%), injection site swelling (11.8%), fever (11.5%), and injection site redness (10.4%).
+Among participants 16 through 55 years of age who had received at least 1 dose of
+COMIRNATY (N=12,995) or placebo (N=13,026), serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 103 (0.8%)
+COMIRNATY recipients and 117 (0.9%) placebo recipients. In a similar analysis in participants 56 years of age and older (COMIRNATY=8,931, placebo=8,895), serious adverse events were reported by 165 (1.8%) COMIRNATY recipients and 151 (1.7%) placebo recipients who received at least 1 dose of COMIRNATY or placebo, respectively. In these analyses, 58.2% of study participants had at least 4 months of
+22
+
+follow-up after Dose 2. There were no notable patterns between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY.
+From Dose 1 through the March 13, 2021 data cutoff date, there were a total of 38 deaths, 21 in the COMIRNATY group and 17 in the placebo group. None of the deaths were considered related to vaccination.
+Since the issuance of the EUA (December 11, 2020), post-authorization safety data has been reported from individuals 16 years of age and older following any dose of
+COMIRNATY. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Below are presented adverse reactions categorized as important identified risks in the pharmacovigilance plan that have occurred during the conduct of the clinical trial and have been reported following the issuance of the EUA.
+Myocarditis/Pericarditis
+During the time from Dose 1 to unblinding in Study C4591001, one report of pericarditis was identified in the COMIRNATY group, occurring in a male participant 255 years of age, with no medical history, 28 days after Dose 2; the event was assessed by the investigator as not related to the study intervention and was ongoing at the time of the data cutoff. One report of myocarditis was identified in a male participant <55 years of age in the placebo group, occurring 5 days after his second placebo dose.
+Post-EUA safety surveillance reports received by FDA and CDC identified serious risks for myocarditis and pericarditis following administration of COMIRNATY. Reporting rates for medical chart-confirmed myocarditis/pericarditis in VAERS have been higher among males under 40 years of age than among females and older males and have been highest in males 12-17 years of age (65 cases per million doses administered as per CDC communication on August 20, 2021), particularly following the second dose, and onset of symptoms within 7 das following vaccination. Although some cases of vaccine-associated myocarditis/pericarditis required intensive care support, available data from short-term follow up suggest that most individuals have had resolution of symptoms with conservative management. Information is not yet available about potential long-term sequelae and outcomes in affected individuals. A mechanism of action by which the vaccine could cause myocarditis and pericarditis has not been established.
+These safety findings of increased risk for myocarditis/pericarditis led to warning in section 5.2 Warning and Precautions of the PI.
+Myocarditis and pericarditis are considered important identified risks in the pharmacovigilance plan included in the BLA. Of note, the Applicant will be required to conduct postmarketing requirement (PMR) safety studies under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to assess the known serious risks of mvocarditis and pericarditis as well as an unexpected serious risk for subclinical myocarditis (see Section 11c Recommendation for Postmarketing Activities, for study details).
+23
+
+Moreover, since vaccine-associated myocarditis/pericarditis is the most clinically significant identified risk, FDA undertook a quantitative benefit-risk assessment to model the excess risk of myocarditis/pericarditis vs. the expected benefits of preventing COVID-19 and associated hospitalizations, ICU admissions, and deaths. For estimation of risk, the model took a conservative approach by relying on non-chart-confirmed cases from a US healthcare claims database (OPTUM) that could provide a control group and greater confidence in denominators for vaccine exposures. Thus, the estimates of excess risk in this model are higher than the rates estimated from reports to VAERS (an uncontrolled passive surveillance system), with an estimated excess risk approaching 200 cases per million vaccinated males 16-17 years of age (the age/sex-stratified group with the highest risk). For estimation of benefit, the model output was highly dependent on the assumed COVID-19 incidence, as well as assumptions about vaccine efficacy and duration of protection. The assessment therefore considered a range of scenarios including but not limited to a "most likely" scenario associated with recent Delta variant surge and diminished vaccine effectiveness (70% overall, 80% against COVID-19 hospitalization) compared to that observed in the clinical trial. The "worst-case" scenario with low COVID-19 incidence reflecting the July 2021 nadir and the same somewhat diminished vaccine effectiveness as in the "most likely" scenario.
+For males and females 18 years of age and older and for females 16-17 years of age, even before accounting for morbidity prevented from non-hospitalized COVID-19, the model predicts that the benefits of prevented COVID-19 hospitalizations, ICU admissions and deaths would clearly outweigh the predicted excess risk of vaccine-associated myocarditis/pericarditis under all conditions examined. For males 16-17 years of age, the model predicts that the benefits of prevented COVID-19 hospitalizations, ICU admissions and deaths would clearly outweigh the predicted excess risk of vaccine-associated myocarditis/pericarditis under the "most likely" scenario, but that predicted excess cases of vaccine-associated myocarditis/pericarditis would exceed COVID-19 hospitalizations and deaths under the "worst case" scenario. However, this predicted numerical imbalance does not account for the greater severity and length of hospitalization, on average, for COVID-19 compared with vaccine-associated myocarditis/pericarditis.
+Additionally, the "worst case" scenario model predicts prevention of >13,000 cases of non-hospitalized COVID-19 per million vaccinated males 16-17 years of age, which would include prevention of clinically significant morbidity and/or long-term sequelae associated with some of these cases. Finally, the model does not account for indirect societal/public health benefits of vaccination. Considering these additional factors, FDA concluded that even under the "worst case" scenario the benefits of vaccination sufficiently outweigh risks to support approval of the vaccine in males 16-17 years of age.
+Mitigation of the observed risks and associated uncertainties will be accomplished through labeling (including warning statements) and through continued safety surveillance and postmarketing studies to further assess and understand these risks, including an immunogenicity and safety study of lower dose levels of COMIRNATY in individuals 12 through <30 years of age. The Applicant will be required to conduct postmarketing requirement (PMR) safety studies under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to assess the known serious risks of myocarditis and pericarditis and an unexpected serious risk for subclinical myocarditis (see section 11c for study details).
+24
+
+Anaphylaxis
+The risk of anaphylaxis was recognized early in the post-authorization time period and it is included as an important identified risk in the PVP. The estimated crude reporting rate for anaphylaxis is 6.0 cases per million doses. Therefore, the incidence of anaphylaxis after receipt of COMIRNATY is comparable with those reported after receipt of other vaccines.
+There were no reports of anaphylaxis associated with COMIRNATY in clinical study participants through the cutoff date of March 13, 2021.
+A contraindication for individuals with known history of a severe allergic reaction (e.g., anaphylaxis) to any component of COMIRNATY is included in section 4 of the PI.
+Additionally, a warning statement is included in section 5.1 of the PI instructing that
+"appropriate medical treatment used to manage immediate allergic reactions must be immediately available in the event an acute anaphylactic reaction occurs following administration of COMIRNATY"
+Pharmacovigilance Plan (PVP)
+The Applicant's proposed pharmacovigilance plan (version 1.1) includes the following important risks and missing information:
+• Important identified risks: Anaphylaxis; Myocarditis and Pericarditis
+• Important potential risk: Vaccine-Associated Enhanced Disease (VAED), including
+Vaccine-Associated Enhanced Respiratory Disease (VAERD)
+• Missing information: Use in pregnancy and lactation; Vaccine effectiveness; Use in pediatric individuals <12 years of age
+In addition to routine pharmacovigilance, the Applicant will conduct the postmarketing studies listed in Section 11c Recommendation for Postmarketing Activities.
+Adverse event reporting under 21 CFR 600.80 and the postmarketing studies in Section 11c are adequate to monitor the postmarketing safety for COMIRNATY.
+8. Labeling
+The proprietary name, COMIRNATY, was reviewed by CBER's Advertising and
+Promotional Labeling Branch (APLB) on July 2, 2021, and found to be acceptable. CBER communicated this decision to the Applicant on July 6, 2021. The ALB found the PI and package/container labels to be acceptable from a promotional and comprehension perspective. The Review Committee negotiated revisions to the PI, including modifying the proposed proper name from "COVID-19 mRNA vaccine (nucleoside-modified)" to
+"COVID-19 Vaccine, mRNA" and including a warning for an increased risk of myocarditis and pericarditis following administration of COMIRNATY. All labeling issues regarding the PI and the carton and container labels were acceptably resolved after exchange of information and discussions with the Applicant.
+25
+
+9. Advisory Committee Meetings
+Vaccines and Related Biological Products Committee (VRBPAC) meetings were convened on October 22, 2020 to discuss, in general, development for EUA and licensure of vaccines to prevent COVID-19 and on December 10, 2020, to discuss BioNTech Manufacturing GmbH/Pfizer's EU request for the Pfizer-BioNTech COVID-19 Vaccine.
+On October 22, 2020, the VRBPAC was presented with the following items for
+discussion (no vote):
+1. Please discuss FDA's approach to safety and effectiveness data as outlined in the respective guidance documents.
+2. Please discuss considerations for continuation of blinded Phase 3 clinical trials if an EUA has been issued for an investigational COVID-19 vaccine.
+3. Please discuss studies following licensure and/or issuance of an EUA for COVID-19 vaccines to
+a. Further evaluate safety, effectiveness and immune markers of protection
+b. Evaluate the safety and effectiveness in specific populations
+In general, the VRBPAC endorsed FDA's approach and recommendations on the safety and effectiveness data necessary to support a BLA and EUA for COVID-19 vaccines as outlined in the respective guidance documents. VRBPAC members recommended for the median follow-up of 2 month to be the minimum follow-up period and suggested longer follow-up periods to evaluate, both safety and efficacy, if feasible. The VRBPAC endorsed the importance of additional studies to further evaluate safety and effectiveness of the vaccine after EUA issuance and/or licensure and underscored the need to evaluate the safety and effectiveness of COVID-19 vaccines in specific populations.
+On December 10, 2020, VRBPAC discussed Pfizer- BioNTech Manufacturing GmbH's EUA request for their vaccine to prevent COVID-19 in individuals 16 years of age and older. The committee discussed the safety and efficacy data derived from the clinical disease endpoint efficacy study C4591001
+The VRPBAC voted on one question:
+1. Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its risks for use in individuals 16 years of age and older?
+The results of the vote were as follows:
+Yes = 17
+No = 4
+Abstain = 1
+The VRBPAC was presented with the following items for discussion (no vote):
+1. Pfizer has proposed a plan for continuation of blinded, placebo-controlled follow-up in ongoing trials if the vaccine were made available under EUA. Please discuss
+26
+
+Pfizer's plan, including how loss of blinded, placebo-controlled follow-up in ongoing trials should be addressed.
+2. Please discuss any gaps in plans described today and in the briefing documents for further evaluation of vaccine safety and effectiveness in populations wh receive the Pfizer-BioNTech COVID-19 Vaccine under an EUA.
+The committee discussed potential implications of loss of blinded, placebo-controlled follow-up in ongoing trials including how this may impact availability of safety data to support a BLA. The VRBPAC commented on the need to further assess vaccine effect on asymptomatic infection and viral shedding, and further evaluation of safety and effectiveness in subpopulations such as HIV-infected individuals, individuals with prior exposure to SARS-CoV-2.
+FDA did not refer this application to the VRBPAC because our review of the information submitted to this BLA did not raise concerns or controversial issues that would have benefited from an advisory committee discussion.
+10. Other Relevant Regulatory Issues
+a. Identification of BLA Lots
+Upon CBER's request inquiring about what BLA-compliant EUA-labeled lots may be available for use upon licensure of COMIRNATY, the Applicant submitted information listing which lots they considered to be manufactured according to the BLA. To address the issue of these lots not bearing the vial label associated with BLA approval, CBER worked with the Applicant to develop a Dear HCP letter to be included with lots considered by CBER to be BLA-compliant. This letter explained that some lots labeled for EUA use were also considered BLA-compliant and refers HCP to a website for additional information. CBER requested and the Applicant agreed that only EUA-labeled lots that had also undergone CBER lot release according to the BLA would be considered BLA-compliant and listed at the website included in the Dear HCP letter.
+b. Exception to the 21 CFR 610.15(a) Requirement for a Preservative Under 21 CFR 610.15(a), a vaccine product in multiple-dose containers must (absent certain exceptions) contain a preservative. The Applicant submitted a request for exception to this requirement and provided a justification for the multi-dose presentation of COMIRNATY not containing a preservative. CBER considered the Applicant's request for an exception to the 21 CFR 610.15(a) for COMIRNATY as a multiple dose preservative-free presentation acceptable.
+11. Recommendations and Benefit/Risk Assessment
+a. Recommended Regulatory Action
+Based on the review of the clinical, pre-clinical, and product-related data submitted in the original BLA, the Review Committee recommends approval of COMIRNATY for the labeled indication and usage.
+27
+
+b. Benefit/Risk Assessment
+Considering the data submitted to support the safety and effectiveness of
+COMIRNATY that have been presented and discussed in this document, as well as the seriousness of COVID-19, the Review Committee is in agreement that the risk/benefit balance for COMIRNATY is favorable and supports approval for use in individuals 16 years of age and older.
+c. Recommendation for Postmarketing Activities BioNTech Manufacturing GmbH has committed to conduct the following postmarketing activities, which will be included in the approval letter.
+POSTMARKETING REQUIREMENTS UNDER SECTION 505(0)
+1. Study C4591009, entitled "A Non-Interventional Post-Approval Safety Study of the Pfizer-BioNTech COVID-19 mRNA Vaccine in the United States," to evaluate the occurrence of myocarditis and pericarditis following administration of COMIRNATY
+Final Protocol Submission: August 31, 2021
+Monitoring Report Submission: October 31, 2022
+Interim Report Submission: October 31, 2023
+Study Completion: June 30, 2025
+Final Report Submission: October 31, 2025
+2. Study C4591021, entitled "Post Conditional Approval Active Surveillance Study
+Among Individuals in Europe Receiving the Pfizer-BioNTech Coronavirus Disease
+2019 (COVID-19) Vaccine," to evaluate the occurrence of myocarditis and pericarditis following administration of COMIRNATY
+Final Protocol Submission: August 11, 2021
+Progress Report Submission: September 30, 2021
+Interim Report 1 Submission: March 31, 2022
+Interim Report 2 Submission: September 30, 2022
+Interim Report 3 Submission: March 31, 2023
+Interim Report 4 Submission: September 30, 2023
+Interim Report 5 Submission: March 31, 2024
+Study Completion: March 31, 2024
+Final Report Submission: September 30, 2024
+3. Study C4591021 substudy to describe the natural history of myocarditis and pericarditis following administration of COMIRNATY
+Final Protocol Submission: January 31, 2022
+Study Completion: March 31, 2024
+Final Report Submission: September 30, 2024
+4. Study C4591036, a prospective cohort study with at least 5 years of follow-up for potential long-term sequelae of myocarditis after vaccination (in collaboration with Pediatric Heart Network)
+28
+
+Final Protocol Submission: November 30, 2021
+Study Completion: December 31, 2026
+Final Report Submission: May 31, 2027
+5. Study C4591007 substudy to prospectively assess the incidence of subclinical myocarditis following administration of the second dose of COMIRNATY in a subset of participants 5 through 15 years of age
+Final Protocol Submission: September 30, 2021
+Study Completion: November 30, 2023
+Final Report Submission: May 31, 2024
+6. Study C4591031 substudy to prospectively assess the incidence of subclinical myocarditis following administration of a third dose of COMIRNATY in a subset of participants 16 to 30 years of age
+Final Protocol Submission: November 30, 2021
+Study Completion: June 30, 2022
+Final Report Submission: December 31, 2022
+POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
+UNDER SECTION 506B
+7. Study C4591022, entitled "Pfizer-BioNTech COVID-19 Vaccine Exposure during
+Pregnancy: A Non-Interventional Post-Approval Safety Study of Pregnancy and Infant Outcomes in the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry"
+Final Protocol Submission: July 1, 2021
+Study Completion: June 1, 2025
+Final Report Submission: December 1, 2025
+8. Study C4591007 substudy to evaluate the immunogenicity and safety of lower dose levels of COMIRNATY in individuals 12 through <30 years of age
+Final Protocol Submission: September 30, 2021
+Study Completion: November 30, 2023
+Final Report Submission: May 31, 2024
+9. Study C4591012, entitled "Post-emergency Use Authorization Active Safety
+Surveillance Study Among Individuals in the Veteran's Affairs Health System Receiving Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) Vaccine"
+Final Protocol Submission: January 29, 2021
+Study Completion: June 30, 2023
+Final Report Submission: December 31, 2023
+10. Study C4591014, entitled "Pfizer-BioNTech COVID-19 BNT1622 Vaccine
+Effectiveness Study - Kaiser Permanente Southern California"
+29
+
+Final Protocol Submission: March 22, 2021
+Study Completion: December 31, 2022
+Final Report Submission: June 30, 2023
+PEDIATRIC REQUIREMENTS
+11. Deferred pediatric study C4591001 to evaluate the safety and effectiveness of
+COMIRNATY in children 12 years through 15 years of age
+Final Protocol Submission: October 7, 2020
+Study Completion: May 31, 2023
+Final Report Submission: October 31, 2023
+12. Deferred pediatric study C4591007 to evaluate the safety and effectiveness of
+COMIRNATY in children 6 months to <12 years of age
+Final Protocol Submission: February 8, 2021
+Study Completion: November 30, 2023
+Final Report Submission: May 31, 2024
+13. Deferred pediatric study C4591023 to evaluate the safety and effectiveness of
+COMIRNATY in infants <6 months of age
+Final Protocol Submission: January 31, 2022
+Study Completion: July 31, 2024
+Final Report Submission: October 31, 2024
+30
+

docs/Package Insert – COMIRNATY (gray cap).txt

@@ -0,0 +1,1549 @@
+Individuals using assistive technology may not be able to fully access the information contained in this file. For assistance, please call 800-835-4709 or 240-402-8010, extension 1. CBER
+Consumer Affairs Branch or send an e-mail to: ocod@fda.hhs.gov and include 508 Accommodation and the title of the document in the subject line of your e-mail.
+
+HIGHLIGHTS OF PRESCRIBING INFORMATION
+These highlights do not include all the information needed to use
+COMIRNATY safely and effectively. See full prescribing information for COMIRNATY.
+COMIRNATY® (COVID-19 Vaccine, mRNA) suspension for injection, for intramuscular use
+Initial U.S. Approval: 2021
+-RECENT MAJOR CHANGES
+Indications and Usage (1)
+Dosage and Administration (2)
+Dosage and Administration, Preparation for Administration (2.1)
+Dosage and Administration, Administration Information (2.2)
+7/2022
+8/2022
+8/2022
+8/2022
+• INDICATIONS AND USAGE
+COMIRNATY is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older. (1)
+•
+-DOSAGE AND ADMINISTRATION
+COMIRNATY supplied in single dose vials or multiple dose vials with gray caps and labels with gray borders MUST NOT be diluted prior to use. (2.1)
+For intramuscular injection only. (2.2)
+COMIRNATY is administered intramuscularly as a series of 2 doses
+(0.3 mL each) 3 weeks apart. (2.3)
+• DOSAGE FORMS AND STRENGTHS.
+Suspension for injection. A single dose is 0.3 mL. (3)
+- CONTRAINDICATIONS -.-
+Known history of a severe allergic reaction (e.g., anaphylaxis) to any component of COMIRNATY. (4)
+FULL PRESCRIBING INFORMATION: CONTENTS*
+INDICATIONS AND USAGE
+2
+DOSAGE AND ADMINISTRATION
+2.1
+Preparation for Administration
+2.2
+Administration Information
+2.3
+Vaccination Schedule
+3
+DOSAGE FORMS AND STRENGTHS
+CONTRAINDICATIONS
+5
+WARNINGS AND PRECAUTIONS
+5.1
+Management of Acute Allergic Reactions
+5.2
+Mvocarditis and Pericarditis
+5.3
+Syncope
+5.4
+Altered Immunocompetence
+5.5
+Limitation of Effectiveness
+6
+ADVERSE REACTIONS
+6.1
+Clinical Trials Experience
+6.2
+Postmarketing Experience
+USE IN SPECIFIC POPULATIONS
+8.1
+Pregnancy
+- WARNINGS AND PRECAUTIONS
+Postmarketing data demonstrate increased risks of myocarditis and pericarditis, particularly within 7 days following the second dose. (5.2)
+Syncope (fainting) may occur in association with administration of injectable vaccines, including COMIRNATY. Procedures should be in place to avoid injury from fainting. (5.4)
+- ADVERSE REACTIONS
+In clinical studies of participants 16 through 55 years of age, the most commonly reported adverse reactions (≥10%) were pain at the injection site (88.6%), fatigue (70.1%), headache (64.9%), muscle pain (45.5%), chills (41.5%), joint pain (27.5%), fever (17.8%), and injection site swelling (10.6%). (6.1)
+In clinical studies of participants 56 years of age and older, the most commonly reported adverse reactions (≥10%) were pain at the injection site (78.2%), fatigue (56.9%), headache, (45.9%), muscle pain (32.5%). chills (24.8%), joint pain (21.5%), injection site swelling (11.8%), fever (11.5%), and injection site redness (10.4%). (6.1)
+In clinical studies of adolescents 12 through 15 years of age, the most commonly reported adverse reactions (≥8%) were pain at the injection site (90.5%), fatigue (77.5%), headache (75.5%), chills (49.2%), muscle pain (42.2%). fever (24.3%), joint pain (20.2%), injection site swelling (9.2%), and injection site redness (8.6%). (6. 1)
+To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
+1-800-438-1985 or VAERS at 1-800-822-7967 or http://vaers.hhs.gov.
+See 17 for PATIENT COUNSELING INFORMATION.
+Revised: 4/2023
+8.2
+Lactation
+8.4
+Pediatric Use
+8.5
+Geriatric Use
+11 DESCRIPTION
+12
+CLINICAL PHARMACOLOGY
+12.1 Mechanism of Action
+13 NONCLINICAL TOXICOLOGY
+13.1
+Carcinogenesis, Mutagenesis, Impairment of Fertility
+14 CLINICAL STUDIES
+14.1 Efficacy in Participants 16 Years of Age and Older
+14.2 Efficacy in Adolescents 12 Through 15 Years of Age
+14.3
+Immunogenicity in Adolescents 12 Through 15 Years of Age
+16 HOW SUPPLIED/STORAGE AND HANDLING
+17 PATIENT COUNSELING INFORMATION
+* Sections or subsections omitted from the full prescribing information are not listed
+
+FULL PRESCRIBING INFORMATION
+1 INDICATIONS AND USAGE
+COMIRNATY is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19)
+caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older.
+2 DOSAGE AND ADMINISTRATION
+For intramuscular injection only.
+The storage, preparation, and administration information in this Prescribing Information apply to COMIRNATY supplied in:
+• single dose vials with gray caps and labels with gray borders, and
+• multiple dose vials with gray caps and labels with gray borders.
+COMIRNATY supplied in vials with gray caps and labels with gray borders MUST NOT be diluted prior to use.
+2.1 Preparation for Administration
+• COMIRNATY vials with gray caps and labels with gray borders contain a frozen suspension without preservative. Each vial must be thawed prior to administration. DO NOT DILUTE prior to use.
+• Vials may be thawed in the refrigerator 2°C to 8°C (35°F to 46°F)1 or at room temperature [up to 25°C (77°F)].
+• Refer to thawing and preparation instructions in the panels below.
+Preparation Instructions
+COMIRNATY Vial with Gray Cap and Label with Gray Border -
+Vial Verification
+Gray cap
+DO NOT DILUTE
+• Verify that the vial of COMIRNATY has a gray cap and a label with a gray border.
+Gray cap and label with gray border.
+2
+
+Preparation Instructions
+Thawing Prior to Use
+Store in the refrigerator for up to 10 weeks prior to use.
+• Thaw vial(s) of COMIRNATY before use either by:
+• Allowing vial(s) to thaw in the refrigerator [2°C tc
+8°C (35°F to 46°F)].
+A carton of 10 single dose vials may take up to 2 hours to thaw.
+A carton of 10 multiple dose vials may take up to 6 hours to thaw.
+Allowing vials) to sit at room temperature [up to
+25°C (77°F)] for 30 minutes.
+• Thawed vials can be stored in the refrigerator [2°C to
+8°C (35°F to 46°F)] for up to 10 weeks prior to use.
+• Thawed vials may be stored at room temperature [up to
+25°C (77°F)1 for up to 12 hours prior to use.
+• Before use, mix by inverting vaccine vial gently 10 times.
+• Do not shake.
+• Prior to mixing, the thawed vaccine may contain white to off-white opaque amorphous particles.
+• After mixing, the vaccine should appear as a white to off-white suspension with no visible particles.
+• Do not use if liquid is discolored or if particles are observed after mixing.
+Gently × 10
+Preparation of Individual 0.3 mL Doses
+10.2
+0.3
+E0.4
+Withdraw 0.3 mL dose of vaccine.
+Single Dose Vial
+• Withdraw a single 0.3 mL dose of COMIRNATY vaccine.
+• Administer immediately.
+• Discard vial and any excess volume.
+Multiple Dose Vial
+• Multiple dose vials contain 6 doses of 0.3 mL each.
+• Withdraw 0.3 mL of COMIRNATY preferentially using low dead-volume syringes and/or needles. If standard syringes and needles are used, there may not be sufficient volume to extract 6 doses from a single vial.
+• Administer immediately.
+• If the amount of vaccine remaining in a multiple dose vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume.
+3
+
+Preparation Instructions
+Multiple Dose Vial - Record Date and Time of First Puncture
+DO NOT DILUT
+Record the date and time of first vial puncture on the
+COMIRNATY multiple dose vial label.
+• Store between 2°C to 25°C (35°F to 77°F).
+• Discard any unused vaccine 12 hours after first puncture.
+Record the date and time of first puncture.
+Use within 12 hours after first puncture.
+2.2
+Administration Information
+Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The vaccine will be a white to off-white suspension.
+Do not administer if vaccine is discolored or contains particulate matter.
+After withdrawing a single 0.3 mL dose of COMIRNATY, administer immediately.
+2.3
+Vaccination Schedule
+COMIRNATY is administered intramuscularly as a series of 2 doses (0.3 mL each) 3 weeks apart.
+There are no data available on the interchangeability of COMIRNATY with COVID-19 vaccines from other manufacturers to complete the vaccination series. Individuals who have received 1 dose of COMIRNATY should receive a second dose of COMIRNATY to complete the vaccination series.
+3 DOSAGE FORMS AND STRENGTHS
+COMIRNATY is a suspension for injection. Each dose of COMIRNATY supplied in vials with gray caps and labels with gray borders is 0.3 mL.
+4 CONTRAINDICATIONS
+Do not administer COMIRNATY to individuals with known history of a severe allergic reaction (e.g., anaphylaxis) to any component of COMIRNATY [see Description (11)].
+4
+
+5 WARNINGS AND PRECAUTIONS
+5.1
+Management of Acute Allergic Reactions
+Appropriate medical treatment used to manage immediate allergic reactions must be immediately available in the event an acute anaphylactic reaction occurs following administration of COMIRNATY.
+5.2
+Myocarditis and Pericarditis
+Postmarketing data demonstrate increased risks of myocarditis and pericarditis, particularly within 7 days following the second dose. The observed risk is higher among males under 40 years of age than among females and older males. The observed risk is highest in males 12 through 17 years of age. Although some cases required intensive care support, available data from short-term follow-up suggest that most individuals have had resolution of symptoms with conservative management. Information is not yet available about potential long-term sequelae. The CDC has published considerations related to myocarditis and pericarditis after vaccination, including for vaccination of individuals with a history of myocarditis or pericarditis (https://www.cdc.gov/vaccines/covid-19/clinical-considerations/myocarditis.html).
+5.3
+Syncope
+Syncope (fainting) may occur in association with administration of injectable vaccines, including
+COMIRNATY. Procedures should be in place to avoid injury from fainting.
+5.4
+Altered Immunocompetence
+Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to COMIRNATY.
+5.5
+Limitation of Effectiveness
+COMIRNATY may not protect all vaccine recipients.
+6 ADVERSE REACTIONS
+In clinical studies, the most commonly reported (≥10%) adverse reactions in participants 16 through 55 years of age following any dose were pain at the injection site (88.6%), fatigue (70. 1%), headache (64.9%), muscle pain (45.5%), chills (41.5%), joint pain (27.5%), fever (17.8%), and injection site swelling (10.6%).
+In clinical studies, the most commonly reported (≥10%) adverse reactions in participants 56 years of age and older following any dose were pain at the injection site (78.2%), fatigue (56.9%), headache, (45.9%), muscle pain (32.5%), chills (24.8%), joint pain (21.5%), injection site swelling (11.8%), fever (11.5%), and injection site redness (10.4%).
+In a clinical study, the most commonly reported (≥8%) adverse reactions in adolescents 12 through 15 years of age following any dose were pain at the injection site (90.5%), fatigue (77.5%), headache (75.5%), chills (49.2%), muscle pain (42.2%), fever (24.3%), joint pain (20.2%), injection site swelling (9.2%), and injection site redness (8.6%).
+
+6.1 Clinical Trials Experience
+Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.
+The safety of COMIRNATY was evaluated in participants 12 years of age and older in 2 clinical studies conducted in Germany (Study 1), United States, Argentina, Brazil, Turkey, South Africa, and Germany (Study 2). Study BNT162-01 (Study 1) was a Phase 1/2, 2-part, dose-escalation trial that enrolled 60 participants, 18 through 55 years of age and 36 participants, 56 through 85 years of age. Study C4591001 (Study 2) is a Phase 1/2/3 multicenter, multinational, randomized, saline placebo-controlled, double-blinded (Phase 2/3), dose-finding, vaccine candidate-selection and efficacy study that has enrolled approximately 46,000 participants 12 years of age or older. Of these, approximately 44,047 participants (22,026 COMIRNATY; 22,021 placebo) in Phase 2/3 are 16 years of age or older (including 378 and 376 participants 16 through 17 years of age in the COMIRNATY and placebo groups, respectively) and
+2,260 adolescents are 12 through 15 years of age (1,131 and 1,129 in the COMIRNATY and placebo groups, respectively). Upon issuance of the Emergency Use Authorization for COMIRNATY, participants were unblinded to offer placebo participants COMIRNATY. Participants were unblinded in a phased manner over a period of months to offer placebo participants COMIRNATY. Study 2 also included 200 participants with confirmed stable human immunodeficiency virus (HIV) infection; HIV-positive participants are included in safety population disposition but are summarized separately in safety analyses. Confirmed stable HIV infection was defined as documented viral load <50 copies/mL and CD4 count >200 cells/mm? within 6 months before enrollment, and on stable antiretroviral therapy for at least 6 months.
+In Study 2, all participants 12 through 15 years of age, and 16 years and older in the reactogenicity subset were monitored for solicited local and systemic reactions and use of antipyretic medication after each vaccination in an electronic diary. Participants are being monitored for unsolicited adverse events, including serious adverse events, throughout the study [from Dose 1 through 1 month (all unsolicited adverse events) or 6 months (serious adverse events) after the last vaccination]. Tables 1 through 6 present the frequency and severity of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo.
+Participants 16 Years of Age and Older
+At the time of the analysis of the ongoing Study 2 with a data cutoff of March 13, 2021, there were 25,651 (58.2%) participants (13,031 COMIRNATY and 12,620 placebo) 16 years of age and older followed for
+>4 months after the second dose.
+Demographic characteristics in Study 2 were generally similar with regard to age, gender, race, and ethnicity among participants who received COMIRNATY and those who received placebo. Overall, among the total participants who received either COMIRNATY or placebo, 50.9% were male, 49.1% were female, 79.3% were 16 through 64 years of age, 20.7% were 65 years of age and older, 82.0% were White, 9.6% were Black or African American, 25.9% were Hispanic/Latino, 4.3% were Asian, and 1.0% were American Indian or Alaska Native.
+Local and Svstemic Adverse Reactions Solicited in the Stud 2
+In participants 16 through 55 years of age after receiving Dose 2, the mean duration of pain at the injection site was 2.5 days (range 1 to 70 days), for redness 2.2 days (range 1 to 9 days), and for swelling 2.1 days (range 1 to 8 days) for participants in the COMIRNATY group. In participants 56 years of age and older after receiving
+6
+
+Dose 2, the mean duration of pain at the injection site was 2.4 days (range 1 to 36 days), for redness 3.0 days (range 1 to 34 days), and for swelling 2.6 days (range 1 to 34 days) for participants in the COMIRNATY group.
+Table 1: Study 2 - Frequency and Percentages of Participants with Solicited Local Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Participants 16 Through 55 Years of Age - Reactogenicity Subset of the Safety Population*
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Na=2899
+Na=2908
+nb (%)
+nb (%)
+COMIRNATY
+Dose 2
+Na=2682 nb (%)
+Placebo
+Dose 2
+Na=2684 nb (%)
+Redness°
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+156 (5.4)
+113 (3.9)
+36 (1.2)
+7 (0.2)
+28 (1.0)
+19 (0.7)
+6 (0.2)
+3 (0.1)
+151 (5.6)
+90 (3.4)
+50 (1.9)
+11 (0.4)
+18 (0.7)
+12 (0.4)
+6 (0.2)
+O
+Swelling
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+184(6.3)
+124(4.3)
+54 (1.9)
+6 (0.2)
+16 (0.6)
+6 (0.2)
+8 (0.3)
+2 (0.1)
+183 (6.8)
+110 (4.1)
+66 (2.5)
+7 (0.3)
+5 (0.2)
+3 (0.1)
+2 (0.1)
+0
+Pain at the injection site
+Any
+2426 (83.7)
+414 (14.2)
+2101 (78.3)
+Mild
+1464 (50.5)
+391 (13.4)
+1274 (47.5)
+Moderate
+923 (31.8)
+20 (0.7)
+788 (29.4)
+312 (11.6)
+284 (10.6)
+28 (1.0)
+Severe
+39 (1.3)
+3 (0.1)
+39 (1.5)
+Notes: Reactions were collected in the electronic diary (e-diary) from Day 1 to Day 7 after vaccination
+No Grade 4 solicited local reactions were reported in participants 16 through 55 years of age.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention. Participants with chronic, stable HIV infection were excluded.
+a. N = Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. The N for each
+reaction was the same, therefore, this information was included in the column header.
+b. n = Number of participants with the specified reaction.
+c. Mild: >2.0 to 25.0 cm; Moderate: >5.0 to 210.0 cm; Severe: >10.0 cm.
+d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
+Table 2: Study 2 - Frequency and Percentages of Participants with Solicited Systemic Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Participants 16 Through 55 Years of Age - Reactogenicity Subset of the Safety Population*
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Na=2899
+Na=2908
+nb (%)
+nb (%)
+COMIRNATY
+Dose 2
+Na=2682 nb (%)
+Placebo
+Dose 2
+Na=2684 nb (%)
+Fever
+>38.0°C
+≥38.0°C to 38.4°C
+>38.4°C to 38.9°C
+>38.9°C to 40.0°C
+>40.0°C
+Fatigue
+Any
+119 (4.1)
+86 (3.0)
+25 (0.9)
+8 (0.3)
+25 (0.9)
+16 (0.6)
+5 (0.2)
+4 (0.1)
+440 (16.4)
+254 (9.5)
+146 (5.4)
+39 (1.5)
+1 (0.0)
+11 (0.4)
+5 (0.2)
+4 (0.1)
+2 (0.1)
+O
+1431 (49.4)
+960 (33.0)
+1649 (61.5)
+614 (22.9)
+
+COMIRNATY
+Placebo
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Dose 2
+Dose 2
+Na=2899
+Na=2908
+N°=2682
+N°=2684
+nb (%)
+nb (%)
+nb (%)
+nb (%)
+Mild
+760 (26.2)
+570 (19.6)
+558 (20.8)
+317 (11.8)
+Moderate
+630 (21.7)
+372 (12.8)
+949 (35.4)
+283 (10.5)
+Severe
+41 (1.4)
+18 (0.6)
+142 (5.3)
+14 (0.5)
+Headache
+Any
+1262 (43.5)
+975 (33.5)
+1448 (54.0)
+652 (24.3)
+Mild
+785 (27.1)
+633 (21.8)
+699 (26.1)
+404 (15.1)
+Moderate
+444 (15.3)
+318 (10.9)
+658 (24.5)
+230 (8.6)
+Severe
+33(1.1)
+24 (0.8)
+91 (3.4)
+18 (0.7)
+Chills°
+Any
+479 (16.5)
+199 (6.8)
+1015 (37.8)
+114 (4 2)
+Mild
+338 (11.7)
+148 (5.1)
+477 (17.8)
+89 (3.3)
+Moderate
+126 (4.3)
+49 (1.7)
+469 (17.5)
+23 (0.9)
+Severe
+15 (0.5)
+2 (0.1)
+69 (2.6)
+2 (0.1)
+Vomitingd
+Any
+34 (1.2)
+36 (1.2)
+58 (2.2)
+30 (1.1)
+Mild
+29 (1.0)
+30 (1.0)
+42 (1.6)
+20 (0.7)
+Moderate
+5 (0.2)
+5 (0.2)
+12 (0.4)
+10 (0.4)
+Severe
+1 (0.0)
+4 (0.1)
+Diarrhea®
+Any
+309 (10.7)
+323 (11.1)
+269 (10.0)
+205 (7.6)
+Mild
+251 (8.7)
+264 (9.1)
+219 (8.2)
+169 (6.3)
+Moderate
+55 (1.9)
+58 (2.0)
+44 (1.6)
+35 (1.3)
+Severe
+3 (0.1)
+1 (0.0)
+6 (0.2)
+1 (0.0)
+New or worsened muscle pain°
+Any
+664 (22.9)
+329 (11.3)
+1055 (39.3)
+237 (8.8)
+Mild
+353 (12.2)
+231 (7.9)
+441 (16.4)
+150 (5.6)
+Moderate
+296 (10.2)
+96 (3.3)
+552 (20.6)
+84 (3.1)
+Severe
+15 (0.5)
+2 (0.1)
+62 (2.3)
+3 (0.1)
+New or worsened joint pain"
+Any
+342 (11.8)
+168 (5.8)
+638 (23.8)
+147 (5.5)
+Mild
+200 (6.9)
+112 (3.9)
+291 (10.9)
+82 (3.1)
+Moderate
+137 (4.7)
+55 (1.9)
+320 (11.9)
+61 (2.3)
+Severe
+5 (0.2)
+1 (0.0)
+27 (1.0)
+4 (0.1)
+Use of antipyretic or pain medication
+805 (27.8)
+398 (13.7)
+1213 (45.2)
+320 (11.9)
+Notes: Reactions and use of antipyretic or pain medication were collected in the electronic diary (e-diary) from Day 1 to Day 7 after each dose.
+No Grade 4 solicited systemic reactions were reported in participants 16 through 55 years of age.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention. Participants with chronic, stable HIV infection were excluded.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. The N for each reaction or use of antipyretic or pain medication was the same, therefore, this information was included in the column header.
+b. n = Number of participants with the specified reaction.
+c. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity.
+d. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration.
+e. Mild: 2 to 3 loose stools in 24 hours; Moderate: 4 to 5 loose stools in 24 hours; Severe: 6 or more loose stools in 24 hours.
+f. Severity was not collected for use of antipyretic or pain medication.
+8
+
+Table 3: Study 2 - Frequency and Percentages of Participants with Solicited Local Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Participants 56 Years of Age and Older - Reactogenicity Subset of the Safety Population*
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Na=2008
+Na=1989
+nb (%)
+n° (%)
+COMIRNATY
+Placebo
+Dose 2
+Dose 2
+Na=1860
+Na=1833
+n° (%)
+nb (%)
+Redness°
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+106 (5.3)
+71 (3.5)
+30 (1.5)
+5 (0.2)
+20 (1.0)
+13 (0.7)
+5 (0.3)
+2 (0.1)
+133 (7.2)
+65 (3.5)
+58 (3.1)
+10 (0.5)
+14 (0.8)
+10 (0.5)
+3 (0.2)
+1 (0.1)
+Swelling
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+141 (7.0)
+87 (4.3)
+52 (2.6)
+2 (0.1)
+23 (1.2)
+11 (0.6)
+12 (0.6)
+0
+145 (7.8)
+80 (4.3)
+61 (3.3)
+4 (0.2)
+13 (0.7)
+5 (0.3)
+7 (0.4)
+1 (0.1)
+Pain at the injection sited
+Any (>2.0 cm)
+1408 (70.1)
+185 (9.3)
+1230 (66.1)
+Mild
+1108 (55.2)
+177 (8.9)
+873 (46.9)
+Moderate
+296 (14.7)
+8 (0.4)
+347 (18.7)
+Severe
+4 (0.2)
+0
+10 (0.5)
+143 (7.8)
+138 (7.5)
+5 (0.3)
+0
+Notes: Reactions were collected in the electronic diary (e-diary) from Day 1 to Day 7 after vaccination.
+No Grade 4 solicited local reactions were reported in participants 56 years of age and older.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention. Participants with chronic, stable HIV infection were excluded.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. The N for each reaction was the same, therefore, the information was included in the column header.
+b. n = Number of participants with the specified reaction.
+c. Mild: >2.0 to 35.0 cm; Moderate: >5.0 to <10.0 cm; Severe: >10.0 cm.
+d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
+Table 4: Study 2 - Frequency and Percentages of Participants with Solicited Systemic Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Participants 56 Years of Age and Older - Reactogenicity Subset of the Safety Population*
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Na=2008
+Na=1989
+nb (%)
+nb (%)
+COMIRNATY
+Dose 2
+Na=1860 nb (%)
+Placebo
+Dose 2
+Na=1833 n" (%)
+Fever
+>38.0°C
+≥38.0°C to 38.4°C
+>38.4°C to 38.9°C
+>38.9°C to 40.0°C
+>40.0°C
+26 (1.3)
+23 (1.1)
+2 (0.1)
+1 (0.0)
+O
+8 (0.4)
+3 (0.2)
+3 (0.2)
+2 (0.1)
+O
+219 (11.8)
+158 (8.5)
+54 (2.9)
+7 (0.4)
+O
+4 (0.2)
+2 (0.1)
+1 (0.1)
+1 (0.1)
+0
+9
+
+COMIRNATY
+Dose 1
+Na=2008 n° (%)
+Placebo
+Dose 1
+Na=1989 nb (%)
+COMIRNATY
+Dose 2
+N°=1860 nb (%)
+Placebo
+Dose 2
+Na=1833 nb (%)
+Fatigue
+Any
+677 (33.7)
+447 (22.5)
+949 (51.0)
+306 (16.7)
+Mild
+415 (20.7)
+281 (14.1)
+391 (21.0)
+183 (10.0)
+Moderate
+259 (12.9)
+163 (8.2)
+497 (26.7)
+121 (6.6)
+Severe
+3 (0.1)
+3 (0.2)
+60 (3.2)
+2 (0.1)
+Grade 4
+0
+0
+1 (0.1)
+0
+Headache
+Any
+503 (25.0)
+363 (18.3)
+733 (39.4)
+259 (14.1)
+Mild
+381 (19.0)
+267 (13.4)
+464 (24.9)
+189 (10.3)
+Moderate
+120 (6.0)
+93 (4.7)
+256 (13.8)
+65 (3.5)
+Severe
+2 (0.1)
+3 (0.2)
+13 (0.7)
+5 (0.3)
+Chills°
+Any
+130 (6.5)
+69 (3.5)
+435 (23.4)
+57 (3.1)
+Mild
+102 (5.1)
+49 (2.5)
+229 (12.3)
+45 (2.5)
+Moderate
+28 (1.4)
+19 (1.0)
+185 (9.9)
+12 (0.7)
+Severe
+0
+1 (0.1)
+21 (1.1)
+0
+Vomitingd
+Anv
+10 (0.5)
+9 (0.5)
+13 (0.7)
+5 (0.3)
+Mild
+9 (0.4)
+9 (0.5)
+10 (0.5)
+5 (0.3)
+Moderate
+1 (0.0)
+O
+1 (0.1)
+0
+Severe
+0
+2 (0.1)
+0
+Diarrhea®
+Any
+168 (8.4)
+130 (6.5)
+152 (8.2)
+102 (5.6)
+Mild
+137 (6.8)
+109 (5.5)
+125 (6.7)
+76 (4.1)
+Moderate
+27 (1.3)
+20 (1.0)
+25 (1.3)
+22(1.2)
+Severe
+4 (0.2)
+1 (0.1)
+2 (0.1)
+4(0.2)
+New or worsened muscle pain°
+Any
+274 (13.6)
+165 (8.3)
+537 (28.9)
+99 (5.4)
+Mild
+183 (9.1)
+111 (5.6)
+229 (12.3)
+65 (3.5)
+Moderate
+90 (4.5)
+51 (2.6)
+288 (15.5)
+33 (1.8)
+Severe
+1 (0.0)
+3 (0.2)
+20 (1.1)
+1 (0.1)
+New or worsened joint pain
+Any
+175 (8.7)
+124 (6.2)
+353 (19.0)
+72 (3.9)
+Mild
+119 (5.9)
+78 (3.9)
+183 (9.8)
+44 (2.4)
+Moderate
+53 (2.6)
+45 (2.3)
+161 (8.7)
+27 (1.5)
+Severe
+3 (0.1)
+1 (0.1)
+9 (0.5)
+1 (0.1)
+Use of antipyretic or pain medicationf
+382 (19.0)
+224 (11.3)
+688 (37.0)
+170 (9.3)
+Notes: Reactions and use of antipyretic or pain medication were collected in the electronic diary (e-diary) from Day 1 to Day 7 after each dose.
+The only Grade 4 solicited systemic reaction reported in participants 56 years of age and older was fatigue.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention. Participants with chronic, stable HIV infection were excluded.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. N for each reaction or use of antipyretic or pain medication was the same, therefore was included in the column header.
+b. n = Number of participants with the specified reaction.
+10
+
+c. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity; Grade 4 reactions were defined in the clinical study protocol as emergency room visit or hospitalization for severe fatigue, severe headache, severe chills, severe muscle pain, or severe joint pain.
+d. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration; Grade 4 emergency visit or hospitalization for severe vomiting.
+e. Mild: 2 to 3 loose stools in 24 hours; Moderate: 4 to 5 loose stools in 24 hours; Severe: 6 or more loose stools in 24 hours; Grade 4: emergency room or hospitalization for severe diarrhea.
+f. Severity was not collected for use of antipyretic or pain medication.
+In participants with chronic, stable HIV infection the frequencies of solicited local and systemic adverse reactions were similar to or lower than those observed for all participants 16 years of age and older.
+Unsolicited Adverse Events
+Overall, 11,253 (51.1%) participants in the COMIRNATY group and 11,316 (51.4%) participants in the placebo group had follow-up time between ≥4 months to <6 months after Dose 2 in the blinded placebo-controlled follow-up period with an additional 1,778 (8.1%) and 1,304 (5.9%) with >6 months of blinded follow-up time in the COMIRNATY and placebo groups, respectively.
+A total of 12,006 (54.5%) participants originally randomized to COMIRNATY had >6 months total (blinded and unblinded follow-up after Dose 2.
+In an analysis of all unsolicited adverse events reported following any dose, through 1 month after Dose 2, in participants 16 years of age and older (N=43,847; 21,926 COMIRNATY group vs. 21,921 placebo group), those assessed as adverse reactions not already captured by solicited local and systemic reactions were nausea (274 vs. 87), malaise (130 vs. 22), lymphadenopathy (83 vs. 7), asthenia (76 vs. 25), decreased appetite (39 vs. 9), hyperhidrosis (31 vs. 9), lethargy (25 vs. 6), and night sweats (17 vs. 3).
+In analvses of all unsolicited adverse events in Study 2 from Dose 1 up to the participant unblinding date, 58.2% of study participants had at least 4 months of follow-up after Dose 2. Among participants 16 through
+55 years of age who received at least 1 dose of study vaccine, 12,995 of whom received COMIRNATY and
+13,026 of whom received placebo, unsolicited adverse events were reported by 4,396 (33.8%) participants in the COMIRNATY group and 2,136 (16.4%) participants in the placebo group. In a similar analysis in participants 56 years of age and older that included 8,931 COMIRNATY recipients and 8,895 placebo recipients, unsolicited adverse events were reported by 2,551 (28.6%) participants in the COMIRNATY group and 1,432 (16.1%) participants in the placebo group. Among participants with confirmed stable HIV infection that included 100 COMIRNATY recipients and 100 placebo recipients, unsolicited adverse events were reported by 29 (29%) participants in the COMIRNATY group and 15 (15%) participants in the placebo group. The higher frequency of reported unsolicited adverse events among COMIRNATY recipients compared to placebo recipients was primarily attributed to events that are consistent with adverse reactions solicited among participants in the reactogenicity subset (Table 3 and Table 4).
+Throughout the placebo-controlled safety follow-up period, Bell's palsy (facial paralysis) was reported by 4 participants in the COMIRNATY group and 2 participants in the placebo group. Onset of facial paralysis was Day 37 after Dose 1 (participant did not receive Dose 2) and Days 3, 9, and 48 after Dose 2. In the placebo group the onset of facial paralysis was Day 32 and Day 102. Currently available information is insufficient to determine a causal relationship with the vaccine. In the analysis of blinded, placebo-controlled follow-up, there were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic or neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no
+11
+
+notable patterns of specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.
+Serious Adverse Events
+In Study 2, among participants 16 through 55 years of age who had received at least 1 dose of vaccine or
+placebo (COMIRNATY =12,995; placebo = 13,026), serious adverse events from Dose 1 up to the participant
+unblinding date in ongoing follow-up were reported by 103 (0.8%) COMIRNATY recipients and 117 (0.9%)
+placebo recipients. In a similar analysis, in participants 56 years of age and older (COMIRNATY = 8,931;
+placebo = 8,895), serious adverse events were reported by 165 (1.8%) COMIRNATY recipients and 151 (1.7%)
+placebo recipients who received at least 1 dose of COMIRNATY or placebo, respectively. In these analyses, 58.2% of study participants had at least 4 months of follow-up after Dose 2. Among participants with confirmed stable HIV infection serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 2 (2%) COMIRNATY recipients and 2 (2%) placebo recipients.
+In the analysis of blinded, placebo-controlled follow-up, there were no notable patterns between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of serious adverse events that would suggest a causal relationship to COMIRNATY.
+Adolescents 12 Through 15 Years of Age
+In Study 2, 2,260 adolescents (1,131 COMIRNATY; 1,129 placebo) were 12 through 15 years of age. At the time of the analysis of the ongoing Study 2 with a data cutoff of September 2, 2021, there were 1,559 (69.0%) adolescents (786 COMIRNATY and 773 placebo) 12 through 15 years of age followed for >4 months after the second dose. The safety evaluation in Study 2 is ongoing.
+Demographic characteristics in Study 2 were generally similar with regard to age, gender, race, and ethnicity among adolescents who received COMIRNATY and those who received placebo. Overall, among the adolescents who received COMIRNATY, 50.1% were male and 49.9% were female, 85.8% were White, 4.6% were Black or African American, 11.7% were Hispanic/Latino, 6.4% were Asian, and 0.4% were American Indian/Alaska Native.
+Local and Systemic Adverse Reactions Solicited in Study 2
+In adolescents 12 through 15 years of age after receiving Dose 2, the mean duration of pain at the injection site was 2.5 days (range 1 to 11 days), for redness 1.8 days (range 1 to 5 days), and for swelling 1.6 days (range 1 to 5 days) in the COMIRNATY group.
+Table 5: Study 2 - Frequency and Percentages of Adolescents With Solicited Local Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Adolescents 12 Through 15 Years of Age - Safety Population *
+COMIRNATY
+Dose 1
+N°=1127 ab (%)
+Placebo
+Dose 1
+Na=1127 nb (%)
+COMIRNATY
+Dose 2
+Na=1097 nb (%)
+Placebo
+Dose 2
+Na=1078 rb (%)
+Redness®
+Any (>2 cm)
+Mild
+Moderate
+Severe
+65 (5.8)
+44 (3.9)
+20 (1.8)
+1 (0.1)
+12 (1.1)
+11 (1.0)
+1 (0.1)
+0 (0.0)
+55 (5.0)
+29 (2.6)
+26 (2.4)
+0 (0.0)
+10 (0.9)
+8 (0.7)
+2 (0.2)
+0 (0.0)
+12
+
+COMIRNATY
+Dose 1
+Na=1127 nb (%)
+Placebo
+Dose 1
+Na=1127 n° (%)
+COMIRNATY
+Dose 2
+Na=1097 nb (%)
+Placebo
+Dose 2
+Na=1078 nb (%)
+Swelling®
+Any (>2 cm)
+Mild
+Moderate
+Severe
+78 (6.9)
+55 (4.9)
+23 (2.0)
+0 (0.0)
+11 (1.0)
+9 (0.8)
+2 (0.2)
+0 (0.0)
+54 (4.9)
+36 (3.3)
+18 (1.6)
+0 (0.0)
+Pain at the iniection sited
+Any
+971 (86.2)
+263 (23.3)
+866 (78.9)
+Mild
+467 (41.4)
+227 (20.1)
+466 (42.5)
+Moderate
+493 (43.7)
+36 (3.2)
+393 (35.8)
+Severe
+11 (1.0)
+0 (0.0)
+7 (0.6)
+Note: Reactions were collected in the electronic diary (e-diary) from Day 1 to Day 7 after vaccination
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
+b. n = Number of participants with the specified reaction.
+c. Mild: >2.0 to <5.0 cm; Moderate: >5.0 to <10.0 cm; Severe: >10.0 cm.
+d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
+6 (0.6)
+4 (0.4)
+2 (0.2)
+0 (0.0)
+193 (17.9)
+164 (15.2)
+29 (2.7)
+0 (0.0)
+Table 6: Study 2 - Frequency and Percentages of Adolescents with Solicited Systemic Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Adolescents 12 Through 15 Years of Age - Safety Population*
+COMIRNATY
+Dose 1
+Na=1127 nb (%)
+Placebo
+Dose 1
+Na=1127 nb (%)
+COMIRNATY
+Dose 2
+Na=1097 nb (%)
+Placebo
+Dose 2
+Na=1078 nb (%)
+Fever
+≥38.0°C
+>38.0°C to 38.4°C
+>38.4°C to 38.9°C
+>38.9°C to 40.0°C
+>40.0°C
+Fatigue
+Any
+Mild
+Moderate
+Severe
+Headache
+Any
+Mild
+Moderate
+Severe
+Chills°
+Any
+Mild
+Moderate
+Severe
+114 (10.1)
+74 (6.6)
+29 (2.6)
+10 (0.9)
+1 (0.1)
+12 (1.1)
+8 (0.7)
+2 (0.2)
+2 (0.2)
+0 (0.0)
+215 (19.6)
+107 (9.8)
+83 (7.6)
+25 (2.3)
+0 (0.0)
+7 (0.6)
+5 (0.5)
+1 (0.1)
+1 (0.1)
+0 (0.0)
+677 (60.1)
+278 (24.7)
+384 (34.1)
+15 (1.3)
+457 (40.6)
+250 (22.2)
+199 (17.7)
+8 (0.7)
+726 (66.2)
+232 (21.1)
+468 (42.7)
+26 (2.4)
+264(24.5)
+133 (12.3)
+127 (11.8)
+4 (0.4)
+623 (55.3)
+361 (32.0)
+251 (22.3)
+11 (1.0)
+396 (35.1)
+256 (22.7)
+131 (11.6)
+9 (0.8)
+708 (64.5)
+302 (27.5)
+384 (35.0)
+22 (2.0)
+264 (24.5)
+170 (15.8)
+93 (8.6)
+1 (0.1)
+311 (27.6)
+195 (17.3)
+111 (9.8)
+5 (0.4)
+109 (9.7)
+82 (7.3)
+25 (2.2)
+2 (0.2)
+455 (41.5)
+221 (20.1)
+214 (19.5)
+20 (1.8)
+74 (6.9)
+53 (4.9)
+21 (1.9)
+0 (0.0)
+13
+
+COMIRNATY
+Dose 1
+Na=1127 nb (%)
+Placebo
+Dose 1
+Na=1127 nb (%)
+COMIRNATY
+Placebo
+Dose 2
+Dose 2
+N°=1097
+Na=1078
+nb (%)
+nb (%)
+Vomiting
+Any
+Mild
+Moderate
+Severe
+31 (2.8)
+30 (2.7)
+0 (0.0)
+1 (0.1)
+10 (0.9)
+8 (0.7)
+2 (0.2)
+0 (0.0)
+29 (2.6)
+25 (2.3)
+4 (0.4)
+0 (0.0)
+12 (1.1)
+11 (1.0)
+1 (0.1)
+0 (0.0)
+Diarrhea®
+Any
+Mild
+Moderate
+Severe
+90 (8.0)
+77 (6.8)
+13 (1.2)
+0 (0.0)
+82 (7.3)
+72 (6.4)
+10 (0.9)
+0 (0.0)
+65 (5.9)
+59 (5.4)
+6 (0.5)
+0 (0.0)
+44 (4.1)
+39 (3.6)
+5 (0.5)
+0 (0.0)
+New or worsened muscle pain°
+Any
+Mild
+Moderate
+Severe
+272 (24.1)
+125 (11.1)
+145 (12.9)
+2 (0.2)
+148 (13.1)
+88 (7.8)
+60 (5.3)
+0 (0.0)
+355 (32.4)
+152 (13.9)
+197 (18.0)
+6 (0.5)
+90 (8.3)
+51 (4.7)
+37 (3.4)
+2 (0.2)
+New or worsened ioint pain°
+Any
+Mild
+Moderate
+Severe
+109 (9.7)
+66 (5.9)
+42 (3.7)
+1 (0.1)
+77 (6.8)
+50 (4.4)
+27 (2.4)
+0 (0.0)
+173 (15.8)
+91 (8.3)
+78 (7.1)
+4 (0.4)
+51 (4.7)
+30 (2.8)
+21 (1.9)
+0 (0.0)
+Use of antipyretic or pain medication
+413 (36.6)
+557 (50.8)
+95 (8.8)
+111 (9.8)
+Note: Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary) from Day 1 to Day 7 after each dose.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.
+a. N= Number of participants reporting at least 1 yes or no response for the specified event after the specified dose.
+b. n = Number of participants with the specified reaction.
+c. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity.
+d. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration.
+e. Mild: 2 to 3 loose stools in 24 hours; Moderate: 4 to 5 loose stools in 24 hours; Severe: 6 or more loose stools in 24 hours.
+f. Severity was not collected for use of antipyretic or pain medication.
+Unsolicited Adverse Events
+In Study 2, 2,260 adolescents (1,131 COMIRNATY; 1,129 placebo) were 12 through 15 years of age. Of these, 634 (56.1%) participants in the COMIRNATY group and 629 (55.7%) participants in the placebo group had follow-up time between >4 months to <6 months after Dose 2 in the blinded placebo-controlled follow-up period with an additional 152 (13.4%) and 144 (12.8%) with >6 months of blinded follow-up time in the COMIRNATY and placebo groups, respectively.
+A total of 1,113 (98.4%) participants 12 through 15 years of age originally randomized to COMIRNATY had
+>6 months total (blinded and unblinded) follow-up after Dose 2.
+An analysis of all unsolicited adverse events in Study 2 from Dose 1 up to the participant unblinding date was conducted. Among participants 12 through 15 years of age who received at least one dose of study vaccine, unsolicited adverse events were reported by 95 (8.4%) participants in the COMIRNATY group and 113 (10.0%) participants in the placebo group.
+14
+
+In an analysis of all unsolicited adverse events reported during blinded follow-up from Dose 1 through 1 month after Dose 2, in adolescents 12 to 15 years of age, those assessed as adverse reactions not already captured by solicited local and systemic reactions were lymphadenopathy (9 vs. 2), and nausea (5 vs. 2).
+In the analysis of blinded, placebo-controlled follow-up, there were no other notable patterns or numerical imbalances between treatment groups for specific categories of unsolicited adverse events (including other neurologic or neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.
+Serious Adverse Events
+In Study 2, among participants 12 through 15 years of age who had received at least 1 dose of vaccine or
+placebo (COMIRNATY = 1,131; placebo = 1,129), serious adverse events from Dose 1 up to the participant
+unblinding date in ongoing follow-up were reported by 10 (0.9%) COMIRNATY recipients and 2 (0.2%) placebo recipients. In these analyses, 69.0% of study participants had at least 4 months of follow-up after Dose 2. In the analysis of blinded, placebo-controlled follow-up, there were no notable patterns between treatment groups for specific categories of serious adverse events (including neurologic, neuro- inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of serious adverse events that would suggest a causal relationship to COMIRNATY.
+6.2 Postmarketing Experience
+The following adverse reactions have been identified during postmarketing use of COMIRNATY, including under Emergency Use Authorization. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.
+Cardiac Disorders: myocarditis, pericarditis
+Gastrointestinal Disorders: diarrhea, vomiting
+Immune System Disorders: severe allergic reactions, including anaphylaxis, and other hypersensitivity reactions (e.g., rash, pruritus, urticaria, angioedema)
+Musculoskeletal and Connective Tissue Disorders: pain in extremity (arm)
+Nervous System Disorders: syncope, dizziness
+8 USE IN SPECIFIC POPULATIONS
+8.1 Pregnancy
+There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to COMIRNATY during pregnancy. Women who are vaccinated with COMIRNATY during pregnancy are encouraged to enroll in the registry by visiting https://mothertobaby.org/ongoing-study/covid19-vaccines/.
+Risk Summary
+All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Available data on COMIRNATY administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.
+15
+
+A developmental toxicity study has been performed in female rats administered the equivalent of a single human dose of COMIRNATY on 4 occasions, twice prior to mating and twice during gestation. These studies revealed no evidence of harm to the fetus due to the vaccine (see Animal Data).
+Data
+Animal Data
+In a developmental toxicity study, 0.06 mL of a vaccine formulation containing the same quantity of nucleoside-modified messenger ribonucleic acid (mRNA) (30 mcg) and other ingredients included in a single human dose of COMIRNATY was administered to female rats by the intramuscular route on 4 occasions: 21 and 14 days prior to mating, and on gestation days 9 and 20. No vaccine-related adverse effects on female fertility, fetal development, or postnatal development were reported in the study.
+8.2 Lactation
+Risk Summary
+It is not known whether COMIRNATY is excreted in human milk. Data are not available to assess the effects of COMIRNATY on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for COMIRNATY and any potential adverse effects on the breastfed child from COMIRNATY or from the underlying maternal condition.
+For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.
+8.4 Pediatric Use
+Safety and effectiveness of COMIRNATY in individuals 12 through 17 years of age is based on safety and effectiveness data in this age group and in adults /see Adverse Reactions (6) and Clinical Studies (14.1)].
+The safety and effectiveness of COMIRNATY in individuals younger than 12 years of age have not been established.
+8.5 Geriatric Use
+Of the total number of COMIRNATY recipients in Study 2 as of March 13, 2021 (N = 22,026),
+20.7% (n =4,552) were 65 years of age and older and 4.2% (n = 925) were 75 years of age and older [see
+Clinical Studies (14.1)]. No overall differences in safety or effectiveness were observed between these recipients and younger recipients.
+11 DESCRIPTION
+COMIRNATY (COVID-19 Vaccine, mRNA) is a sterile suspension for injection for intramuscular use. Each 0.3 mL dose of COMIRNATY contains 30 mcg of a nucleoside-modified messenger RNA (mRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2.
+Each 0.3 mL dose of COMIRNATY supplied in vials with gray caps and labels with gray borders also includes the following ingredients:
+lipids (0.43 mg ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide,
+16
+
+0.09 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.19 mg cholesterol), 0.06 mg tromethamine, 0.4 mg tromethamine hydrochloride, and 31 mg sucrose.
+COMIRNATY does not contain preservative.
+The vial stoppers are not made with natural rubber latex.
+12 CLINICAL PHARMACOLOGY
+12.1 Mechanism of Action
+The nucleoside-modified mRNA in COMIRNATY is formulated in lipid particles, which enable delivery of the mRNA into host cells to allow expression of the SARS-CoV-2 S antigen. The vaccine elicits an immune response to the S antigen, which protects against COVID-19.
+13 NONCLINICAL TOXICOLOGY
+13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
+COMIRNATY has not been evaluated for the potential to cause carcinogenicity, genotoxicity, or impairment of male fertility. In a developmental toxicity study in rats with COMIRNATY there were no vaccine-related effects on female fertility [see Use in Specific Populations (8.1)].
+14 CLINICAL STUDIES
+14.1 Efficacy in Participants 16 Years of Age and Older
+Study 2 is an ongoing, multicenter, multinational, randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in participants 12 years of age and older. Randomization was stratified by age: 12 through 15 years of age, 16 through 55 years of age, or 56 years of age and older, with a minimum of 40% of participants in the ≥56-year stratum. The study excluded participants who were immunocompromised and those who had previous clinical or microbiological diagnosis of COVID-19.
+Participants with preexisting stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 6 weeks before enrollment, were included as were participants with known stable infection with HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV).
+In Study 2, based on data accrued through March 13, 2021, approximately 44,000 participants 12 years of age and older were randomized equally and received 2 doses of COMIRNATY or placebo. Participants are planned to be followed for up to 24 months, for assessments of safety and efficacy against COVID-19.
+Overall, among the total participants who received COMIRNATY or placebo, 51.4% or 50.3% were male and 48.6% or 49.7% were female, 79.1% or 79.2% were 16 through 64 years of age, 20.9% or 20.8% were 65 years of age and older, 81.9% or 82.1% were White, 9.5% or 9.6% were Black or African American, 1.0% or 0.9% were American Indian or Alaska Native, 4.4% or 4.3% were Asian, 0.3% or 0.2% Native Hawaiian or other Pacific Islander, 25.6% or 25.4% were Hispanic/Latino, 73.9% or 74.1% were non-Hispanic/Latino, 0.5% or 0.5% did not report ethnicity, 46.0% or 45.7% had comorbidities [participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as subiects who had at least 1 of the Charlson comorbidity index category or body mass index (BMI) >30 kg/m 1, respectively. The mean age at vaccination was 49.8 or 49.7 years and median age was 51.0 or 51.0 in participants who received COMIRNATY or placebo, respectively.
+17
+
+Efficacy Against COVID-19
+The population for the analysis of the protocol pre-specified primary efficacy endpoint included
+36,621 participants 12 years of age and older (18,242 in the COMIRNATY group and 18,379 in the placebo group) who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose.
+The population in the protocol pre-specified primary efficacy analvsis included all participants 12 years of age and older who had been enrolled from July 27, 2020, and followed for the development of COVID-19 through November 14, 2020. Participants 18 through 55 years of age and 56 years of age and older began enrollment from July 27, 2020, 16 through 17 years of age began enrollment from September 16, 2020, and 12 through 15 years of age began enrollment from October 15, 2020.
+For participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, vaccine efficacy against confirmed COVID-19 occurring at least 7 days after Dose 2 was 95.0% (95% credible interval: 90.3,
+97.6), which met the pre-specified success criterion. The case split was 8 COVID-19 cases in the COMIRNATY group compared to 162 COVID-19 cases in the placebo group.
+The population for the updated vaccine efficacy analysis included participants 16 years of age and older who had been enrolled from July 27, 2020, and followed for the development of COVID-19 during blinded placebo-controlled follow-up through March 13, 2021, representing up to 6 months of follow-up after Dose 2.
+There were 12,796 (60.8%) participants in the COMIRNATY group and 12,449 (58.7%) in the placebo group followed for >4 months after Dose 2 in the blinded placebo-controlled follow-up period.
+SARS-CoV-2 variants of concern identified from COVID-19 cases for this age group from this data cutoff include B. 1.1.7 (Alpha) and B. 1.351 (Beta). Representation of identified variants among cases in vaccine versus placebo recipients did not suggest decreased vaccine effectiveness against these variants.
+The updated vaccine efficacy information is presented in Table 7.
+Table 7: Vaccine Efficacy - First COVID-19 Occurrence From 7 Days After Dose 2, by Age
+Subgroup - Participants 16 Years of Age and Older Without Evidence of Infection and Participants With or Without Evidence of Infection Prior to 7 Days After Dose 2 - Evaluable
+Efficacy (7 Days) Population During the Placebo-Controlled Follow-up Period
+First COVID-19 occurrence from 7 days after Dose 2 in participants without evidence of prior
+SARS-CoV-2 infection*
+COMIRNATY
+Placebo
+Na=19,993
+Na=20,118
+Cases
+Cases
+nib
+nib
+Subgroup
+Surveillance Time® (n2d) Surveillance Time* (n2d)
+77
+833
+All participants
+6.092 (19,711)
+5.857 (19,741)
+70
+709
+16 through 64 years
+4.859 (15,519)
+4.654 (15,515)
+7
+124
+65 vears and older
+1.233 (4192)
+1.202 (4226)
+Vaccine Efficacy %
+(95% CI)
+91.1
+(88.8, 93.1)
+90.5
+(87.9, 92.7)
+94.5
+(88.3, 97.8)
+18
+
+First COVID-19 occurrence from 7 days after Dose 2 in participants with or without* evidence of prior
+SARS-CoV-2 infection
+COMIRNATY
+Placebo
+Na=21,047
+Na=21,210
+Cases
+Cases
+nib
+nib
+Vaccine Efficacy %
+Subgroup
+Surveillance Time' (n20)
+Surveillance Time (n29)
+(95% CIE)
+81
+854
+90.9
+All participants
+6.340 (20,533)
+6.110 (20,595)
+(88.5, 92.8)
+74
+726
+90.2
+16 through 64 years
+5.073 (16,218)
+4.879 (16,269)
+(87.5, 92.4)
+7
+128
+94.7
+65 years and older
+1.267 (4315)
+1.232 (4326)
+(88.7, 97.9)
+Note: Confirmed cases were determined by Reverse Transcription- Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell, sore throat; diarrhea; vomiting).
+* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+a. N= Number of participants in the specified group.
+b. n1 = Number of participants meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
+Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d. n2 = Number of participants at risk for the endpoint.
+e. Two-sided confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time.
+Subgroup analyses of vaccine efficacy (although limited by small numbers of cases in some subgroups) did not suggest meaningful differences in efficacy across genders, ethnic groups, geographies, or for participants with obesity or medical comorbidities associated with high risk of severe COVID-19.
+Efficacy Against Severe COVID-19
+Efficacy analyses of secondary efficacy endpoints supported benefit of COMIRNATY in preventing severe
+COVID-19. Vaccine efficacy against severe COVID-19 is presented only for participants with or without prior SARS-CoV-2 infection (Table 8) as the COVID-19 case counts in participants without prior SARS-CoV-2 infection were the same as those in participants with or without prior SARS-CoV-2 infection in both the COMIRNATY and placebo groups.
+19
+
+Table 8: Vaccine Efficacy - First Severe COVID-19 Occurrence in Participants 16 Years of Age and
+Older With or Without* Prior SARS-CoV-2 Infection Based on Protocol or Centers for Disease Control and Prevention (CDC) Definition From 7 Das After Dose 2 - Evaluable
+Efficacy (7 Days) Population During the Placebo-Controlled Follow-up
+Vaccine Efficacy - First Severe COVID-19 Occurrence
+COMIRNATY
+Placebo
+Cases
+Cases
+nia
+n1a
+Surveillance Time' (n2°
+Surveillance Time® (n29)
+21
+7 days after Dose 2d
+6.353 (20.540)
+6.237 (20,629)
+Vaccine Efficacy %
+(95% CI)
+95.3
+(70.9, 99.9)
+Vaccine Efficacy - First Severe COVID-19 Occurrence Based on CDC Definition
+COMIRNATY
+Placebo
+Cases
+Cases
+nia
+nia
+Vaccine Efficacy %
+Surveillance Time® (n2°) Surveillance Time® (n2°)
+(95% CId'
+31
+100
+7 davs after Dose 2d
+6.345 (20.513)
+6.225 (20,593)
+(87.6, 100.0)
+Note: Confirmed cases were determined by Reverse Transcription- Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell, sore throat; diarrhea; vomiting).
+* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+† Severe illness from COVID-19 is defined in the protocol as confirmed COVID-19 and presence of at least 1 of the following:
+• Clinical signs at rest indicative of severe systemic illness (respiratory rate >30 breaths per minute, heart rate >125 beats per minute, saturation of oxygen <93% on room air at sea level, or ratio of arterial oxygen partial pressure to fractional inspired oxygen <300 mm Hg);
+• Respiratory failure [defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation (ECMO)];
+• Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or requiring vasopressors);
+• Significant acute renal, hepatic, or neurologic dysfunction;
+• Admission to an Intensive Care Unit:
+• Death.
+#Severe illness from COVID-19 as defined by CDC is confirmed COVID-19 and presence of at least 1 of the following:
+• Hospitalization;
+• Admission to the Intensive Care Unit;
+• Intubation or mechanical ventilation;
+• Death.
+a. n1 = Number of participants meeting the endpoint definition.
+b. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
+Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+c. n2 = Number of participants at risk for the endpoint.
+d. Two-side confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time.
+14.2 Efficacy in Adolescents 12 Through 15 Years of Age
+A descriptive efficacy analysis of Study 2 has been performed in 2,260 adolescents 12 through 15 years of age evaluating confirmed COVID-19 cases accrued up to a data cutoff date of September 2, 2021.
+The vaccine efficacy information in adolescents 12 through 15 years of age is presented in Table 9.
+20
+
+Table 9: Vaccine Efficacy - First COVID-19 Occurrence From 7 Days After Dose 2: Without Evidence
+of Infection and With or Without Evidence of Infection Prior to 7 Days After Dose 2 - Blinded Placebo-Controlled Follow-up Period, Adolescents 12 Through 15 Years of Age Evaluable Efficacy (7 Days) Population
+First COVID-19 occurrence from 7 days after Dose 2 in adolescents 12 through 15 years of age without evidence of prior SARS-CoV-2 infection*
+COMIRNATY
+Placebo
+Na=1057
+Na=1030
+Cases
+Cases
+nib
+nib
+Surveillance Time^ (n24)
+Surveillance Time' (n2d)
+Adolescents
+0
+28
+12 through 15 years of age
+0.343 (1043)
+0.322 (1019)
+Vaccine Efficacy %
+(95% CI°)
+100.0
+(86.8, 100.0)
+First COVID-19 occurrence from 7 days after Dose 2 in adolescents 12 through 15 years of age with or without evidence of prior SARS-CoV-2 infection
+COMIRNATY
+Placebo
+Na=1119
+Na=1109
+Cases
+Cases
+nib
+n1b
+Vaccine Efficacy %
+Surveillance Time^ (n2d)
+Surveillance Time (n2d)
+(95% CI)
+Adolescents
+0
+30f
+100.0
+12 through 15 years of age
+0.362 (1098)
+0.345 (1088)
+(87.5, 100.0)
+Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat; diarrhea; vomiting).
+* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+a. N= Number of participants in the specified group.
+b. n1 = Number of participants meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
+Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d. n2 = Number of participants at risk for the endpoint.
+e. Two-side confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted for surveillance time.
+The only SARS-CoV-2 variant of concern identified from COVID-19 cases in this age group from this data cutoff was B. 1.1.7
+(Alpha).
+14.3 Immunogenicity in Adolescents 12 Through 15 Years of Age
+In Study 2, an analysis of SARS-CoV-2 50% neutralizing titers (NT50) 1 month after Dose 2 in a randomly selected subset of participants demonstrated non-inferior immune responses (within 1.5-fold) comparing adolescents 12 through 15 years of age to participants 16 through 25 years of age who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2 (Table 10).
+21
+
+Table 10: Summary of Geometric Mean Ratio for 50% Neutralizing Titer - Comparison of Adolescents
+12 Through 15 Years of Age to Participants 16 Through 25 Years of Age (Immunogenicity
+Subset) - Participants Without Evidence of Infection up to 1 Month After Dose 2 - Dose 2
+Evaluable Immunogenicity Population
+COMIRNATY
+12 Through 15 Years
+16 Through 25 Years
+na=190
+na=170
+12 Through 15 Years/
+16 Through 25 Years
+Met
+Noninferiority
+GMRd
+(95% CId)
+Objective
+(YIN)
+Time
+Point
+GMT
+(95% CI°
+GMT
+(95% CI°
+Assay
+SARS-CoV-2 neutralization
+1 month
+assay - NT50
+after
+(titer)f
+1253.6
+708.1
+1.77
+Dose 2
+(1117.7, 1406.1)
+(625.9, 801.1)
+(1.50, 2.09)
+Y
+Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titer; LLOQ = lower limit of
+quantitation; NAAT = nucleic-acid amplification test; NT50 = 50% neutralizing titer; SARS-CoV-2 = severe acute respiratory
+svndrome coronavirus 2.
+Note: Participants who had no serological or virological evidence (up to 1 month after receipt of the last dose) of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and
+2), and had negative NAAT (nasal swab) at any unscheduled visit up to 1 month after Dose 2 were included in the analysis.
+a. n= Number of participants with valid and determinate assay results for the specified assay at the given dose/sampling time point
+b. Protocol-specified timing for blood sample collection.
+c. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titers and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ.
+d. GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titers (Group 1 [12 through 15 years of age] - Group 2 [16 through 25 years of age]) and the corresponding CI (based on the Student t distribution).
+e. Noninferiority is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 0.67.
+f. SARS-CoV-2 NT50 were determined using the SARS-CoV-2 mNeonGreen Virus Microneutralization Assay. The assay uses a fluorescent reporter virus derived from the USA WA1/2020 strain and virus neutralization is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized.
+16 HOW SUPPLIED/STORAGE AND HANDLING
+Single Dose Vials: COMIRNATY is a suspension for intramuscular injection. Single dose vials with gray caps and labels with gray borders are supplied in a carton containing 10 single dose vials. One vial contains 1 dose of 0.3 mL.
+• Carton of 10 single dose vials: NDC 0069-3125-10
+• Single dose vial: NDC 0069-3125-01
+Multiple Dose Vials: COMIRNATY is a suspension for intramuscular injection. Multiple dose vials with gray caps and labels with gray borders are supplied in a carton containing 10 multiple dose vials or 25 multiple dose vials. One vial contains 6 doses of 0.3 mL.
+• Carton of 10 multiple dose vials: NDC 0069-2025-10
+Carton of 25 multiple dose vials: NDC 0069-2025-25
+• Multiple dose vial: NDC 0069-2025-01
+During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light.
+Do not refreeze thawed vials.
+22
+
+Vial Storage Prior to Use
+Cartons of COMIRNATY single dose vials and multiple dose vials with gray caps and labels with gray borders will arrive frozen at ultra-cold conditions in thermal containers with dry ice.
+Once received, frozen vials may be immediately transferred to the refrigerator [2°C to 8°C (35°F to 46°F)], thawed and stored for up to 10 weeks. The 10-week refrigerated expiry date should be recorded on the carton at the time of transfer. A carton of 10 single dose vials may take up to 2 hours to thaw at this temperature.
+A carton of 10 multiple dose vials may take up to 6 hours to thaw at this temperature.
+Alternatively, frozen vials may be stored in an ultra-low temperature freezer at -90°C to -60°C (-130°F to -76°F).
+Do not store vials at -25°C to -15°C (-13°F to 5°F). Once vials are thawed, they should not be refrozen.
+If cartons of COMIRNATY single dose vials or multiple dose vials with gray caps and labels with gray borders are received at 2°C to 8°C, they should be stored at 2°C to 8°C. Check that the carton has been updated to reflect the 10-week refrigerated expiry date.
+Regardless of storage condition, the vaccine should not be used after the expiration date printed on the vial and
+cartons.
+Vial Storage During Use
+If not previously thawed at 2°C to 8°C (35°F to 46°F), allow COMIRNATY single dose vials and multiple dose vials to thaw at room temperature [up to 25°C (77°F)] for 30 minutes.
+DO NOT DILUTE SINGLE DOSE VIALS OR MULTIPLE DOSE VIALS PRIOR TO USE.
+COMIRNATY single dose vials and multiple dose vials with gray caps and labels with gray borders may be stored at room temperature [8°C to 25°C (46 F to 77°F) for a total of 12 hours prior to the first puncture. After first puncture, multiple dose vials should be held between 2°C to 25°C (35°F to 77°F). Multiple dose vials should be discarded 12 hours after first puncture.
+Transportation of Vials
+If local redistribution is needed, single dose vials and multiple dose vials may be transported at -90°C to -60°C (-130°F to -76°F), or at 2°C to 8°C (35°F to 46°F).
+17 PATIENT COUNSELING INFORMATION
+Inform vaccine recipient of the potential benefits and risks of vaccination with COMIRNATY.
+Inform vaccine recipient of the importance of completing the 2 dose vaccination series.
+There is a pregnancy exposure registry for COMIRNATY. Encourage individuals exposed to COMIRNATY around the time of conception or during pregnancy to register by visiting https://mothertobaby.org/ongoing-study/covid19-vaccines/.
+Advise vaccine recipient to report any adverse events to their healthcare provider or to the Vaccine Adverse Event Reporting System at 1-800-822-7967 and www.vaers.hhs.gov.
+23
+
+Prior to administering the vaccine, give the vaccine recipient the Vaccine Information Fact Sheet for Recipients and Caregivers about COMIRNATY (COVID-19 Vaccine, mRNA) and the Pfizer-BioNTech COVID-19
+Vaccine to Prevent Coronavirus Disease 2019 (COVID-19) for Use in Individuals 12 Years of Age and Older.
+The Vaccine Information Fact Sheet for Recipients and Caregivers is available at www.cvdvaccine-us.com.
+This product's labeling may have been updated. For the most recent prescribing information, please visit https://dailymed.nlm.nih.gov/dailymed/
+BIONTECH
+Manufactured for
+BioNTech Manufacturing GmbH
+An der Goldgrube 12
+55131 Mainz, Germany
+@Pfizer
+Manufactured by
+Pfizer Inc., New York, NY 10017
+LAB-1490-4.0
+US Govt. License No. 2229
+24
+

docs/Package Insert – COMIRNATY (purple cap).txt

@@ -0,0 +1,1593 @@
+Individuals using assistive technology may not be able to fully access the information contained in this file. For assistance, please call 800-835-4709 or 240-402-8010, extension 1. CBER
+Consumer Affairs Branch or send an e-mail to: ocod@fda.hhs.gov and include 508 Accommodation and the title of the document in the subject line of your e-mail.
+
+HIGHLIGHTS OF PRESCRIBING INFORMATION
+These highlights do not include all the information needed to use
+COMIRNATY safely and effectively. See full prescribing information for COMIRNATY.
+COMIRNATY® (COVID-19 Vaccine, mRNA) suspension for injection, for intramuscular use
+Initial U.S. Approval: 2021
+-RECENT MAJOR CHANGES
+Indications and Usage (1)
+Dosage and Administration, Preparation for Administration (2.1)
+7/2022
+7/2022
+• INDICATIONS AND USAGE
+COMIRNATY is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older. (1)
+•
+-DOSAGE AND ADMINISTRATION.
+COMIRNATY supplied in multiple dose vials with purple caps and labels with purple borders MUST BE DILUTED before use. (2.1)
+For intramuscular injection only. (2.2)
+COMIRNATY is administered intramuscularly as a series of 2 doses
+(0.3 mL each) 3 weeks apart. (2.3)
+DOSAGE FORMS AND STRENGTHS
+Suspension for injection. After preparation, a single dose is 0.3 mL. (3)
+- CONTRAINDICATIONS
+Known history of a severe allergic reaction (e.g., anaphylaxis) to any component of COMIRNATY. (4)
+FULL PRESCRIBING INFORMATION: CONTENTS*
+1 INDICATIONS AND USAGE
+2
+DOSAGE AND ADMINISTRATION
+2.1
+Preparation for Administration
+2.2
+Administration Information
+2.3
+Vaccination Schedule
+DOSAGE FORMS AND STRENGTHS
+CONTRAINDICATIONS
+5
+WARNINGS AND PRECAUTIONS
+5.1
+Management of Acute Allergic Reactions
+5.2
+Mvocarditis and Pericarditis
+5.3
+Syncope
+5.4
+Altered Immunocompetence
+5.5
+Limitation of Effectiveness
+6
+ADVERSE REACTIONS
+6.1
+Clinical Trials Experience
+6.2
+Postmarketing Experience
+§ USE IN SPECIFIC POPULATIONS
+8.1
+Pregnancy
+- WARNINGS AND PRECAUTIONS
+Postmarketing data demonstrate increased risks of myocarditis and pericarditis, particularly within 7 days following the second dose. (5.2)
+Syncope (fainting) may occur in association with administration of injectable vaccines, including COMIRNATY. Procedures should be in place to avoid injury from fainting. (5.4)
+- ADVERSE REACTIONS
+In clinical studies of participants 16 through 55 years of age, the most commonly reported adverse reactions (>10%) were pain at the injection site (88.6%), fatigue (70.1%), headache (64.9%), muscle pain (45.5%), chills (41.5%), joint pain (27.5%), fever (17.8%), and injection site swelling (10.6%). (6.1)
+In clinical studies of participants 56 years of age and older, the most commonly reported adverse reactions (≥10%) were pain at the injection site (78.2%), fatigue (56.9%), headache, (45.9%), muscle pain (32.5%). chills (24.8%), joint pain (21.5%), injection site swelling (11.8%), fever (11.5%), and injection site redness (10.4%). (6.1)
+In clinical studies of adolescents 12 through 15 years of age, the most commonly reported adverse reactions (≥8%) were pain at the injection site (90.5%), fatigue (77.5%), headache (75.5%), chills (49.2%), muscle pain (42.2%). fever (24.3%), joint pain (20.2%), injection site swelling (9.2%), and injection site redness (8.6%). (6. 1)
+To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
+1-800-438-1985 or VAERS at 1-800-822-7967 or http://vaers.hhs.gov.
+See 17 for PATIENT COUNSELING INFORMATION.
+Revised: 4/2023
+8.2
+Lactation
+8.4
+Pediatric Use
+8.5
+Geriatric Use
+11 DESCRIPTION
+12 CLINICAL PHARMACOLOGY
+12.1 Mechanism of Action
+13 NONCLINICAL TOXICOLOGY
+13.1
+Carcinogenesis, Mutagenesis, Impairment of Fertility
+14 CLINICAL STUDIES
+14.1 Efficacy in Participants 16 Years of Age and Older
+14.2 Efficacy in Adolescents 12 Through 15 Years of Age
+14 3
+Immunogenicity in Adolescents 12 Through 15 Years of Age
+16 HOW SUPPLIED/STORAGE AND HANDLING
+17 PATIENT COUNSELING INFORMATION
+* Sections or subsections omitted from the full prescribing information are not listed.
+
+FULL PRESCRIBING INFORMATION
+1
+INDICATIONS AND USAGE
+COMIRNATY is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older.
+2
+DOSAGE AND ADMINISTRATION
+For intramuscular injection only.
+2.1
+Preparation for Administration
+| The storage, preparation, and administration information in this Prescribing Information apply to COMIRNATY for individuals 12 years of age and older supplied in multiple dose vials with purple caps and labels with purple borders, which MUST BE DILUTED before use.
+COMIRNATY Multiple Dose Vial with a Purple Cap and Label with a Purple Border
+Doses Per Vial
+Age Range
+After Dilution
+12 years and older
+Dilution Information
+Dilute with 1.8 mL sterile 0.9%
+Sodium Chloride Injection, US prior
+to use
+Dose Volume
+6
+0.3 mL
+Dose Preparation
+Each vial MUST BE DILUTED before administering the vaccine.
+Prior to Dilution
+• COMIRNATY multiple dose vial with a purple cap and label with a purple border contains a volume of 0.45 mL, supplied as a frozen suspension that does not contain preservative.
+• Each vial must be thawed before dilution.
+• Vials may be thawed in the refrigerator [2°C to 8°C (35°F to 46°F)] or at room temperature [up to 25°C (77°F)] [see How Supplied/Storage and Handling (16)].
+• Refer to thawing instructions in the panels below.
+Dilution
+• Dilute the vial contents using 1.8 mL of sterile 0.9% Sodium Chloride Injection, US to form
+COMIRNATY. Do not add more than 1.8 mL of diluent.
+• ONLY use sterile 0.9% Sodium Chloride Injection, US as the diluent. Do not use bacteriostatic 0.9%
+Sodium Chloride Injection or any other diluent.
+• Vials of sterile 0.9% Sodium Chloride Injection, US are provided but shipped separately. Use the provided diluent or another sterile 0.9% Sodium Chloride Injection, USP as the diluent. o Provided diluent vials are single-use only; discard after 1.8 mL is withdrawn. o If another sterile 0.9% Sodium Chloride Injection, USP is used as the diluent, discard after
+1.8 mL is withdrawn.
+2
+
+• Do not dilute more than 1 vial of COMIRNATY using the same diluent vial.
+• After dilution, 1 vial of COMIRNATY contains 6 doses of 0.3 mL each.
+• Refer to dilution and dose preparation instructions in the panels below.
+Dilution and Preparation Instructions
+COMIRNATY Multiple Dose Vial with Purple Cap and Label with Purple Border
+Vial Verification
+Purple cap
+DILUTE BEFORE USE
+• Verify that the vial of COMIRNATY has a purple plastic cap and a label with a purple border.
+V Purple plastic cap and label with purple border.
+COMIRNATY Multiple Dose Vial with Purple Cap and Label with Purple Border - Thawing Prior to Dilution
+No more than
+2 hours at room temperature (up to 25°C/77°F).
+• Thaw vial(s) of COMIRNATY before dilution either by:
+o Allowing vial(s) to thaw in the refrigerator [2°C
+to 8°C (35°F to 46°F)I. A carton of vials may take up to 3 hours to thaw, and thawed vials can be stored in the refrigerator for up to 1 month.
+Allowing vial(s) to sit at room temperature [up to
+25°C (77°F)] for 30 minutes.
+• Using either thawing method, vials must reach room temperature before dilution and must be diluted within 2 hours.
+3
+
+Dilution and Preparation Instructions
+• Before dilution invert vaccine vial gently 10 times.
+• Do not shake.
+• Inspect the liquid in the vial prior to dilution. The liquid is a white to off-white suspension and may contain white to off-white opaque amorphous
+• particles.
+Do not use if liquid is discolored or if other particles are observed.
+Gently × 10
+COMIRNATY Multiple Dose Vial with Purple Cap and Label with Purple Border -
+Dilution
+• ONLY use sterile 0.9% Sodium Chloride Injection,
+USP as the diluent.
+• Withdraw 1.8 mL of diluent into a transfer syringe
+(21-gauge or narrower needle).
+• Add 1.8 mL of sterile 0.9% Sodium Chloride
+Injection, USP into the vaccine vial.
+Z
+Add 1.8 mL of sterile 0.9% sodium chloride injection, USP.
+4
+
+Dilution and Preparation Instructions
+• Equalize vial pressure before removing the needle from the vaccine vial by withdrawing 1.8 mL air into the empty diluent syringe.
+Pull back plunger to 1.8 mL to remove air from vial.
+• Gently invert the vial containing COMIRNATY
+10 times to mix.
+• Do not shake.
+Inspect the vaccine in the vial.
+• The vaccine will be an off-white suspension. Do not use if vaccine is discolored or contains particulate matter.
+Gently × 10
+5
+
+Dilution and Preparation Instructions
+DILUTE BEFORE,
+• Record the date and time of dilution on the
+COMIRNATY vial label.
+• Store between 2°C to 25°C (35°F to 77°F).
+• Discard any unused vaccine 6 hours after dilution.
+Record the date and time of dilution.
+Use within 6 hours after dilution.
+COMIRNATY Multiple Dose Vial with Purple Cap and Label with Purple Border -
+Preparation of Individual 0.3 mL Doses
+10.2
++ 0.3
+0.4
+Withdraw 0.3 mL of COMIRNATY preferentially using low dead-volume syringes and/or needles.
+• Each dose must contain 0.3 mL of vaccine.
+• If the amount of vaccine remaining in a single vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume.
+• Administer immediately.
+Withdraw 0.3 mL dose of vaccine.
+2.2
+Administration Information
+Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The vaccine will be an off-white suspension. Do not administer if vaccine is discolored or contains particulate matter.
+Administer a single 0.3 mL dose of COMIRNATY intramuscularly.
+After dilution, vials of COMIRNATY with purple caps and labels with purple borders contain 6 doses of 0.3 mL of vaccine. Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial If standard syringes and needles are used, there may not be sufficient volume to extract 6 doses from a single vial. Irrespective of the type of syringe and needle,
+• each dose must contain 0.3 mL of vaccine.
+• if the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume.
+do not pool excess vaccine from multiple vials.
+6
+
+2.3
+Vaccination Schedule
+COMIRNATY is administered intramuscularly as a series of 2 doses (0.3 mL each) 3 weeks apart.
+There are no data available on the interchangeability of COMIRNATY with COVID-19 vaccines from other manufacturers to complete the vaccination series. Individuals who have received 1 dose of COMIRNATY should receive a second dose of COMIRNATY to complete the vaccination series.
+DOSAGE FORMS AND STRENGTHS
+COMIRNATY is a suspension for injection. After preparation, each dose of COMIRNATY supplied in vials with purple caps and labels with purple borders is 0.3 mL.
+4
+CONTRAINDICATIONS
+Do not administer COMIRNATY to individuals with known history of a severe allergic reaction (e.g., anaphylaxis) to any component of the COMIRNATY [see Description (11)].
+WARNINGS AND PRECAUTIONS
+5.1
+Management of Acute Allergic Reactions
+Appropriate medical treatment used to manage immediate allergic reactions must be immediately available in the event an acute anaphylactic reaction occurs following administration of COMIRNATY.
+5.2
+Myocarditis and Pericarditis
+Postmarketing data demonstrate increased risks of myocarditis and pericarditis, particularly within 7 days following the second dose. The observed risk is higher among males under 40 years of age than among females and older males. The observed risk is highest in males 12 through 17 years of age. Although some cases required intensive care support, available data from short-term follow-up suggest that most individuals have had resolution of symptoms with conservative management. Information is not yet available about potential long-term sequelae. The CDC has published considerations related to myocarditis and pericarditis after vaccination, including for vaccination of individuals with a history of myocarditis or pericarditis (https://www.cdc.gov/vaccines/covid-19/clinical-considerations/myocarditis.html).
+5.3
+Syncope
+Syncope (fainting) may occur in association with administration of injectable vaccines, including
+COMIRNATY. Procedures should be in place to avoid injury from fainting.
+5.4
+Altered Immunocompetence
+Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the COMIRNATY.
+5.5
+Limitation of Effectiveness
+COMIRNATY may not protect all vaccine recipients.
+7
+
+6
+ADVERSE REACTIONS
+In clinical studies, the most commonly reported (≥10%) adverse reactions in participants 16 through 55 years of age following any dose were pain at the injection site (88.6%), fatigue (70.1%), headache (64.9%), muscle pain (45.5%), chills (41.5%), joint pain (27.5%), fever (17.8%), and injection site swelling (10.6%).
+In clinical studies, the most commonly reported (≥10%) adverse reactions in participants 56 years of age and older following any dose were pain at the injection site (78.2%), fatigue (56.9%), headache, (45.9%), muscle pain (32.5%), chills (24.8%), joint pain (21.5%), injection site swelling (11.8%), fever (11.5%), and injection site redness (10.4%).
+In a clinical study, the most commonly reported (≥8%) adverse reactions in adolescents 12 through 15 years of age following any dose were pain at the injection site (90.5%), fatigue (77.5%), headache (75.5%), chills (49.2%), muscle pain (42.2%), fever (24.3%), joint pain (20.2%), injection site swelling (9.2%), and injection site redness (8.6%).
+6.1 Clinical Trials Experience
+Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.
+The safety of COMIRNATY was evaluated in participants 12 years of age and older in 2 clinical studies conducted in Germany (Study 1), United States, Argentina, Brazil, Turkey, South Africa, and Germany (Study 2). Study BNT162-01 (Study 1) was a Phase 1/2, 2-part, dose-escalation trial that enrolled 60 participants, 18 through 55 years of age and 36 participants, 56 through 85 years of age. Study C4591001 (Study 2) is a Phase 1/2/3 multicenter, multinational, randomized, saline placebo-controlled, double-blinded (Phase 2/3), dose-finding, vaccine candidate-selection and efficacy study that has enrolled approximately 46,000 participants 12 years of age or older. Of these, approximately 44,047 participants (22,026 COMIRNATY; 22,021 placebo) in Phase 2/3 are 16 years of age or older (including 378 and 376 participants 16 through 17 years of age in the COMIRNATY and placebo groups, respectively) and
+2,260 adolescents are 12 through 15 years of age (1,131 and 1,129 in the COMIRNATY and placebo groups, respectively). Upon issuance of the Emergency Use Authorization for COMIRNATY, participants were unblinded to offer placebo participants COMIRNATY. Participants were unblinded in a phased manner over a period of months to offer placebo participants COMIRNATY. Study 2 also included 200 participants with confirmed stable human immunodeficiency virus (HIV) infection; HIV-positive participants are included in safety population disposition but are summarized separately in safety analyses. Confirmed stable HIV infection was defined as documented viral load <50 copies/mL and CD4 count >200 cells/mm? within 6 months before enrollment, and on stable antiretroviral therapy for at least 6 months.
+In Study 2, all participants 12 through 15 years of age, and 16 years and older in the reactogenicity subset were monitored for solicited local and systemic reactions and use of antipyretic medication after each vaccination in an electronic diary. Participants are being monitored for unsolicited adverse events, including serious adverse events, throughout the study [from Dose 1 through 1 month (all unsolicited adverse events) or 6 months (serious adverse events) after the last vaccination]. Tables 1 through 6 present the frequency and severity of solicited local and systemic reactions, respectively, within 7 days following each dose of COMIRNATY and placebo.
+8
+
+Participants 16 Years of Age and Older
+At the time of the analysis of the ongoing Study 2 with a data cutoff of March 13, 2021, there were 25,651 (58.2%) participants (13,031 COMIRNATY and 12,620 placebo) 16 years of age and older followed for
+>4 months after the second dose.
+Demographic characteristics in Study 2 were generally similar with regard to age, gender, race, and ethnicity among participants who received COMIRNATY and those who received placebo. Overall, among the total participants who received either COMIRNATY or placebo, 50.9% were male, 49.1% were female, 79.3% were 16 through 64 years of age, 20.7% were 65 years of age and older, 82.0% were White, 9.6% were Black or African American, 25.9% were Hispanic/Latino, 4.3% were Asian, and 1.0% were American Indian or Alaska Native.
+Local and Systemic Adverse Reactions Solicited in the Study 2
+In participants 16 through 55 years of age after receiving Dose 2, the mean duration of pain at the injection site was 2.5 days (range 1 to 70 days), for redness 2.2 days (range 1 to 9 days), and for swelling 2.1 days (range 1 to 8 days) for participants in the COMIRNATY group. In participants 56 years of age and older after receiving Dose 2, the mean duration of pain at the injection site was 2.4 days (range 1 to 36 days), for redness 3.0 days (range 1 to 34 days), and for swelling 2.6 days (range 1 to 34 days) for participants in the COMIRNATY group.
+Table 1: Study 2 - Frequency and Percentages of Participants with Solicited Local Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Participants 16 Through 55 Years of Age - Reactogenicity Subset of the Safety Population*
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Na=2899
+Na=2908
+nb (%)
+nb (%)
+COMIRNATY
+Dose 2
+Na=2682 nb (%)
+Placebo
+Dose 2
+Na=2684 nb (%)
+Redness®
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+156 (5.4)
+113 (3.9)
+36 (1.2)
+7 (0.2)
+28 (1.0)
+19 (0.7)
+6 (0.2)
+3 (0.1)
+151 (5.6)
+90 (3.4)
+50 (1.9)
+11 (0.4)
+18 (0.7)
+12 (0.4)
+6 (0.2)
+O
+Swelling
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+184(6,3)
+124(4.3)
+54 (1.9)
+6 (0.2)
+16 (0.6)
+6 (0.2)
+8 (0.3)
+2 (0.1)
+183 (6.8)
+110 (4.1)
+66 (2.5)
+7 (0.3)
+5 (0.2)
+3 (0.1)
+2 (0.1)
+0
+Pain at the iniection sited
+Any
+2426 (83.7)
+414 (14.2)
+2101 (78.3)
+Mild
+1464 (50.5)
+391 (13.4)
+1274 (47.5)
+Moderate
+923 (31.8)
+20 (0.7)
+788 (29.4)
+312 (11.6)
+284 (10.6)
+28 (1.0)
+Severe
+39 (1.3)
+3 (0.1)
+39 (1.5)
+Notes: Reactions were collected in the electronic diary (e-diary) from Day 1 to Day 7 after vaccination.
+No Grade 4 solicited local reactions were reported in participants 16 through 55 years of age.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention. Participants with chronic, stable HIV infection were excluded.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. The N for each reaction was the same, therefore, this information was included in the column header.
+b. n = Number of participants with the specified reaction.
+c. Mild: >2.0 to <5.0 cm; Moderate: >5.0 to <10.0 cm; Severe: >10.0 cm.
+d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
+9
+
+Table 2: Study 2 - Frequency and Percentages of Participants with Solicited Systemic Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Participants 16 Through 55 Years of Age - Reactogenicity Subset of the Safety Population*
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Na=2899
+Na=2908
+nb (%)
+nb (%)
+COMIRNATY
+Dose 2
+Na=2682 nb (%)
+Placebo
+Dose 2
+Na=2684 nb (%)
+Fever
+>38.0°C
+≥38.0°C to 38.4°C
+>38.4°C to 38.9°C
+>38.9°C to 40.0°C
+>40.0°C
+Fatigue
+Any
+Mild
+Moderate
+Severe
+Headache
+Any
+Mild
+Moderate
+Severe
+Chills°
+Any
+Mild
+Moderate
+Severe
+Vomiting
+Any
+Mild
+Moderate
+Severe
+Diarrheg®
+Any
+Mild
+Moderate
+Severe
+New or worsened muscle pain°
+Any
+Mild
+Moderate
+Severe
+New or worsened ioint pain°
+Any
+Mild
+Moderate
+Severe
+119 (4.1)
+86 (3.0)
+25 (0.9)
+8 (0.3)
+1431 (49.4)
+760 (26.2)
+630 (21.7)
+41 (1.4)
+1262 (43.5)
+785 (27.1)
+444(15.3)
+33 (1.1)
+479 (16.5)
+338 (11.7)
+126 (4.3)
+15 (0.5)
+34 (1.2)
+29 (1.0)
+5 (0.2)
+0
+309 (10.7)
+251 (8.7)
+55 (1.9)
+3 (0.1)
+664 (22.9)
+353 (12.2)
+296 (10.2)
+15 (0.5)
+342 (11.8)
+200 (6.9)
+137 (4.7)
+5 (0.2)
+25 (0.9)
+16 (0.6)
+5 (0.2)
+4 (0.1)
+960 (33.0)
+570 (19.6)
+372 (12.8)
+18 (0.6)
+975 (33.5)
+633 (21.8)
+318 (10.9)
+24 (0.8)
+199 (6.8)
+148 (5.1)
+49 (1.7)
+2 (0.1)
+36 (1.2)
+30 (1.0)
+5 (0.2)
+1 (0.0)
+323 (11.1)
+264 (9.1)
+58 (2.0)
+1 (0.0)
+329 (11.3)
+231 (7.9)
+96 (3.3)
+2 (0.1)
+168 (5.8)
+112 (3.9)
+55 (1.9)
+1 (0.0)
+10
+440 (16.4)
+254 (9.5)
+146 (5.4)
+39 (1.5)
+1 (0.0)
+1649 (61.5)
+558 (20.8)
+949 (35.4)
+142 (5.3)
+1448 (54.0)
+699 (26.1)
+658 (24.5)
+91 (3.4)
+1015 (37.8)
+477 (17.8)
+469 (17.5)
+69 (2.6)
+58 (2.2)
+42 (1.6)
+12 (0.4)
+4 (0.1)
+269 (10.0)
+219 (8.2)
+44 (1.6)
+6 (0.2)
+1055 (39.3)
+441 (16.4)
+552 (20.6)
+62 (2.3)
+638 (23.8)
+291 (10.9)
+320 (11.9)
+27 (1.0)
+11 (0.4)
+5 (0.2)
+4 (0.1)
+2 (0.1)
+O
+614 (22.9)
+317 (11.8)
+283 (10.5)
+14 (0.5)
+652 (24.3)
+404 (15.1)
+230 (8.6)
+18 (0.7)
+114(4.2)
+89 (3.3)
+23 (0.9)
+2 (0.1)
+30 (1.1)
+20 (0.7)
+10 (0.4)
+O
+205 (7.6)
+169 (6.3)
+35 (1.3)
+1 (0.0)
+237 (8.8)
+150 (5.6)
+84 (3.1)
+3 (0.1)
+147 (5.5)
+82 (3.1)
+61 (2.3)
+4 (0.1)
+
+COMIRNATY
+Dose 1
+Na=2899 nb (%)
+Placebo
+Dose 1
+Na=2908 nb (%)
+COMIRNATY
+Dose 2
+N°=2682 nb (%)
+Placebo
+Dose 2
+Na=2684 nb (%)
+Use of antipyretic or pain medication
+805 (27.8)
+398 (13.7)
+1213 (45.2)
+320 (11.9)
+Notes: Reactions and use of antipyretic or pain medication were collected in the electronic diary (e-diary) from Day 1 to Day 7 after each dose.
+No Grade 4 solicited systemic reactions were reported in participants 16 through 55 years of age.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention. Participants with chronic, stable HIV infection were excluded.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. The N for each reaction or use of antipyretic or pain medication was the same, therefore, this information was included in the column header.
+b. n = Number of participants with the specified reaction.
+c. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity.
+d. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration.
+e. Mild: 2 to 3 loose stools in 24 hours; Moderate: 4 to 5 loose stools in 24 hours; Severe: 6 or more loose stools in 24 hours.
+f. Severity was not collected for use of antipyretic or pain medication.
+Table 3: Study 2 - Frequency and Percentages of Participants with Solicited Local Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Participants 56 Years of Age and Older - Reactogenicity Subset of the Safety Population*
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Na=2008
+Na=1989
+nb (%)
+nb (%)
+COMIRNATY
+Dose 2
+Na=1860 nb (%)
+Placebo
+Dose 2
+Na=1833 nb (%)
+Redness°
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+106 (5.3)
+71 (3.5)
+30 (1.5)
+5 (0.2)
+20 (1.0)
+13 (0.7)
+5 (0.3)
+2 (0.1)
+133 (7.2)
+65 (3.5)
+58 (3.1)
+10 (0.5)
+14 (0.8)
+10 (0.5)
+3 (0.2)
+1 (0.1)
+Swelling
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+141 (7.0)
+87 (4.3)
+52 (2.6)
+2 (0.1)
+23 (1.2)
+11 (0.6)
+12 (0.6)
+0
+145 (7.8)
+80 (4.3)
+61 (3.3)
+4 (0.2)
+13 (0.7)
+5 (0.3)
+7 (0.4)
+1 (0.1)
+Pain at the injection sited
+Any (>2.0 cm)
+1408 (70.1)
+185 (9.3)
+1230 (66.1)
+Mild
+1108 (55.2)
+177 (8.9)
+873 (46.9)
+Moderate
+296 (14.7)
+8 (0.4)
+347 (18.7)
+Severe
+4 (0.2)
+0
+10 (0.5)
+143 (7.8)
+138 (7.5)
+5 (0.3)
+0
+Notes: Reactions were collected in the electronic diary (-diary) from Day 1 to Day 7 after vaccination.
+No Grade 4 solicited local reactions were reported in participants 56 years of age and older.
+ Randomized participants in the safety analysis population who received at least 1 dose of the study intervention. Participants with
+chronic, stable HIV infection were excluded.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. The N for each reaction was the same, therefore, the information was included in the column header.
+b. n = Number of participants with the specified reaction.
+c. Mild: >2.0 to <5.0 cm; Moderate: >5.0 to <10.0 cm; Severe: >10.0 cm.
+d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
+11
+
+Table 4: Study 2 - Frequency and Percentages of Participants with Solicited Systemic Reactions, by Maximum Severity, Within 7 Days After Each Dose - Participants 56 Years of Age and Older - Reactogenicity Subset of the Safety Population*
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Na=2008
+Na=1989
+nb (%)
+nb (%)
+COMIRNATY
+Dose 2
+N°=1860 n° (%)
+Placebo
+Dose 2
+Na=1833 nb (%)
+Fever
+>38.0°C
+≥38.0°C to 38.4°C
+>38.4°C to 38.9°C
+>38.9°C to 40.0°C
+>40.0°C
+Fatigue
+Any
+Mild
+Moderate
+Severe
+Grade 4
+Headache
+Any
+Mild
+Moderate
+Severe
+Chills
+Any
+Mild
+Moderate
+Severe
+Vomiting
+Any
+Mild
+Moderate
+Severe
+Diarrhea®
+Any
+Mild
+Moderate
+Severe
+New or worsened muscle pain°
+Any
+Mild
+Moderate
+Severe
+26 (1.3)
+23 (1.1)
+2 (0.1)
+1 (0.0)
+O
+677 (33.7)
+415 (20.7)
+259 (12.9)
+3 (0.1)
+503 (25.0)
+381 (19.0)
+120 (6.0)
+2 (0.1)
+130 (6.5)
+102 (5.1)
+28 (1.4)
+0
+10 (0.5)
+9 (0.4)
+1 (0.0)
+0
+168 (8.4)
+137 (6.8)
+27 (1.3)
+4 (0.2)
+274 (13.6)
+183 (9.1)
+90 (4.5)
+1 (0.0)
+8 (0.4)
+3 (0.2)
+3 (0.2)
+2 (0.1)
+0
+447 (22.5)
+281 (14.1)
+163 (8.2)
+3 (0.2)
+O
+363 (18.3)
+267 (13.4)
+93 (4.7)
+3 (0.2)
+69 (3.5)
+49 (2.5)
+19 (1.0)
+1 (0.1)
+9 (0.5)
+9 (0.5)
+0
+130 (6.5)
+109 (5.5)
+20 (1.0)
+1 (0.1)
+165 (8.3)
+111 (5.6)
+51 (2.6)
+3 (0.2)
+219 (11.8)
+158 (8.5)
+54 (2.9)
+7 (0.4)
+0
+949 (51.0)
+391 (21.0)
+497 (26.7)
+60 (3.2)
+1 (0.1)
+733 (39.4)
+464 (24.9)
+256 (13.8)
+13 (0.7)
+435 (23.4)
+229 (12.3)
+185 (9.9)
+21 (1.1)
+13 (0.7)
+10 (0.5)
+1 (0.1)
+2 (0.1)
+152 (8.2)
+125 (6.7)
+25 (1.3)
+2 (0.1)
+537 (28.9)
+229 (12.3)
+288 (15.5)
+20 (1.1)
+4 (0.2)
+2 (0.1)
+1 (0.1)
+1 (0.1)
+0
+306 (16.7)
+183 (10.0)
+121 (6.6)
+2 (0.1)
+O
+259 (14.1)
+189 (10.3)
+65 (3.5)
+5 (0.3)
+57 (3.1)
+45 (2.5)
+12 (0.7)
+5 (0.3)
+5 (0.3)
+0
+102 (5.6)
+76 (4.1)
+22 (1.2)
+4 (0.2)
+99 (5.4)
+65 (3.5)
+33 (1.8)
+1 (0.1)
+12
+
+COMIRNATY
+Dose 1
+Na=2008 nb (%)
+Placebo
+Dose 1
+Na=1989 nb (%)
+COMIRNATY
+Dose 2
+N°=1860 nb (%)
+Placebo
+Dose 2
+Na=1833 nb (%)
+New or worsened ioint pain°
+Any
+175 (8.7)
+124 (6.2)
+353 (19.0)
+72 (3.9)
+Mild
+119 (5.9)
+78 (3.9)
+183 (9.8)
+44 (2.4)
+Moderate
+53 (2.6)
+45 (2.3)
+161 (8.7)
+27 (1.5)
+Severe
+3 (0.1)
+1 (0.1)
+9 (0.5)
+1 (0.1)
+Use of antipyretic or pain medication"
+382 (19.0)
+224 (11.3)
+688 (37.0)
+170 (9.3)
+Notes: Reactions and use of antipyretic or pain medication were collected in the electronic diary (e-diary) from Day 1 to Day 7 after each dose.
+The only Grade 4 solicited systemic reaction reported in participants 56 years of age and older was fatigue.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention. Participants with chronic, stable HIV infection were excluded.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose. N for each reaction or use of antipyretic or pain medication was the same, therefore was included in the column header.
+b. n = Number of participants with the specified reaction.
+c. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity; Grade 4 reactions were defined in the clinical study protocol as emergency room visit or hospitalization for severe fatigue, severe headache, severe chills, severe muscle pain, or severe joint pain.
+d. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration; Grade 4 emergency visit or hospitalization for severe vomiting.
+e. Mild: 2 to 3 loose stools in 24 hours; Moderate: 4 to 5 loose stools in 24 hours; Severe: 6 or more loose stools in 24 hours; Grade 4: emergency room or hospitalization for severe diarrhea.
+f. Severity was not collected for use of antipyretic or pain medication.
+In participants with chronic, stable HIV infection the frequencies of solicited local and systemic adverse reactions were similar to or lower than those observed for all participants 16 years of age and older.
+Unsolicited Adverse Events
+Overall, 11,253 (51.1%) participants in the COMIRNATY group and 11,316 (51.4%) participants in the placebo group had follow-up time between >4 months to <6 months after Dose 2 in the blinded placebo-controlled follow-up period with an additional 1,778 (8.1%) and 1,304 (5.9%) with ≥6 months of blinded follow-up time in the COMIRNATY and placebo groups, respectively.
+A total of 12,006 (54.5%) participants originally randomized to COMIRNATY had >6 months total (blinded and unblinded) follow-up after Dose 2.
+In an analysis of all unsolicited adverse events reported following any dose, through 1 month after Dose 2, in participants 16 years of age and older (N=43,847; 21,926 COMIRNATY group vs. 21,921 placebo group), those assessed as adverse reactions not already captured by solicited local and systemic reactions were nausea (274 vs. 87), malaise (130 vs. 22), lymphadenopathy (83 vs. 7), asthenia (76 vs. 25), decreased appetite (39 vs. 9), hyperhidrosis (31 vs. 9), lethargy (25 vs. 6), and night sweats (17 vs. 3).
+In analyses of all unsolicited adverse events in Study 2 from Dose 1 up to the participant unblinding date, 58.2% of study participants had at least 4 months of follow-up after Dose 2. Among participants 16 through
+55 years of age who received at least 1 dose of study vaccine, 12,995 of whom received COMIRNATY and
+13,026 of whom received placebo, unsolicited adverse events were reported by 4,396 (33.8%) participants in the COMIRNATY group and 2,136 (16.4%) participants in the placebo group. In a similar analysis in participants 56 years of age and older that included 8,931 COMIRNATY recipients and 8,895 placebo
+13
+
+recipients, unsolicited adverse events were reported by 2,551 (28.6%) participants in the COMIRNATY group and 1,432 (16.1%) participants in the placebo group. Among participants with confirmed stable HIV infection that included 100 COMIRNATY recipients and 100 placebo recipients, unsolicited adverse events were reported by 29 (29%) participants in the COMIRNATY group and 15 (15%) participants in the placebo group.
+The higher frequency of reported unsolicited adverse events among COMIRNATY recipients compared to placebo recipients was primarily attributed to events that are consistent with adverse reactions solicited among participants in the reactogenicity subset (Table 3 and Table 4).
+Throughout the placebo-controlled safety follow-up period, Bell's palsy (facial paralysis) was reported by 4 participants in the COMIRNATY group and 2 participants in the placebo group. Onset of facial paralysis was Day 37 after Dose 1 (participant did not receive Dose 2) and Days 3, 9, and 48 after Dose 2. In the placebo group the onset of facial paralysis was Day 32 and Day 102. Currently available information is insufficient to determine a causal relationship with the vaccine. In the analysis of blinded, placebo-controlled follow-up, there were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic or neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.
+Serious Adverse Events
+In Study 2, among participants 16 through 55 years of age who had received at least 1 dose of vaccine or
+placebo (COMIRNATY =12,995; placebo = 13,026), serious adverse events from Dose 1 up to the participant
+unblinding date in ongoing follow-up were reported by 103 (0.8%) COMIRNATY recipients and 117 (0.9%)
+placebo recipients. In a similar analysis, in participants 56 years of age and older (COMIRNATY = 8,931;
+placebo = 8,895), serious adverse events were reported by 165 (1.8%) COMIRNATY recipients and 151 (1.7%)
+placebo recipients who received at least 1 dose of COMIRNATY or placebo, respectively. In these analyses, 58.2% of study participants had at least 4 months of follow-up after Dose 2. Among participants with confirmed stable HIV infection serious adverse events from Dose 1 up to the participant unblinding date in ongoing follow-up were reported by 2 (2%) COMIRNATY recipients and 2 (2%) placebo recipients.
+In the analysis of blinded, placebo-controlled follow-up, there were no notable patterns between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of serious adverse events that would suggest a causal relationship to COMIRNATY.
+Adolescents 12 Through 15 Years of Age
+In Study 2, 2,260 adolescents (1,131 COMIRNATY; 1,129 placebo) were 12 through 15 years of age. At the time of the analysis of the ongoing Study 2 with a data cutoff of September 2, 2021, there were 1,559 (69.0%) adolescents (786 COMIRNATY and 773 placebo) 12 through 15 years of age followed for >4 months after the second dose. The safety evaluation in Study 2 is ongoing.
+Demographic characteristics in Study 2 were generally similar with regard to age, gender, race, and ethnicity among adolescents who received COMIRNATY and those who received placebo. Overall, among the adolescents who received COMIRNATY, 50.1% were male and 49.9% were female, 85.8% were White, 4.6% were Black or African American, 11.7% were Hispanic/Latino, 6.4% were Asian, and 0.4% were American Indian/Alaska Native.
+14
+
+Local and Systemic Adverse Reactions Solicited in Study 2
+In adolescents 12 through 15 years of age after receiving Dose 2, the mean duration of pain at the injection site was 2.5 days (range 1 to 11 days), for redness 1.8 days (range 1 to 5 days), and for swelling 1.6 days (range 1 to 5 days) in the COMIRNATY group.
+Table 5: Study 2 - Frequency and Percentages of Adolescents With Solicited Local Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Adolescents 12 Through 15 Years of Age - Safety Population*
+COMIRNATY
+Dose 1
+Na=1127 nb (%)
+Placebo
+Dose 1
+Na=1127 nb (%)
+COMIRNATY
+Dose 2
+Na=1097 nb (%)
+Placebo
+Dose 2
+N°=1078 nb (%)
+Redness°
+Any (>2 cm)
+Mild
+Moderate
+Severe
+65 (5.8)
+44 (3.9)
+20 (1.8)
+1 (0.1)
+12 (1.1)
+11 (1.0)
+1 (0.1)
+0 (0.0)
+55 (5.0)
+29 (2.6)
+26 (2.4)
+0 (0.0)
+Swelling
+Any (>2 cm)
+Mild
+Moderate
+Severe
+78 (6.9)
+55 (4.9)
+23 (2.0)
+0 (0.0)
+11 (1.0)
+9 (0.8)
+2 (0.2)
+0 (0.0)
+54 (4.9)
+36 (3.3)
+18 (1.6)
+0 (0.0)
+Pain at the injection site
+Any
+971 (86.2)
+263 (23.3)
+866 (78.9)
+Mild
+467 (41.4)
+227 (20.1)
+466 (42.5)
+Moderate
+493 (43.7)
+36 (3.2)
+393 (35.8)
+Severe
+11 (1.0)
+0 (0.0)
+7 (0.6)
+Note: Reactions were collected in the electronic diary (e-diary) from Day 1 to Day 7 after vaccination.
+* Randomized participants in the safetv analvsis population who received at least 1 dose of the study intervention.
+a. N= Number of participants reporting at least 1 yes or no response for the specified reaction after the specified dose.
+b. n = Number of participants with the specified reaction.
+c. Mild: >2.0 to 55.0 cm; Moderate: >5.0 to <10.0 cm; Severe: >10.0 cm.
+d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
+10 (0.9)
+8 (0.7)
+2 (0.2)
+0 (0.0)
+6 (0.6)
+4 (0.4)
+2 (0.2)
+0 (0.0)
+193 (17.9)
+164 (15.2)
+29 (2.7)
+0 (0.0)
+Table 6: Study 2 - Frequency and Percentages of Adolescents with Solicited Systemic Reactions, by
+Maximum Severity, Within 7 Days After Each Dose - Adolescents 12 Through 15 Years of Age - Safety Population*
+COMIRNATY
+Dose 1
+Na=1127 nb (%)
+Placebo
+Dose 1
+Na=1127 nb (%)
+COMIRNATY
+Dose 2
+Na=1097 nb (%)
+Placebo
+Dose 2
+Na=1078 nb (%)
+Fever
+>38 0°C
+>38.0°C to 38.4°C
+>38.4°C to 38.9°C
+>38.9°C to 40.0°C
+>40.0°0
+Fatigue
+Any
+Mild
+114 (10.1)
+74 (6.6)
+29 (2.6)
+10 (0.9)
+1 (0.1)
+12 (1.1)
+8 (0.7)
+2 (0.2)
+2 (0.2)
+0 (0.0)
+215 (19.6)
+107 (9.8)
+83 (7.6)
+25 (2.3)
+0 (0.0)
+7 (0.6)
+5 (0.5)
+1 (0.1)
+1 (0.1)
+0 (0.0)
+677 (60.1)
+278 (24.7)
+457 (40.6)
+250 (22.2)
+15
+726 (66.2)
+232 (21.1)
+264 (24.5)
+133 (12.3)
+
+COMIRNATY
+Placebo
+COMIRNATY
+Placebo
+Dose 1
+Dose 1
+Dose 2
+Dose 2
+Na=1127
+Na=1127
+N°=1097
+N°=1078
+nb (%)
+n" (%)
+nb (%)
+nb (%)
+Moderate
+384 (34.1)
+199 (17.7)
+468 (42.7)
+127 (11.8)
+Severe
+15 (1.3)
+8 (0.7)
+26 (2.4)
+4 (0.4)
+Headache
+Any
+623 (55.3)
+396 (35.1)
+708 (64.5)
+264 (24.5)
+Mild
+361 (32.0)
+256 (22.7)
+302 (27.5)
+170 (15.8)
+Moderate
+251 (22.3)
+131 (11.6)
+384 (35.0)
+93 (8.6)
+Severe
+11 (1.0)
+9 (0.8)
+22 (2.0)
+1 (0.1)
+Chills°
+Any
+311 (27.6)
+109 (9.7)
+455 (41.5)
+74 (6.9)
+Mild
+195 (17.3)
+82 (7.3)
+221 (20.1)
+53 (4.9)
+Moderate
+111 (9.8)
+25 (2.2)
+214 (19.5)
+21 (1.9)
+Severe
+5 (0.4)
+2 (0.2)
+20 (1.8)
+0 (0.0)
+Vomiting
+Any
+31 (2.8)
+10 (0.9)
+29 (2.6)
+12 (1.1)
+Mild
+30 (2.7)
+8 (0.7)
+25 (2.3)
+11 (1.0)
+Moderate
+0 (0.0)
+2 (0.2)
+4 (0.4)
+1 (0.1)
+Severe
+1 (0.1)
+0 (0.0)
+0 (0.0)
+0 (0.0)
+Diarrhea®
+Any
+90 (8.0)
+82 (7.3)
+65 (5.9)
+44 (4.1)
+Mild
+77 (6.8)
+72 (6.4)
+59 (5.4)
+39 (3.6)
+Moderate
+13 (1.2)
+10 (0.9)
+6 (0.5)
+5 (0.5)
+Severe
+0 (0.0)
+0 (0.0)
+0 (0.0)
+0 (0.0)
+New or worsened muscle pain°
+Any
+272 (24.1)
+148 (13.1)
+355 (32.4)
+90 (8.3)
+Mild
+125 (11.1)
+88 (7.8)
+152 (13.9)
+51 (4.7)
+Moderate
+145 (12.9)
+60 (5.3)
+197 (18.0'
+37 (3.4)
+Severe
+2 (0.2)
+0 (0.0)
+6 (0.5)
+2 (0.2)
+New or worsened ioint pain°
+Any
+109 (9.7)
+77 (6.8)
+173 (15.8)
+51 (4.7)
+Mild
+66 (5.9)
+50 (4.4)
+91 (8.3)
+30 (2.8)
+Moderate
+42 (3.7)
+27 (2.4)
+78 (7.1)
+21 (1.9)
+Severe
+1 (0.1)
+0 (0.0)
+4 (0.4)
+0 (0.0)
+Use of antipyretic or pain medicationf
+413 (36.6)
+111 (9.8)
+557 (50.8)
+95 (8.8)
+Note: Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary) from Day 1 to Day 7 after each dose.
+* Randomized participants in the safety analysis population who received at least 1 dose of the study intervention.
+a. N= Number of participants reporting at least 1 yes or no response for the specified event after the specified dose.
+b. n = Number of participants with the specified reaction.
+c. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity.
+d. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration.
+e. Mild: 2 to 3 loose stools in 24 hours; Moderate: 4 to 5 loose stools in 24 hours; Severe: 6 or more loose stools in 24 hours.
+f. Severity was not collected for use of antipyretic or pain medication.
+Unsolicited Adverse Events
+In Study 2, 2,260 adolescents (1,131 COMIRNATY; 1,129 placebo) were 12 through 15 years of age. Of these, 634 (56.1%) participants in the COMIRNATY group and 629 (55.7%) participants in the placebo group had
+16
+
+follow-up time between ≥4 months to <6 months after Dose 2 in the blinded placebo-controlled follow-up period with an additional 152 (13.4%) and 144 (12.8%) with ≥6 months of blinded follow-up time in the
+COMIRNATY and placebo groups, respectively.
+A total of 1,113 (98.4%) participants 12 through 15 years of age originally randomized to COMIRNATY had
+>6 months total (blinded and unblinded) follow-up after Dose 2.
+An analysis of all unsolicited adverse events in Study 2 from Dose 1 up to the participant unblinding date was conducted. Among participants 12 through 15 years of age who received at least one dose of study vaccine, unsolicited adverse events were reported by 95 (8.4%) participants in the COMIRNATY group and 113 (10.0%) participants in the placebo group.
+In an analysis of all unsolicited adverse events reported during blinded follow-up from Dose 1 through 1 month after Dose 2, in adolescents 12 to 15 years of age, those assessed as adverse reactions not already captured by solicited local and systemic reactions were lymphadenopathy (9 vs. 2), and nausea (5 vs. 2).
+In the analysis of blinded, placebo-controlled follow-up, there were no other notable patterns or numerical imbalances between treatment groups for specific categories of unsolicited adverse events (including other neurologic or neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of non-serious adverse events that would suggest a causal relationship to COMIRNATY.
+Serious Adverse Events
+In Study 2, among participants 12 through 15 years of age who had received at least 1 dose of vaccine or
+placebo (COMIRNATY = 1,131; placebo = 1,129), serious adverse events from Dose 1 up to the participant
+unblinding date in ongoing follow-up were reported by 10 (0.9%) COMIRNATY recipients and 2 (0.2%) placebo recipients. In these analyses, 69.0% of study participants had at least 4 months of follow-up after Dose 2. In the analysis of blinded, placebo-controlled follow-up, there were no notable patterns between treatment groups for specific categories of serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to COMIRNATY. In the analysis of unblinded follow-up, there were no notable patterns of specific categories of serious adverse events that would suggest a causal relationship to COMIRNATY.
+6.2
+Postmarketing Experience
+The following adverse reactions have been identified during postmarketing use of COMIRNATY, including under Emergency Use Authorization. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.
+Cardiac Disorders: myocarditis, pericarditis
+Gastrointestinal Disorders: diarrhea, vomiting
+Immune System Disorders: severe allergic reactions, including anaphylaxis, and other hypersensitivity reactions (e.g., rash, pruritus, urticaria, angioedema)
+Musculoskeletal and Connective Tissue Disorders: pain in extremity (arm)
+Nervous System Disorders: syncope, dizziness
+17
+
+USE IN SPECIFIC POPULATIONS
+8.1
+Pregnancy
+There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to COMIRNATY during pregnancy. Women who are vaccinated with COMIRNATY during pregnancy are encouraged to enroll in the registry by visiting https://mothertobaby.org/ongoing-study/covid19-vaccines/
+Risk Summary
+All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Available data on COMIRNATY administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.
+A developmental toxicity study has been performed in female rats administered the equivalent of a single human dose of COMIRNATY on 4 occasions, twice prior to mating and twice during gestation. These studies revealed no evidence of harm to the fetus due to the vaccine (see Animal Data).
+Data
+Animal Data
+In a developmental toxicity study, 0.06 mL of a vaccine formulation containing the same quantity of nucleoside-modified messenger ribonucleic acid (mRNA) (30 mcg) and other ingredients included in a single human dose of COMIRNATY was administered to female rats by the intramuscular route on 4 occasions: 21 and 14 days prior to mating, and on gestation days 9 and 20. No vaccine-related adverse effects on female fertility, fetal development, or postnatal development were reported in the study.
+8.2
+Lactation
+Risk Summary
+It is not known whether COMIRNATY is excreted in human milk. Data are not available to assess the effects of COMIRNATY on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for COMIRNATY and any potential adverse effects on the breastfed child from COMIRNATY or from the underlying maternal condition.
+For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.
+8.4
+Pediatric Use
+Safety and effectiveness of COMIRNATY in individuals 12 through 17 years of age is based on safety and effectiveness data in this age group and in adults I see Adverse Reactions (6) and Clinical Studies (14.1)].
+The safety and effectiveness of COMIRNATY in individuals younger than 12 years of age have not been established.
+8.5
+Geriatric Use
+Of the total number of COMIRNATY recipients in Study 2 as of March 13, 2021 (N = 22,026),
+20.7% (n = 4,552) were 65 years of age and older and 4.2% (n = 925) were 75 years of age and older [see
+18
+
+Clinical Studies (14.1)]. No overall differences in safety or effectiveness were observed between these recipients and younger recipients.
+11
+DESCRIPTION
+COMIRNATY (COVID-19 Vaccine, mRNA) is a sterile suspension for injection for intramuscular use.
+COMIRNATY is supplied as a frozen suspension in multiple dose vials with purple caps and labels with purple borders; each vial must be diluted with 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP prior to use to form the vaccine. Each 0.3 mL dose of COMIRNATY supplied in multiple dose vials with purple caps and labels with purple borders contains 30 mcg of a nucleoside-modified messenger RNA (mRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2.
+Each 0.3 mL dose of the COMIRNATY supplied in multiple dose vials with purple caps and labels with purple borders also includes the following ingredients:
+lipids (0.43 mg ((4-hydroxybutylazanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide,
+0.09 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.2 mg cholesterol), 0.01 mg potassium chloride, 0.01 mg monobasic potassium phosphate, 0.36 mg sodium chloride, 0.07 mg dibasic sodium phosphate dihydrate, and 6 mg sucrose. The diluent (sterile 0.9% Sodium Chloride Injection, USP) contributes an additional 2.16 mg sodium chloride per dose.
+COMIRNATY does not contain preservative.
+The vial stoppers are not made with natural rubber latex.
+12
+CLINICAL PHARMACOLOGY
+12.1 Mechanism of Action
+The nucleoside-modified mRNA in COMIRNATY is formulated in lipid particles, which enable delivery of the mRNA into host cells to allow expression of the SARS-CoV-2 S antigen. The vaccine elicits an immune response to the S antigen, which protects against COVID-19.
+13
+NONCLINICAL TOXICOLOGY
+13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
+COMIRNATY has not been evaluated for the potential to cause carcinogenicity, genotoxicity, or impairment of male fertility. In a developmental toxicity study in rats with COMIRNATY there were no vaccine-related effects on female fertility [see Use in Specific Populations (8.1)].
+14
+CLINICAL STUDIES
+14.1 Efficacy in Participants 16 Years of Age and Older
+Study 2 is an ongoing, multicenter, multinational, randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in participants 12 ears of age and older. Randomization was stratified by age: 12 through 15 years of age, 16 through 55 years of age, or 56 years of age and older, with a minimum of 40% of participants in the >56-year stratum. The study excluded participants who were immunocompromised and those who had previous clinical or microbiological diagnosis of COVID-19.
+Participants with preexisting stable disease, defined as disease not requiring significant change in therapy or
+19
+
+hospitalization for worsening disease during the 6 weeks before enrollment, were included as were participants with known stable infection with HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV).
+In Study 2, based on data accrued through March 13, 2021, approximately 44,000 participants 12 years of age and older were randomized equally and received 2 doses of COMIRNATY or placebo. Participants are planned to be followed for up to 24 months, for assessments of safety and efficacy against COVID-19.
+Overall, among the total participants who received COMIRNATY or placebo, 51.4% or 50.3% were male and 48.6% or 49.7% were female, 79.1% or 79.2% were 16 through 64 years of age, 20.9% or 20.8% were 65 years of age and older, 81.9% or 82.1% were White, 9.5% or 9.6% were Black or African American, 1.0% or 0.9% were American Indian or Alaska Native, 4.4% or 4.3% were Asian, 0.3% or 0.2% Native Hawaiian or other Pacific Islander, 25.6% or 25.4% were Hispanic/Latino, 73.9% or 74. 1% were non-Hispanic/Latino, 0.5% or 0.5% did not report ethnicity, 46.0% or 45.7% had comorbidities [participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as subiects who had at least 1 of the Charlson comorbidity index category or body mass index (BMI) ≥30 kg/m?1, respectively. The mean age at vaccination was 49.8 or 49.7 years and median age was 51.0 or 51.0 in participants who received COMIRNATY or placebo, respectively.
+Efficacy Against COVID-19
+The population for the analysis of the protocol pre-specified primary efficacy endpoint included
+36,621 participants 12 years of age and older (18,242 in the COMIRNATY group and 18,379 in the placebo group) who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose.
+The population in the protocol pre-specified primary efficacy analysis included all participants 12 years of age and older who had been enrolled from July 27, 2020, and followed for the development of COVID-19 through November 14, 2020. Participants 18 through 55 years of age and 56 years of age and older began enrollment from July 27, 2020, 16 through 17 years of age began enrollment from September 16, 2020, and 12 through 15 years of age began enrollment from October 15, 2020.
+For participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, vaccine efficacy against confirmed COVID-19 occurring at least 7 days after Dose 2 was 95.0% (95% credible interval: 90.3,
+97.6), which met the pre-specified success criterion. The case split was 8 COVID-19 cases in the COMIRNATY group compared to 162 COVID-19 cases in the placebo group.
+The population for the updated vaccine efficacy analysis included participants 16 years of age and older who had been enrolled from July 27, 2020, and followed for the development of COVID-19 during blinded placebo-controlled follow-up through March 13, 2021, representing up to 6 months of follow-up after Dose 2.
+There were 12,796 (60.8%) participants in the COMIRNATY group and 12,449 (58.7%) in the placebo group followed for >4 months after Dose 2 in the blinded placebo-controlled follow-up period.
+SARS-CoV-2 variants of concern identified from COVID-19 cases for this age group from this data cutoff include B. 1.1.7 (Alpha) and B. 1.351 (Beta). Representation of identified variants among cases in vaccine versus placebo recipients did not suggest decreased vaccine effectiveness against these variants.
+The updated vaccine efficacy information is presented in Table 7.
+20
+
+Table 7: Vaccine Efficacy - First COVID-19 Occurrence From 7 Days After Dose 2, by Age
+Subgroup - Participants 16 Years of Age and Older Without Evidence of Infection and Participants With or Without Evidence of Infection Prior to 7 Days After Dose 2 - Evaluable
+Efficacy (7 Days) Population During the Placebo-Controlled Follow-up Period
+First COVID-19 occurrence from 7 days after Dose 2 in participants without evidence of prior
+SARS-CoV-2 infection*
+COMIRNATY
+Placebo
+Na=19,993
+Na=20,118
+Cases
+Cases
+nib
+nib
+Subgroup
+Surveillance Time' (n2d)
+Surveillance Time^ (n24)
+77
+833
+All participants
+6.092 (19,711)
+5.857 (19,741)
+70
+709
+16 through 64 years
+4.859 (15,519)
+4.654 (15,515)
+7
+124
+65 years and older
+1.233 (4192)
+1.202 (4226)
+Vaccine Efficacy %
+(95% CI°)
+91.1
+(88.8, 93.1)
+90.5
+(87.9, 92.7)
+94.5
+(88.3, 97.8)
+First COVID-19 occurrence from 7 days after Dose 2 in participants with or without* evidence of prior
+SARS-CoV-2 infection
+COMIRNATY
+Placebo
+Na=21,047
+Na=21,210
+Cases
+Cases
+nib
+n1b
+Vaccine Efficacy %
+Subgroup
+Surveillance Time' (n29)
+Surveillance Time (n2d)
+(95% CI)
+81
+854
+90.9
+All participants
+6.340 (20,533)
+6.110 (20,595)
+(88.5, 92.8)
+74
+726
+90.2
+16 through 64 years
+5.073 (16.218)
+4.879 (16.269)
+(87.5, 92.4)
+7
+128
+94.7
+65 vears and older
+1.267 (4315)
+1.232 (4326)
+(88.7, 97.9)
+Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat; diarrhea; vomiting).
+Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+a. N= Number of participants in the specified group.
+b. n1 = Number of participants meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
+Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d. n2 = Number of participants at risk for the endpoint.
+e. Two-sided confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time.
+Subgroup analyses of vaccine efficacy (although limited by small numbers of cases in some subgroups) did not suggest meaningful differences in efficacy across genders, ethnic groups, geographies, or for participants with obesity or medical comorbidities associated with high risk of severe COVID-19.
+Efficacy Against Severe COVID-19
+Efficacy analyses of secondary efficacy endpoints supported benefit of COMIRNATY in preventing severe
+COVID-19. Vaccine efficacy against severe COVID-19 is presented only for participants with or without prior
+21
+
+SARS-CoV-2 infection (Table 8) as the COVID-19 case counts in participants without prior SARS-CoV-2 infection were the same as those in participants with or without prior SARS-CoV-2 infection in both the
+COMIRNATY and placebo groups.
+Table 8: Vaccine Efficacy - First Severe COVID-19 Occurrence in Participants 16 Years of Age and
+Older With or Without* Prior SARS-CoV-2 Infection Based on Protocol or Centers for Disease Control and Prevention (CDC) Definition From 7 Davs After Dose 2 - Evaluable
+Efficacy (7 Days) Population During the Placebo-Controlled Follow-up
+Vaccine Efficacy - First Severe COVID-19 Occurrence
+COMIRNATY
+Placebo
+Cases
+Cases
+n1a
+n1a
+Surveillance Timel (n2°)
+Surveillance Time (n2°
+1
+21
+7 days after Dose 2d
+6.353 (20.540)
+6.237 (20.629)
+Vaccine Efficacy %
+(95% CI)
+95.3
+(70.9, 99.9)
+Vaccine Efficacy - First Severe COVID-19 Occurrence Based on CDC Definition
+COMIRNATY
+Placebo
+Cases
+Cases
+nia
+n1a
+Vaccine Efficacy %
+Surveillance Time® (n2°)
+Surveillance Time' (n2°)
+(95% CId
+31
+100
+7 davs after Dose 2d
+6.345 (20,513)
+6.225 (20,593)
+(87.6, 100.0)
+Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell, sore throat; diarrhea; vomiting).
+* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+† Severe illness from COVID-19 is defined in the protocol as confirmed COVID-19 and presence of at least 1 of the following:
+• Clinical signs at rest indicative of severe systemic illness (respiratory rate >30 breaths per minute, heart rate >125 beats per minute, saturation of oxygen <93% on room air at sea level, or ratio of arterial oxygen partial pressure to fractional inspired oxygen <300 mm Hg);
+• Respiratory failure [defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation (ECMO)];
+• Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or requiring vasopressors);
+• Significant acute renal, hepatic, or neurologic dysfunction;
+• Admission to an Intensive Care Unit;
+• Death.
+‡ Severe illness from COVID-19 as defined by CDC is confirmed COVID-19 and presence of at least 1 of the following:
+• Hospitalization;
+• Admission to the Intensive Care Unit;
+• Intubation or mechanical ventilation;
+• Death.
+a. n1 = Number of participants meeting the endpoint definition.
+b. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
+Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period
+c. n2 = Number of participants at risk for the endpoint.
+d. Two-side confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the surveillance time.
+14.2 Efficacy in Adolescents 12 Through 15 Years of Age
+A descriptive efficacy analysis of Study 2 has been performed in 2,260 adolescents 12 through 15 years of age evaluating confirmed COVID-19 cases accrued up to a data cutoff date of September 2, 2021.
+22
+
+The vaccine efficacy information in adolescents 12 through 15 years of age is presented in Table 9.
+Table 9: Vaccine Efficacy - First COVID-19 Occurrence From 7 Days After Dose 2: Without Evidence
+of Infection and With or Without Evidence of Infection Prior to 7 Das After Dose 2 - Blinded Placebo-Controlled Follow-up Period, Adolescents 12 Through 15 Years of Age Evaluable Efficacy (7 Days) Population
+First COVID-19 occurrence from 7 days after Dose 2 in adolescents 12 through 15 years of age without evidence of prior SARS-CoV-2 infection*
+COMIRNATY
+Placebo
+Na=1057
+Na=1030
+Cases
+Cases
+nIb
+n]b
+Surveillance Time® (n20)
+Surveillance Time (n2d)
+Adolescents
+28
+12 through 15 years of age
+0.343 (1043)
+0.322 (1019)
+Vaccine Efficacy %
+(95% CI°
+100.0
+(86.8, 100.0)
+First COVID-19 occurrence from 7 days after Dose 2 in adolescents 12 through 15 years of age with or without evidence of prior SARS-CoV-2 infection
+COMIRNATY
+Placebo
+Na=1119
+Na=1109
+Cases
+Cases
+nib
+nib
+Vaccine Efficacy %
+Surveillance Time (n2d)
+Surveillance Time (n2d)
+(95% CI°
+Adolescents
+0
+30f
+100.0
+12 through 15 years of age
+0.362 (1098)
+0.345 (1088)
+(87.5, 100.0)
+Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat, diarrhea; vomiting).
+* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT (nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 davs after Dose 2 were included in the analysis.
+a. N= Number of participants in the specified group.
+b. n1 = Number of participants meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
+Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d. n2 = Number of participants at risk for the endpoint.
+e. Two-side confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted for surveillance time.
+f.
+The only SARS-CoV-2 variant of concern identified from COVID-19 cases in this age group from this data cutoff was B. 1.1.7
+(Alpha).
+14.3 Immunogenicity in Adolescents 12 Through 15 Years of Age
+In Study 2, an analysis of SARS-CoV-2 50% neutralizing titers (NT50) 1 month after Dose 2 in a randomly selected subset of participants demonstrated non-inferior immune responses (within 1.5-fold) comparing adolescents 12 through 15 years of age to participants 16 through 25 years of age who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2 (Table 10).
+23
+
+Table 10: Summary of Geometric Mean Ratio for 50% Neutralizing Titer - Comparison of Adolescents
+12 Through 15 Years of Age to Participants 16 Through 25 Years of Age (Immunogenicity
+Subset) - Participants Without Evidence of Infection up to 1 Month After Dose 2 - Dose 2
+Evaluable Immunogenicity Population
+COMIRNATY
+12 Through 15 Years
+16 Through 25 Years
+na=190
+na=170
+Time
+Point
+GMT
+(95% CI°
+GMT
+(95% CI°
+12 Through 15 Years/
+16 Through 25 Years
+Met
+Noninferiority
+GMRd
+(95% CId)
+Objective
+(YIN)
+Assay
+SARS-CoV-2 neutralization
+1 month
+assay - NT50
+after
+(titer)f
+1253.6
+708.1
+1.77
+Dose 2
+(1117.7, 1406.1)
+(625.9, 801.1)
+(1.50, 2.09)
+Y
+Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titer; LLOQ = lower limit of
+quantitation; NAAT = nucleic-acid amplification test; NT50 = 50% neutralizing tier; SARS-CoV-2 = severe acute respiratory
+svndrome coronavirus 2.
+Note: Participants who had no serological or virological evidence (up to 1 month after receipt of the last dose) of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and
+2), and had negative NAAT (nasal swab) at any unscheduled visit up to 1 month after Dose 2 were included in the analysis.
+a. n= Number of participants with valid and determinate assay results for the specified assay at the given dose/sampling time point
+b. Protocol-specified timing for blood sample collection.
+c. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titers and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ.
+d. GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titers (Group 1 [12 through 15 years of age] - Group 2 [16 through 25 years of age]) and the corresponding CI (based on the Student t distribution).
+e. Noninferiority is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 0.67.
+f. SARS-CoV-2 NT50 were determined using the SARS-CoV-2 mNeonGreen Virus Microneutralization Assay. The assay uses a fluorescent reporter virus derived from the USA WA1/2020 strain and virus neutralization is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized.
+16
+HOW SUPPLIED/STORAGE AND HANDLING
+COMIRNATY Suspension for Intramuscular Injection, multiple dose vials with purple caps and labels with purple borders are supplied in a carton containing 25 multiple dose vials (NDC 0069-1000-03) or 195 multiple dose vials (NDC 0069-1000-02). A 0.9% Sodium Chloride Injection, US diluent is provided but shipped separately, and should be stored at controlled room temperature 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. The provided 0.9% Sodium Chloride Injection, US diluent will be supplied either as cartons of 10 mL single-use vials manufactured by Hospira, Inc (NDC 0409-4888-10), or 2 mI single-use vials manufactured by Fresenius Kabi USA, LLC (NDC 63323-186-02).
+After dilution, 1 vial contains 6 doses of 0.3 mL.
+During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light.
+Do not refreeze thawed vials.
+Frozen Vials Prior to Use
+Cartons of COMIRNATY multiple dose vials with purple caps and labels with purple borders arrive in thermal containers with dry ice. Once received, remove the vial cartons immediately from the thermal container and
+24
+
+preferably store in an ultra-low temperature freezer between -90°C to -60°C (-130°F to -76°F) until the expiry date printed on the label.
+Alternatively, vials may be stored at -25°C to - 15°C (-13°F to 5°F) for up to 2 weeks. Vials must be kept frozen and protected from light, in the original cartons, until ready to use. Vials stored at -25°C to - 15°C (-13°F to 5°F) for up to 2 weeks may be returned 1 time to the recommended storage condition of -90°C to -60°C (-130°F to -76°F). Total cumulative time the vials are stored at -25°C to -15°C (-13°F to 5°F) should be tracked and should not exceed 2 weeks.
+If an ultra-low temperature freezer is not available, the thermal container in which COMIRNATY arrives may be used as temporary storage when consistently re-filled to the top of the container with dry ice. Refer to the re-icing guidelines packed in the original thermal container for instructions regarding the use of the thermal container for temporary storage. The thermal container maintains a temperature range of -90°C to -60°C (-130°F
+to -76°F). Storage of the vials between -96°C to -60°C (-141°F to -76°F) is not considered an excursion from the recommended storage condition.
+Transportation of Frozen Vials
+If local redistribution is needed and full cartons containing vials cannot be transported at -90°C to -60°C (-130°F to -76°F), vials may be transported at -25°C to -15°C (-13°F to 5°F). Any hours used for transport at -25°C to -15°C (-139F to 5°F) count against the 2-week limit for storage at -25°C to -15°C (-13°F to 5°F).
+Frozen vials transported at -25°C to -15°C (-13°F to 5°F) may be returned 1 time to the recommended storage condition of -90°C to -60°C (-130°F to -76°F).
+Thawed Vials Before Dilution
+Thawed Under Refrigeration
+Thaw and then store undiluted vials in the refrigerator 2°C to 8°C (35°F to 46°F)] for up to 1 month. A carton of 25 vials or 195 vials may take up to 2 or 3 hours, respectively, to thaw in the refrigerator, whereas a fewer number of vials will thaw in less time.
+Thawed at Room Temperature
+For immediate use, thaw undiluted vials at room temperature [up to 25°C (77°F)] for 30 minutes. Thawed vials can be handled in room light conditions.
+Vials must reach room temperature before dilution.
+Undiluted vials may be stored at room temperature for no more than 2 hours.
+Transportation of Thawed Vials
+Available data support transportation of 1 or more thawed vials at 2°C to 8°C (35°F to 46°F) for up to 12 hours.
+Vials After Dilution
+After dilution, store vials between 2°C to 25°C (35°F to 77°F) and use within 6 hours from the time of dilution.
+During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light.
+Any vaccine remaining in vials must be discarded after 6 hours. Do not refreeze.
+25
+
+17
+PATIENT COUNSELING INFORMATION
+Inform vaccine recipient of the potential benefits and risks of vaccination with COMIRNATY.
+Inform vaccine recipient of the importance of completing the 2 dose vaccination series.
+There is a pregnancy exposure registry for COMIRNATY. Encourage individuals exposed to COMIRNATY around the time of conception or during pregnancy to register by visiting https://mothertobaby.org/ongoing-study/covid19-vaccines/
+Advise vaccine recipient to report any adverse events to their healthcare provider or to the Vaccine Adverse Event Reporting System at 1-800-822-7967 and www.vaers.hhs.gov.
+Prior to administering the vaccine, give the vaccine recipient the Vaccine Information Fact Sheet for Recipients and Caregivers about COMIRNATY (COVID-19 Vaccine, mRNA) and the Pfizer-BioNTech COVID-19
+Vaccine to Prevent Coronavirus Disease 2019 (COVID-19) for Use in Individuals 12 Years of Age and Older.
+The Vaccine Information Fact Sheet for Recipients and Caregivers is available at www.cvdvaccine-us.com.
+This product's labeling may have been updated. For the most recent prescribing information, please visit https://dailymed.nlm.nih.gov/dailymed/.
+BIONTECH
+Manufactured for
+BioNTech Manufacturing GmbH
+An der Goldgrube 12
+55131 Mainz, Germany
+& Pfizer
+Manufactured by
+Pfizer Inc., New York, NY 10017
+LAB-1448-4.0
+US Govt. License No. 2229
+26
+

docs/Pharmacovigilance Plan Review Memo - COMIRNATY.txt

@@ -0,0 +1,697 @@
+Department of Health and Human Services
+Food and Drug Administration (FDA)
+Center for Biologics Evaluation and Research (CBER)
+Office of Biostatistics and Epidemiology (OBE)
+Division of Epidemiology (DE)
+PHARMACOVIGILANCE PLAN REVIEW MEMORANDUM
+From:
+To:
+Through:
+Subiect:
+Sponsor:
+Product:
+BLA Number:
+Proposed Indication:
+Submission Date:
+Action Due Date:
+Deborah L. Thompson, MD, MSPH
+Medical Officer, Analytic Epidemiology Branch (AEB) DE, OBE, CBER, FDA
+Ramachandra Naik, PhD Chair, Review Committee
+Office of Vaccines Research and Review (OVRR), CBER, FDA
+Manette Niu, MD
+Branch Chief, AEB
+DE, OBE, CBER, FDA
+Narayan Nair, MD
+Division Director, DE OBE, CBER, FDA
+Review of Pharmacovigilance Plan
+Pfizer
+BNT162b2 (COVID-19 Vaccine)
+125742/0
+Active immunization to prevent COVID-19 disease caused by SARS-CoV-2 in individuals ≥16 years of age.
+May 18, 2021
+January 16, 2022
+
+1 Objective and Scope
+The purpose of this review is to assess the adequacy of the sponsor's proposed pharmacovigilance plan (PVP) submitted under the original BLA 125742/0 for post-marketing safety monitoring for BNT162b2 (COVID-19 vaccine) and to identify potential safety issues associated with the use of BNT162b2 that may need to be addressed through additional pharmacovigilance activities including safety-related studies such as Post-Marketing Requirements (PMs) and/or Post-Marketing Commitments (PMCs) or a Risk Evaluation and Mitigation Strategy (REMS).
+2 Product Information
+2.1 Product Description
+BNT162b2 contains a nucleoside-modified messenger RNA (modRNA) that encodes the viral spike (S) glycoprotein of SARS-CoV-2. Each vial of vaccine is diluted with 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP prior to use to form the vaccine.
+Each dose includes the following ingredients: lipids (14-
+hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate),2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol), potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose.
+2.2 Authorized Indication and Dosing Regimen
+The Pfizer-BioNTech COVID-19 Vaccine is currently authorized for use under an Emergency Use Authorization (EUA) for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals >12 years of age. The vaccine is administered intramuscularly as a series of two doses (0.3 mL each) given three weeks apart.
+2.3 Proposed Product Indication and Dosing Regimen
+The proposed indication for BNT162b2 is active immunization to prevent COVID-19 disease caused by SARS-CoV-2 in individuals >16 years of age. The vaccine is administered intramuscularly as a series of two doses (0.3 mL each) given three weeks apart.
+3 Materials Reviewed
+• Pharmacovigilance Plan, Version 1.0 (ST 125742/0.1, Module 1.16.1, dated May 17, 2021; received May 18, 2021)
+• Pharmacovigilance Plan, Version 1.1 (ST 125742/0.20, sequence 0021,
+Module 1.16.1, dated July 28, 2021; received July 29, 2021)
+2
+
+• Cumulative Analysis of Post-authorization Adverse Event Reports (ST
+125742/0, Module 5.3.6, received May 6, 2021)
+Summary of Clinical Safety (STN 125742/0, Module 2.7.4; received May 6, 2021)
+• Draft Labeling Text (STN 125742/0.1, Module 1.14; received May 18, 2021)
+• Post-authorization safety surveillance study protocols linked in the PVP
+• Sponsor's IR responses
+• VAERS database and data mining
+4 Summary of Pertinent Regulatory History and Prior Marketed Experience
+Pertinent regulatory history is shown in Table 1. BNT162b2 has received temporary authorization for emergency supply in 28 countries and conditional marketing authorization in 39 countries. As of August 4, 2021, over 194 million doses of BNT16b2 have been administered to over 88 million individuals in the U.S. under the EUA. Per the sponsor's Summary Monthly Safety Report (ST 19736.409), approximately (b) (4) doses of BNT162b2 have been shipped worldwide from December 1, 2020
+through June 30, 2021, which corresponds to approximately 757,863,718 estimated doses administered.
+Table 1: Pertinent Regulatory History
+Date
+April 29, 2020
+July 7, 2020
+December 11, 2020
+May 10, 2021
+May 18, 2021
+June 25, 2021
+Regulatory Action
+IND for BNT162b2 became effective
+Fast Track Designation granted for individuals 18 years of age and older
+Emergency Use Authorization (EUA 27034) granted for active immunization to prevent COVID-19 in individuals
+16 years of age and older
+FDA re-issued EUA letter to expand authorization for use in individuals 12 through 15 years of age with addition of following warning in Fact Sheet for Healthcare Providers: "Syncope (fainting) may occur in association with administration of injectable vaccines, in particular adolescents. Procedures should be in place to avoid injury from fainting."
+Final roll of BLA 125742/0 submitted
+EUA Fact Sheet revised to add Warnings for myocarditis and pericarditis following use of Pfizer-BioNTech
+COVID-19 Vaccine
+
+5 Summary of Sponsor's Safety Database
+5.1 Clinical Studies
+There are two clinical studies for BNT1622 which are summarized in Table 2.
+Table 2: Summary of Clinical Studies for BNT162b2*
+Study
+Description
+Number of
+Data cut-off date
+subiects randomized
+216
+October 23, 2020
+BNT162-01 Phase 1/2 first in human dose
+finding study, open-label, non-randomized, included two age cohorts: 18-55 years and 56-85 years; BNT162b2 was given at 5 dose levels (1, 3, 10, 20, 30 Mg)
+C4591001 (BNT162-02)
+Phase 1/2/3 randomized, placebo-controlled, observer blind study for safety, immunogenicity, and efficacy
+Phase 1: two age cohorts: 18-55 years and 65-85 years; 3 dose levels for BNT162b2: 10, 20, and
+30 Mg, randomized 4:1 to receive active vaccine or placebo; long term follow-up (LTFU) for AEs/SAEs for BNT162b2 30 ug group only
+Phase 2: two age cohorts: 18-55
+years and 56-85 years; BNT162b2 30 ug dose; randomized 1:1 to receive active vaccine or placebo
+Phase 3: three age cohorts: 12-15,
+16-55 years and >55 years;
+BNT162b2 30 Mg dose; randomized
+1:1 to receive active vaccine or placebo
+195 (30 in
+LTFU)
+August 24, 2020
+(March 13, 2021
+for LTFU)
+360
+September 2,
+2020
+43,847
+(includes
+360
+subiects from Phase
+2)
+March 13, 2021
+
+*Adapted from sponsor's Summary of Clinical Safety, Table 1.
+Study BNT162-01
+Study BNT162b2 is an ongoing, first-in-human, open-label, non-randomized Phase 1/2 dose finding and cohort expansion (for dose levels selected during dose finding) study conducted in Germany (not under U.S. IND) among healthy adults age 18 to 85 years of age. Four vaccine candidates from three different RNA platforms were tested. Key safety assessments included physical examinations, electrocardiograms, clinical laboratory tests, solicited local and systemic reactions (recorded in diaries for seven days post-dose), SARS-CoV-2 testing, adverse events (AEs), and serious adverse events (SAEs). Unsolicited treatment emergent As (TEEs) were recorded for 28 days post-second dose. Adverse events of special interest (AESI) included enhanced respiratory disease or flu-like symptomatology that did not resolve after seven days.
+Study C4591001
+Study C4591001 (IND 019736) is a Phase 1/2/3 randomized, placebo-controlled, observer blind study for safety, immunogenicity, and efficacy. Participants are followed for 24 months. Participants ≥16 years who originally received placebo (i.e., normal saline) and became eligible for receipt of BNT162b2 were offered BNT162b2 in a phased process as part of the study.
+Phase 1 evaluated two vaccine candidates (BNT162b1 and BNT162b2) and involved dose-level finding (three dose levels for BNT162b2: 10, 20, and 30 g) among two age cohorts of healthy adults (18-55 and 65-85 years; n=195). Subjects were randomized
+4:1 to receive active vaccine or placebo. Reactogenicity (i.e., local and systemic reactions) was assessed for up to seven days after each dose, As were assessed from dose 1 through 1-month after the last dose, and SAEs were assessed from dose 1 to six months after the last dose. Long-term follow-up for As and SAEs was conducted for the BNT162b2 30 g cohort (n=30) from 1-month post-second dose to the unblinding date (approximately 6-months post-second dose).
+Phase 2/3 was conducted to define the safety profile of BNT162b2 and involved administration of BNT1622 (30 ug dose) to individuals in three age cohorts (12-15 years, 16-55 years and >55 years; n=43,847). Phase 2/3 participants were those judged by investigators to be at higher risk for acquiring COVID-19 (e.g., individuals who use mass transportation or frontline essential workers). Subjects were randomized 1:1 to receive active vaccine or placebo. Phase 2 was conducted to confirm the safety profile seen in Phase 1 and included the first 360 randomized subiects; reactogenicity was assessed for up to seven days after each dose and AEs/SAEs were assessed from dose 1 to 7-days post-second dose. Phase 3 assessed reactogenicity in a subset of subjects (n=9,839) for up to seven days after each dose. Adverse events and SAEs were assessed in all subjects for 1-month post-second dose and up to the unblinding
+
+date. In addition, open-label AEs/SAEs were assessed among participants originally randomized to BNT162b2 (n=20,309) from the date of unblinding to the data cut-off (March 13, 2021). Open-label AEs/SAEs were assessed among participants who were originally randomized to placebo but were vaccinated with BNT162b2 after treatment disclosure (n=19,525) from the date of BNT1622 vaccination to the data-cutoff (March 13, 2021). No AEs of special interest were defined for Study C4591001.
+5.2 Adverse Events
+In Study BNT162-01 most solicited local and systemic reactions were mild or moderate in severity and were short-lived after dosing. Most unsolicited As were also mild to moderate in severity and all resolved; there were no unanticipated safety findings.
+There were no AESs, deaths, or treated-related SAEs reported among participants who received BNT162b2 in Study BNT162-01. Similarly, in Phase 1 and 2 of Study C4591001, reactogenicity was mostly mild to moderate and short-lived after dosing; the AE profile did not suggest any serious safety concerns. There were no treatment-related SAEs or deaths.
+In Phase 3 of Study C4591001, solicited local reactions occurred more commonly in the BNT162b2 group as compared with the placebo group; the majority of local reactions were mild or moderate in severity after both first and second doses and in both younger (<55 years) and older age groups (>55 years. Solicited systemic events and use of antipyretic/pain medication were generally reported less frequently in the placebo group as compared with the BNT162b2 group for both age groups and doses, with the exception of vomiting and diarrhea which were reported at similar frequencies between BNT162b2 and placebo groups. The majority of solicited systemic events were mild or moderate in severity. Solicited systemic events occurred more frequently after Dose 2 of BNT162b2 as compared with Dose 1 in both younger and older age groups.
+Reactogenicity As were generally milder and less frequent in the older age group as compared with the younger age group.
+In the blinded placebo-controlled follow-up period (n=43,847), 30.2% of BNT162b2 recipients and 13.9% of placebo recipients had any AE from Dose 1 to 1-month after Dose 2 and 0.6% and 0.5%, respectively, had an SAE; there were three deaths in the BNT162b2 group and five deaths in the placebo group. The most frequently reported AEs were reactogenicity events including injection site pain (13.3% BNT1622 group vs 1.8% placebo group), pyrexia (6.9% vs 0.4%), fatigue (6.7% vs 1.7%), chills (6.2% vS
+0.5%), headache (6.1% vs 1.9%), myalgia (5.7% vs 0.8%), pain (2.9% vs 0.3%), and arthralgia (1.2% vs 0.5%). Among those in the BNT1622 group, the overall AE frequencies were higher in the younger age group (32.6%) as compared with the older age group (26.7%).
+From Dose 1 to the unblinding date, the As with the highest incidence rates were consistent with the AEs in the Dose 1 to 1-month after Dose 2 analvsis. There were also similar incidence rates of SAEs (3.2 per 100 person-years for BNT162b2 group vs 3.3 per 100 person-years for placebo group) and deaths among BNT162b2 and placebo
+6
+
+recipients (0.2 per 100 person-years for both groups; 15 vs 14 deaths, respectively).
+There were four related-SAEs in the BNT162b2 group (one each of lymphadenopathy, shoulder injury related to vaccine administration, ventricular arrhythmia, and paresthesia of right leg) and one related-SAE in the placebo group (psoriatic arthropathy). The 15 deaths in BNT162b2 group were due to: cardiac arrest (n=4), arteriosclerosis (n=2), and one each of COVID-19 pneumonia, cardiac failure congestive, cardiorespiratory arrest, chronic obstructive pulmonary disease (COPD), emphysematous cholecystitis, hypertensive heart disease, metastatic lung cancer, sepsis, septic shock, shigella sepsis, and an unevaluable event; multiple contributing causes of death could be reported for each subject. The 14 deaths in the placebo group were due to COVID-19 (n=2), multiple organ dysfunction syndrome (n=2), myocardial infarction (n=2), pneumonia (n=2), lacking specific cause (n=2; one "death" and one "missing") and one each of acute respiratory failure, aortic rupture, metastatic biliary cancer, cardiac arrest, cardiorespiratory arrest, dementia, hemorrhagic stroke, liver metastases, and overdose.
+None of the deaths during the Dose 1 to unblinding date time period were assessed by investigators as related to the study intervention.
+From the unblinding date to the data cut-off, the incidence rates of AEs were markedly reduced relative to the AEs reported from Dose 1 to the unblinding date among the original BNT162b2 recipients (n=21,926) (8.8/100,000 person-years vs 83.2/100,000 person-years, respectively). There were 55 SAEs during this time period among the original BNT162b2 recipients, including one related-SAE of myocardial infarction (participant in younger age group with no past medical history [PMH1, onset 71-days after Dose 2, resolved same day). There were three deaths among the original BNT162b2 participants (all in the older age group; one each due to road traffic accident, lung metastases, and myocardial infarction); none of the deaths were assessed by investigators as related to study intervention.
+Among the 19,525 participants who originally received placebo and then received BNT162b2 after unblinding, the most frequently reported As overall were related to reactogenicity and were consistent with As reported among the group that was originally randomized to receive BNT162b2. After vaccination with BNT162b2, there was one related-SAE of anaphylactoid reaction in a patient with an ongoing medical history of drug hypersensitivity and food and seasonal allergies (onset 2-days post-1st dose of BNT162b2; treated with self-administered epinephrine pen and resolved same day). Two deaths occurred following vaccination with BNT162b2 (both in the older age group; one each due to cardiorespiratory arrest and completed suicide), neither of which were assessed by investigators as related to the study intervention.
+The sponsor also provided a review of As of interest requested by FDA (hypersensitivity/anaphylaxis, Bell's palsy/facial paralysis, lymphadenopathy, and appendicitis) and the Center for Disease Control and Prevention's (CDC) AESI list for COVID-19 vaccines. This review was focused on the Dose 1 to unblinding time period.
+For hypersensitivity, there was a higher number and percentage of participants in the BNT162b2 vs placebo groups (182 [0.83%] vs 161 [0.73%], respectively), which was mainly due to skin and subcutaneous tissue disorders (134 [0.61%] vs 119 [0.54%]),
+
+including rash (62 [0.28%] vs 52 (0.24%]), urticaria (18 [0.08%] vs 15 [0.07%]), rash pruritic (8 [0.04%] vs 6 [0.03%]), rash maculo-papular (7 [0.03%] vs 4 [0.02%]), and eczema (7 [0.03%] vs 3 [0.01%]). There were three hypersensitivity SAEs during the blinded placebo-controlled follow-up period: two in the BNT162b2 group (anaphylactic reaction following bee sting and drug hypersensitivity to an antibiotic) and one in the placebo group (anaphylactic shock due to an ant bite; none were considered by investigators as related to the study intervention. Among the original placebo group participants who then received BNT1622 after unblinding there was one anaphvlactoid reaction (assessed as related; reviewed in section 5.2 of this memorandum). For Bell's palsy, there were four cases in the BNT162b2 group (two of which were considered related by investigators) and two in the placebo group during the blinded placebo-controlled follow-up period. Among those who originally received placebo and then received BNT162b2 after unblinding, there were three participants who experienced facial paralysis (all considered related by investigators). Lymphadenopathy was reported in 87 (1.0 per 100 person-years [P]) participants in the BNT162b2 group compared to 8 (0.2 per 100 PY) participants in the placebo group. One lymphadenopathy event (right axilla, normal lymph node biopsy) was considered a related-SAE in the BNT162b2 group and resolved within 66 days. Appendicitis was reported for a total of 15 BNT162b2 participants, including one case of perforated appendicitis, as compared with 12 total reports of appendicitis in the placebo group, including two cases of complicated appendicitis, and one case of perforated appendicitis. All appendicitis cases were reported as SAEs and none were considered related to study intervention by investigators. Among CDC-defined AESIs that occurred from Dose 1 to unblinding in the Phase 2/3 study, the overall number and percentage of participants with any unsolicited AESIs within selected SMQs were similar between the BNT162b2 (224 [1.02%]) and placebo groups (217 [0.99%]); most individual AESI categories were similar between BNT162b2 and placebo groups (or higher in the placebo group) with the exception of hypersensitivity which is discussed above.
+Reviewer comment: The sponsor submitted a revised PVP (Version 1.1) on July 29, 2021 which added the important identified risks of myocarditis and pericarditis and also included clinical trial data for myocarditis and pericarditis through June 18, 2021. The revised PVP indicated that among participants age 16 years and older two SAE cases of pericarditis were found from Phase 3 clinical trial C4591001; both SAEs were deemed by study investigators as not related to study treatment. There were no clinical trial reports of myocarditis as an SAE. Review of the sponsor's safety data did not identify new safety concerns that required further amending the sponsor's PVP.
+5.3 Sponsor's Cumulative Analysis of Post-Authorization Adverse Event Reports
+Cumulative post-authorization safety data, through February 28, 2021:
+The sponsor provided a summary of cumulative post-authorization safety data, including U.S. and foreign post-authorization adverse event reports received through February 28, 2021. The safety database includes As reported spontaneously, by health authorities, and from published medical literature, Pfizer-sponsored marketing
+
+programs, non-interventional studies, and serious As reported from clinical studies regardless of causality assessment.
+There was a total of 42,086 AE reports containing 158,893 events. Most reports were from the U.S. (13,739), followed by the United Kingdom (13,404), Italy (2,578),
+Germany (1,973), France (1,506), Portugal (866), and Spain (756); the remaining 7,324 reports were from 56 other countries. Most reports were in females (29,914 (71.1%) reports); there were 9,182 (21.8%) reports for males and 2,990 (7.1 %) with no sex data.
+Reports by age groups were as follows: <17 years (n=175), 18-30 years (n=4,953), 31-50 years (n=13,886), 51-64 years (n=7,884), 65-74 years (n=3,098), ≥75 years (n=5,214), and unknown (n=6,876). The most commonly reported MedDRA Preferred Terms (PTs) occurring ≥10% were headache (24.1%), pyrexia (18.2%), fatigue (17.4%), chills (13.1%), vaccination site pain (12.3%), nausea (12.3%), and myalgia (11.7%).
+The sponsor included a summary of post-authorization A reports for each safety concern listed in the PVP (see Section 7 of this memorandum for PVP summar). For anaphylaxis (important identified risk), there were 1,002 cases that met the Brighton Collaboration (BC definition level 1 (highest level of certainty) through 4 (reported event with insufficient evidence to meet case definition), including nine fatal events. The sponsor concluded that evaluation of these cases did not reveal any significant new safety information and that anaphylaxis and non-anaphylactic hypersensitivity reactions are appropriately described in the product labeling (Sections 4 Contraindications, 5.1
+Management of Acute Allergic Reactions, and 6 Adverse Reactions of the proposed USPI). In addition, the sponsor did not identify any cases definitively considered to be vaccine-associated enhanced disease (VAED) or vaccine-associated enhanced respiratory disease (VAERD) and concluded that VAED/VAERD remains a theoretical risk for the vaccine (i.e., important potential risk).
+Among "missing information" categories in the PVP, there were 413 reports (84 serious and 329 non-serious) involving use in pregnancy and lactation. There were 270
+maternal cases and four fetus/infant cases. Pregnancy outcomes were reported for 32 cases (including twins who each had two different outcomes reported and included spontaneous abortion (n=23); outcome pending (n=5); premature birth with neonatal death, spontaneous abortion with intrauterine death (2 each); spontaneous abortion with neonatal death and normal outcome (1 each). Among mothers, 124 cases (75 serious and 49 non-serious) were pregnancy-related PTs: spontaneous abortion (n=25); uterine contraction during pregnancy, premature rupture of membranes, abortion, abortion missed, and fetal death (1 each). The four fetus/infant cases reported the following PTs: exposure during pregnancy, fetal growth restriction, maternal exposure during pregnancy, premature baby (2 each); and death neonatal (n=1). There were 133 reports in breastfed infants, including 17 cases (3 serious and 14 non-serious) that reported clinical events that occurred in an infant/child exposed to vaccine via breastfeeding: pyrexia (n=5); rash (n=4); infant irritability (n=3); infantile vomiting, diarrhea, insomnia, and illness (2 each); poor feeding infant, lethargy, abdominal discomfort, vomiting, allergy to vaccine, increased appetite, anxiety, crying, poor quality sleep, eructation, agitation, pain, and urticaria (1 each).
+C
+
+There were 34 reports (24 serious and 10 non-serious) involving 132 As indicating use in pediatric individuals <12 years of age. Events reported more than once included product administered to patient of inappropriate age (n=27); off label use (n=11); pyrexia (n=6); product use issue (n=5); fatigue, headache, nausea (4 each); vaccination site pain (n=3); upper abdominal pain, COVID-19, facial paralysis, lymphadenopathy, malaise, pruritis, and swelling (2 each).
+There were 1,665 reports concerning vaccine effectiveness (1,649 drug ineffective and 16 vaccination failure). Among the 16 cases of vaccination failure, eight individuals had onset of COVID-19 svmptoms within 7-13 days post-2nd vaccine dose and six individuals had onset within 15-29 das post-2nd dose. Six reports were asymptomatic COVID-19 infections. For each concern listed in the PVP, the sponsor concluded that no new safety signals were identified in post-authorization AE data.
+The sponsor also evaluated As in the following ASI categories: anaphylactic reactions, cardiovascular, COVID-19, dermatological, hematological, hepatic, facial paralysis, immune-mediated/autoimmune, musculoskeletal, neurological (including demyelination), other (e.g., herpes viral infections) pregnancy-related, renal, respiratory, thromboembolic events, stroke, and vasculitic events, and concluded that the cumulative case review did not raise new safety issues.
+Finally, the sponsor provided information on reports potentially indicative of medication errors. There were 2,056 reports of medication errors, with or without associated AEs.
+Of these, there were seven death reports; and 1,569 (76.3%) reports were medically confirmed. The sponsor indicated that all medication errors reported in death reports were assessed as non-serious events with unknown outcomes and concluded that based on available information, including causes of death, the relationship between the medication error and the death is weak. Overall, most reports (n=1,371, 66.7%) included only medication errors without any associated clinical adverse events (e.g., poor quality product administered, product temperature excursion issue, underdose, circumstance or information capable of leading to medication error). In 685 reports, there were AEs co-reported; the most frequent As were headache (n=187), pyrexia (n=161), fatigue (n=135), chills (n=127), pain (n=107), vaccination site pain (n=100), nausea (n=89), myalgia (n=88), pain in extremity (n=85), arthralgia (n=68), off label use (n=57), dizziness (n=52), lymphadenopathy (n=47), asthenia (n=46), and malaise (n=41).
+Reviewer comment: The sponsor's cumulative summary of post-authorization data as of the data lock point, February 28, 2021, showed that the most frequently reported AEs were consistent with As described in the EUA Fact Sheet (i.e., headache, pyrexia, fatigue, chills, vaccination site pain, nausea, and myalgia).
+Post-authorization safety data, updated through June/July 2021:
+10
+
+The sponsor submitted a revised PVP (Version 1.1) on July 29, 2021 which included post-authorization data for myocarditis and pericarditis among individuals 16 years of age and older through June 18, 2021. There was a total of 823 AE reports, including 490 reports of myocarditis and 372 reports of pericarditis; 38 reports included both myocarditis and pericarditis. Among the 490 myocarditis reports, 464 (including 78 U.S. reports) met Brighton Collaboration Level 1 to 4 (Version 1.4.2; May 30, 2021). The majority of myocarditis reports (n=325, 66.3%) were in males and the median age was 32 years (range=16-97 years; there were 14 death reports. Among the 371 reports of pericarditis (including 68 U.S. reports), 181 (48.8%) were in males and 185 (49.9%) occurred in females (five reports did not include sex); the median age was 51 years (range=16-92 years) and there were three death reports.
+The sponsor also provided post-authorization data through June 18, 2021 for myocarditis and pericarditis in individuals age 12-15 years. There were 13 reports of myocarditis (none were deaths); 11 met Brighton Collaboration Level 4 (i.e., reported event with insufficient evidence to meet the case definition) and two met Brighton Collaboration Level 5 (i.e., not a case); 10 (90.9%) were male and 1 (9.1%) was female; the median age was 14 years (range=12-15 years). There were four reports of pericarditis (none were deaths); all were male, and the median age was 13.5 years (range=12-15 years).
+The sponsor indicates that a mechanism of action by which the vaccine could cause myocarditis and pericarditis has not been established, however myocarditis and pericarditis are considered an important identified risk in the PVP. The sponsor concluded that the vaccine continues to have a favorable risk benefit balance and that considering the low rates of myocarditis and pericarditis reported following vaccination, balanced with the risk of death and illness (including myocarditis) from SARS-CoV-2, the public health impact of post-vaccination myocarditis and pericarditis is minimal.
+Reviewer comment: There are ongoing analyses, by the sponsor and FDA, to further characterize the new safety signal for myocarditis and pericarditis after the Pfizer-BioNTech COVID-19 vaccine. As described above, the majority of myocarditis reports occurred in males, under 30 years of age. Please see section 6.1 and 8.2 for additional discussion.
+6 Summary of FDA Post-Authorization Safety Data
+6.1 Vaccine Adverse Event Reporting System Data
+Since its authorization on December 11, 2021 through June 11, 2021 a total of 151,543 reports, including 24,961 serious reports (3,512 of which were death reports), have been received and processed (coded, redacted, and quality assurance performed by the Vaccine Adverse Event Reporting System (VAERS) for the Pfizer-BioNTech COVID-19 vaccine. Among all reports the top 10 most frequently reported PTs are headache, fatigue, pyrexia, chills, pain, dizziness, nausea, pain in extremity, arthralgia,
+11
+
+and injection site pain. Among serious reports the top 10 most frequently reported PTs are SARS-CoV-2 test, COVID-19, dyspnea, headache, fatigue, pyrexia, death, SARS-
+Cov-2 test positive, dizziness, and nausea.
+Reviewer comment: Most of the commonly reported PTs in VAERS reports are labeled events in the EUA Fact Sheet (i.e., headache, fatigue, fever, chills, pain, joint pain, nausea, vomiting) or a non-specific A that could be a possible vaccine stress-related response (i.e., dizziness). The PTs of SARS-CoV-2 test and SARS-CoV-2 test positive refer to testing for SARS-CoV-2 infection. The PT of "dyspnea" is a non-specific symptom that may be present in a variety of conditions both serious and non-serious.
+Dyspnea associated with FDA/CDC AESs, such as acute myocardial infarction, pulmonary embolus, or myopericarditis, is monitored as part of routine surveillance for AESIs and/or through death reviews.
+VAERS was queried for the safety concerns listed in the PVP (Section 7 of this memorandum).
+Anaphylaxis:
+For the important identified risk of anaphylaxis, VAERS was queried from December 11, 2020 (the date of authorization) to June 11, 2021. The query was run on June 17, 2021 using the PTs anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, or anaphylactoid shock. The search returned 1,034 reports (1,009 U.S. reports), including 524 serious reports; 12 of the serious reports were death reports. There were
+167,680,391 doses of the Pfizer-BioNTech Covid-19 vaccine administered in the U.S. as of June 14, 2021. This equates to a crude reporting rate for anaphylaxis of 6.0 cases per million doses. Among the 12 deaths, five individuals were female, six were male, and one was of unknown sex; the median age was 81 years (range= 58-86 years; 3 individuals were of unknown age) and the median onset as calculated by VAERS dates was zero days post-vaccination (range=0-16 days). Nine individuals who died reported various chronic underlying conditions including hypertension, asthma, diabetes mellitus, ischemic cardiomyopathy, myocardial infarction, atrial fibrillation, arrythmia, obesity, sleep apnea, and dementia. Three individuals who died had a history of hypersensitivity to penicillin, contrast imaging, or food/fruit allergy. One individual had a history of COVID-19 one-month prior to vaccination and one individual was diagnosed with concomitant COVID-19 pneumonia and acute hypoxic respiratory failure post-vaccination.
+Reviewer comment: Allergic reactions and anaphylaxis are labeled in the EUA Fact Sheet for this product. In addition, the EUA Fact Sheet cites CDC clinical guidelines which recommend observation periods following COVID-19 vaccination. Review of VAERS reports did not identify new safety concerns related to anaphylaxis. Limitations to interpreting this information include that VAERS data are based on passive surveillance and important limitations of passive surveillance data include missing/inaccurate data, unconfirmed diagnoses, potential under-reporting, and variable or incomplete reporting. The methodology for calculating crude reporting rates was
+12
+
+based on reports retrieved from automated queries, which may include duplicate cases as not all cases were manually reviewed to apply the Brighton Collaboration case definition criteria for anaphylaxis (Ruggeberg, 2007). (Note that this is a key difference in the above methodology compared to previous publications [MMWR Jan 15, 2021;
+Gee, 2021; Shimabukuro, 2021], which calculated reporting rates based only on adiudicated cases that were confirmed through medical record review or direct contact with the provider.\ The incidence of anaphvlaxis after receipt of the Pfizer-BioNTech COVID-19 vaccine is comparable with those reported after receipt of other vaccines (Gee, 2021).
+Myocarditis and pericarditis:
+After the issuance of the EUA, FDA and CDC received reports of myocarditis and pericarditis following administration of the Pfizer-BioNTech COVID-19 Vaccine. In accordance with FDA recommendations, the sponsor added myocarditis and pericarditis as important identified risks in the PVP. A VAERS search was performed for the timeframe from December 11, 2020 (the date of authorization) to June 21, 2021. The query was run on June 23, 2021 utilizing the PTs autoimmune myocarditis, autoimmune pericarditis, eosinophilic myocarditis, hypersensitivity myocarditis, myocarditis, pericarditis, pericarditis adhesive, pericarditis constrictive, and pleuropericarditis.
+The query returned 1,023 reports (1012 U.S. reports), including 809 serious reports (seven were death reports concerning six unique individuals), of which 652 reports were in individuals under 30 years of age. The reports concerned 775 (75.8%) males and 238 (23.3%) females; 10 reports concerned individuals of unknown sex. The median age was 21 years (range=12-86 years). The median onset post-vaccination as calculated by VAERS dates was 3 days (range=0-151 days). The six unique death reports (3 U.S. and 3 foreign reports) concerned three males and three females; the median age at death was 66 years (range=19-81 years) and the median onset post-vaccination was 4 days (range=1-22 days). Four deaths occurred following the second dose, one following the first dose, and for one the dose number was not reported. Most death reports contained limited information or described concurrent medical conditions and/or risk factors that might have contributed to the death. A summary of each death report is listed below:
+1394140: 78-year male with no reported PMH died (b) (6)
+post-2nd vaccine. An
+autopsy revealed myocarditis, but limited details were provided.
+1044420: 36-year male with history of anosmia and influenza-like illness (ILI) developed non-specific ILI symptoms a few days post-vaccination. Twenty-two days post-2nd vaccination he developed low grade fevers, malaise, and sore throat. Testing revealed a negative SARS-CoV-2 test and a positive coronavirus nucleocapsid IgG. His symptoms progressed and the patient ultimately deteriorated and died. Autopsy findings included: heart with multifocal myocarditis with mixed inflammatory infiltrate, myocyte necrosis, microthrombi. The death certificate listed the following causes of death: hemorrhagic shock, d/t intraperitoneal bleed, d/t coagulopathy, d/t post COVID-19 syndrome.
+13
+
+1340821: 60-year female reported to have endocarditis following first dose and then myocarditis post-2nd dose (reported by friend, limited details).
+1070309: Foreign report: 72-year female with PMH of cardiac arrest, chest pain, high cholesterol, neoplasm, acute myeloid leukemia, hypertension, high BMI, and GERD had chest pain and pericarditis 3-days post-1st dose. She suffered a cardiac arrest 7-days post-vaccination and died br days post-vaccination due to pericarditis.
+1048413: Foreign report: 19-year male with no PH experienced accelerated heartbeat, shortness of breath (SOB), and sharp pains radiating down left arm 5-days post-2nd vaccination. He was hospitalized in intensive care unit (ICU) and died. The reported cause of death was myocarditis.
+1048221: Foreign report: 81-year female with history of COVID-19 experienced septic shock, extensive mo- and pericarditis, and multiple organ failure 3-days post-vaccination, died * days post-vaccination; autopsy-determined cause of death: Carditis pericardium myocardium.
+In addition to review of reports from automated queries, all U.S. death reports are manually reviewed, and the following death was identified:
+coordination disorder experienced flu-like symptoms for
+deceased; onset of symptoms 1-day post vaccination. The preliminary autopsy report revealed cardiomegaly with biventricular dilatation, bilateral serous pulmonary effusions and serous pericardial effusion, marked pulmonary edema and congestion, and moderate degree of diffuse cerebral edema; SARS-CoV-2 and influenza A/B tests, toxicology, and determination of the cause of death are pending.
+Furthermore, observed to expected (O/E) analyses were performed for risk windows of 7 days and 21 days, stratified by age, sex and dose, using U.S. data retrieved from automated queries of the VAERS database (data lock point July 6, 2021). The following PTs were used: atypical mycobacterium, pericarditis, autoimmune myocarditis, autoimmune pericarditis, bacterial pericarditis, coxsackie myocarditis, coxsackie pericarditis, cytomegalovirus myocarditis, cytomegalovirus pericarditis, enterovirus myocarditis, eosinophilic myocarditis, hypersensitivity myocarditis, immune-mediated myocarditis, myocarditis, myocarditis bacterial, myocarditis helminthic, myocarditis infectious, myocarditis meningococcal, myocarditis mycotic, myocarditis post infection, myocarditis septic, pericarditis, pericarditis adhesive, pericarditis constrictive, pericarditis helminthic, pericarditis infective, pericarditis mycoplasmal, pleuropericarditis, purulent pericarditis, viral myocarditis, and viral pericarditis. The vaccine administration data lock point for the O/E analysis was June 30, 2021. Only results for 7-day risk windows are shown in Tables 3 and 4 (relative risks [RR] with 95% CI >1 in bold font). The O/E analysis, stratified by age and dose number, indicates that the observed number of cases exceeds the expected number of cases (based on pre-COVID-19 pandemic U.S. population-based background incidence rates). The reporting rate and R was higher among males than females for
+14
+
+almost all age groups and higher following dose 2 as compared to dose 1 in most age groups for both males and females. This trend was higher in the 7-day risk window compared to the 21-day risk window, and in the younger age groups. Important limitations of passive surveillance data include missing/inaccurate data, unconfirmed diagnosis and potential under-reporting. There is ongoing follow-up of the reports to obtain additional medical records for assessment of cases.
+Table 3: Reporting Rates and Relative Risk (RR) of Myocarditis and Pericarditis
+Post Vaccination in Males using a 7-Day Risk Window
+Age
+Background
+Group
+Rate*
+(years)
+12 - 17
+2.16a
+Dose 1
+Reporting
+Rate**
+0.99
+18 - 24
+2.16
+0.48
+25 - 29
+2.16
+0.26
+30 - 39
+6.1b
+0.17
+Dose 1
+RR (95%
+CI)
+23.94
+(17.02-
+32.73)
+11.5
+(6.7-
+18.42)
+6.2
+(2.49-
+12.78)
+1.45 (0.7
+-2.67)
+Dose 2
+Reporting
+Rate**
+10.22
+Dose 2
+RR (95%
+CI)
+246.84
+(219.83-
+276.26)
+5.91
+142.84
+(122.17 -
+166)
+1.55
+37.44
+(26.08 -
+52.06)
+0.88
+7.56
+(5.49-
+10.14)
+40 - 49
+6.1
+0.12
+1.04
+0.53
+4.49
+(0.42-
+(2.93-
+2.13)
+6.58)
+50 - 64
+6.1
+0.07
+0.59
+0.14
+1.16
+(0.24-
+(0.6-
+1.22)
+2.03)
+>65
+6.1
+0.07
+0.63
+0.07
+0.61
+(0.25-
+(0.22-
+1.3)
+1.33)
+*Background rates are rates per 100,000 persons per year.
+**Reporting rates are per 100,000 doses of vaccine
+Relative Risk (RR) is the reporting rate compared to the background rate when applied to the proportion of individuals vaccinated in each age group to July 1, 2021
+aGubernot et al, U.S. Population-Based background incidence rates of medical conditions for use in safety assessment of COVID-19 vaccines
+•Roth et al, Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019
+15
+
+Table 4: Reporting Rates and Relative Risk of Myocarditis and Pericarditis post
+Vaccination in Females using a 7-Day Risk Window
+Age
+Group (years)
+12 - 17
+Background
+Rate*
+2.16a
+Dose 1
+Reporting
+Rate**
+0.15
+Dose 1
+RR' (95%
+CI)
+3.51
+Dose 2
+Reporting
+Rate**
+1.06
+(1.29-
+7.64)
+18 - 24
+2.16
+0.1
+2.32
+0.58
+(0.63
+5.94)
+25 - 29
+2.16
+0.07
+1.59
+0.2
+(0.19-
+5.75)
+30 - 39
+4.4b
+0.18
+2.16
+0.16
+(1.12-
+3.78)
+40 - 49
+4.4
+0.06
+0.72
+0.32
+(0.19-
+1.83)
+50 - 64
+4.4
+0.1
+1.23
+0.19
+(0.64-
+2.16)
+>65
+4.4
+0.04
+0.5
+0.08
+(0.16-
+1.17)
+Dose 2
+RR (95%
+CI)
+25.49
+(17.55-
+35.8)
+14.13
+(8.63 -
+21.82)
+4.74
+(1.54 -
+11.05)
+1.91
+(0.87 -
+3.63)
+3.74
+(2.22 -
+5.92)
+2.23
+(1.34-
+3.48)
+0.91
+(0.39-
+1.79)
+*Background rates are rates per 100,000 persons per year.
+**Reporting rates are per 100,000 doses of vaccine
+Relative Risk (RR) is the reporting rate compared to the background rate when applied to the proportion of individuals vaccinated in each age group to July 1, 2021
+aGubernot et al, U.S. Population-Based background incidence rates of medical conditions for use in safety assessment of COVID-19 vaccines
+bRoth et al, Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019
+Reviewer comment: Myocarditis and pericarditis emerged as a safety signal in VAERS and was jointly reviewed by FDA and CDC. Please see section 8.2 for further discussion of this safety signal.
+Vaccine-associated enhanced disease (VAED):
+There are not specific PTs for the important potential risk of vaccine-associated enhanced disease (VAED). Please see reviewer comments below regarding the VAERS search for PTs related to vaccine effectiveness.
+16
+
+Other:
+Categories in the PVP that are considered "missing information" (i.e., use during pregnancy and lactation, vaccine effectiveness, and use in pediatric individuals <12
+years of age), were also queried in VAERS. A VAERS search from December 11, 2020 (the date of authorization) to June 11, 2021 (run on June 22, 2021) for the System Organ Class (SOC) Pregnancy, Puerperium and Perinatal Conditions returned 1,050 reports, including 175 serious reports, 11 of which were deaths. Among the 11 death reports, eight involved a fetal (n=5) or infant death (n=3) and three were maternal deaths. The five fetal deaths were either miscarriage or intrauterine death that occurred less than two weeks post-maternal vaccination. The three infant deaths were: one death from thrombotic thromboctopenic purpura (TTP) in a breastfed infant (symptom onset
+1-day post-2nd-maternal vaccination), one report of premature birth 6-days post-vaccination with subsequent death (vaccine exposure during second trimester), and one report of premature birth at 21 weeks gestation with subsequent death 2-hours after birth (birth 13-davs post-maternal vaccination and complicated by meconium aspiration and maternal chorioamnionitis due to a Staphylococcus aureus infection). The three maternal deaths were: a 32-year old female with asymptomatic Factor V Leiden who died 4-days after childbirth and 52-days post-vaccination (limited details); a 42-year old female with no reported PH who died of a massive pulmonary embolus at 27-weeks gestation, and a 38-year old female with Type I diabetes mellitus, hemochromatosis, and sleep apnea who experienced maternal cardiac arrest with likely amniotic fluid embolism and disseminated intravascular coagulation (DIC) 14-days post-vaccination.
+A separate query (run on July 13, 2021) of VAERS PT event counts for the SOC
+Pregnancy, Puerperium and Perinatal Conditions (from December 11, 2021 to June 11,
+2021) showed a total of 1,589 PTs, including 546 PTs reported for serious reports and
+21 PTs reported for deaths. Among serious reports, the top 10 most frequently reported PTs in the SOC Pregnancy, Puerperium and Perinatal Conditions were: exposure during pregnancy (n=189), abortion spontaneous (n=83), maternal exposure during pregnancy (n=40), fetal death (n=27), premature delivery (n=20), premature labor (n=17), delivery (n=15), induced labor (n=14), premature baby (n=11), and premature separation of placenta (n=9). Among death reports, PTs in the SOC Pregnancy, Puerperium and Perinatal Conditions reported more than once included exposure during pregnancy (n=4), maternal exposure during pregnancy (n=4), fetal death (n=4), spontaneous abortion (n=2), and premature baby (n=2).
+Reviewer comment: Vaccine safety in pregnant women is being evaluated in a randomized controlled trial conducted by the sponsor, active surveillance studies conducted by the sponsor, and the CDC v-safe program. The background incidence of miscarriage varies by age and ranges from 10% in women aged 25-29 years up to 53% in women aged 45 years and older (Magnus, 2019). Review of the most common PTs reported in the SOC Pregnancy, Puerperium and Perinatal Conditions and individual review of VAERS death reports did not suggest patterns indicating a new safety concern that needs to be addressed in the PVP.
+17
+
+For "missing information" regarding vaccine effectiveness, VAERS was searched for the timeframe December 11, 2020 to June 11, 2021 (query run on June 17, 2021) using PTs for vaccination failure and drug ineffective. The search returned 1,788 reports that included the PT "vaccination failure" (n=254) and/or "drug ineffective" (n=1,565); 31 reports contained both PTs. Among the 254 reports including the PT vaccination failure, there were 24 serious reports and eight deaths. Among the eight deaths (three U.S. and five foreign reports), six were female and two were male; the median age was 71 years (range=37-98 years) and median onset as calculated by VAERS dates was 10 days post-vaccination (range=7-63 days). Most deaths occurred in individuals with reported underlying co-morbidities. Among the 1,565 reports of drug ineffective, there were 258 serious reports including 120 deaths. Among the 120 deaths, the majority (n=103, 86%) were foreign reports; 41 individuals were female, 57 were male, and 22 were of unknown sex; the median age was 84 years (range=17-99 years; 29 [24%] with unknown age) and median onset as calculated by VAERS dates was 4 days post-vaccination (range=0-26 days; 22 [18%] had incalculable VAERS dates). Most deaths occurred in individuals with reported underlying co-morbidities or unknown medical history.
+Reviewer comment: There are VAERS reports of deaths due to COVID-19 in patients reported to be fully vaccinated. It is expected there may be some cases of vaccination failure, especially in elderly or immunocompromised subjects. Infection with a variant SARS-CoV-2 virus for which vaccination is less effective is also a possibility. Many reports concern elderly individuals with co-morbidities or contain limited details which makes complete assessment difficult. Generally, passive surveillance and spontaneous adverse event reporting cannot be used to draw conclusions regarding vaccine effectiveness due to the lack of a control group, reporter bias, and underreporting.
+Severe manifestations and death from COVID-19 raise the possibility of vaccine-associated enhanced disease (VAED), which has overlapping clinical manifestations with natural SARS-CoV-2 infection, making it difficult to differentiate VAED from severe COVID-19 disease in individual VAERS reports (Munoz, 2021). VAED is being assessed in a continuation of the Phase 3 clinical studies and active surveillance studies being conducted by the sponsor.
+For "missing information" regarding individuals <12 years of age, VAERS was searched for the timeframe December 11, 2020 to June 11, 2021 (query run on June 22, 2021).
+There was a total of 273 reports in children <12 years of age, including 31 serious reports and two death reports. Among the 31 serious reports, the most commonly reported PTs (>10%) were product administered to patient of inappropriate age (n=15), off-label use (n=11), headache (n=7), exposure via breast milk (n=5), rash (n=5), pyrexia (n=4), product use issue (i.e., product use in unapproved population; n=3), dizziness (n=3), nausea (n=3), and vaccination site pain (n=3). One death report concerned an 11-vear-old female but it was not clear if she had received the vaccine or if she was exposed to other family members who received the vaccine; this report contained limited details and was difficult to interpret. The other death report concerned a 5-month-old breastfed infant who was diagnosed with TTP after the mother received
+18
+
+her 2nd Pfizer-BioNTech vaccine dose; symptom onset 1-day post-maternal vaccination this report was included in the pregnancy and lactation review above).
+Reviewer comment: The Pfizer-BioNTech COVID-19 vaccine is currently authorized for use in individuals age 12 years and older and the BLA has a proposed indication for use in individuals age 16 years and older. Review of VAERS data indicates that individuals younger than age 12 have received the product outside of clinical trials; no patterns of Es were identified to suggest new safety concerns that warrant amendment to the PVP.
+6.2 Data Mining Findings
+Data mining of the VAERS database using Empirica Signal' with a data lock point of June 4, 2021, revealed the following PTs and subgroups had an increased disproportional reporting value (EB05>2) for the Pfizer-BioNTech COVID-19 vaccine (Table 5):
+Table 5: Preferred Terms with Disproportional Reporting in Empirica Signal for the Pfizer-BioNTech COVID-19 Vaccine
+Preferred Term (PT)
+Drug ineffective
+Investigation
+Product preparation issue
+Weight
+US
+EB05
+1.964
+2.053
+2.021
+2.02
+US Adult >65 years
+EB05
+2.034
+2.071
+2.124
+2.028
+US Female
+EB05
+1 770
+2.001
+1 047
+1.98
+Reviewer comment: Reports with PT "drug ineffective" generally describe patients who contracted COVID-19 prior to being fully vaccinated or reports with limited details to assess timing or confirmation of COVID-19 infection or number of vaccine doses. Cases of vaccination failure might not always be reported to a spontaneous adverse event reporting system. Inferences that can be made from VAERS about COVID disease after vaccination are limited. Vaccine effectiveness is monitored through clinical trials, and post-authorization studies conducted by the sponsor. The PT "investigation" is nonspecific and generally refers to investigations performed as part of work-up for signs or symptoms. The PT "product preparation issue" generally concerns reports with issues such as incorrect vaccine reconstitution or lack of reconstitution with diluent. The PT of
+1 Empirica Signal is a web-based platform that uses an automated approach to explore relationships in large datasets by generating statistical scores for combinations of products and events from drug or vaccine databases. Data mining is conducted to evaluate whether any events (i.e., MedDRA PTs) following use of a particular vaccine are disproportionally reported compared to all vaccine reports in VAERS; the threshold for signal detection is an EB05 value >2. (EBO5 is the lower bound of the 90% confidence limit for the Empirical Bayesian Geometric Mean). The data generated from Empirica Signal do not, by themselves, demonstrate causal associations, but the data might serve as a signal for further investigation and can be useful for hypothesis generation and exploration of potential concerns
+19
+
+"weight" is non-specific and may refer to weight gain or loss in a patient or report of the patient's weight. Review of PTs with an EB05>2 did not identify new safety concerns that need to be addressed in the PVP.
+6.3 Discussion of U.S. Package Insert (USPI) Section 6.2 Post-marketing Experience
+Sponsor proposed As for inclusion under Section 6.2 Post-marketing Experience include:
+Cardiac Disorders: myocarditis and pericarditis
+Gastrointestinal Disorders: diarrhea, vomiting
+Immune System Disorders: severe allergic reactions, including anaphylaxis, and other hypersensitivity reactions (e.g., rash, pruritis, urticaria, angioedema)
+Musculoskeletal and Connective Tissue Disorders: pain in extremity (arm)
+OBE/DE recommends inclusion of additional PTs to Section 6.2 Post-marketing
+Experience for:
+• Dizziness
+• Among serious reports (as of August 2, 2021), dizziness ranks in the cumulative top 10 reported PTs with 11,107 events reported. A cumulative VAERS query for the PT dizziness, run on August 3, 2021, returned 35,104 reports (26,131 [74.4%] were U.S. reports), including 3,857 (11.0%) serious reports (145 of these were death reports). There were 26,032 (74.2%) reports concerning females and 8,615 (25.5%) concerning males; 457 (1.3%) reports did not include sex. The median onset based on VAERS dates=0 days (range=0-171 days post-vaccination) and median age=42 years (range=0.1-115 years).
+• Dyspnea
+• Among serious reports (as of August 2, 2021), dyspnea ranks in the cumulative top 10 reported PTs with 10,506 events reported. A cumulative VAERS query for the PT dyspnea, run on August 3, 2021, returned 19,858 reports (12,757 [64.2%] were U.S. reports), including 6,235 (31.4%) serious reports (1,102 of these were death reports). There were 14, 166 (71.3%) reports concerning females and 5,421 (27.3%) concerning males;
+271 (1.4%) reports did not include sex. The median onset based on VAERS dates=0 days (range=0-207 days post-vaccination) and median age=48 years (range=0.1-109 years).
+20
+
+7 Pharmacovigilance Plan
+7.1 Summary of Pharmacovigilance Plan
+The sponsor submitted a PVP proposing routine pharmacovigilance (PV), including data capture aids (DCAs) for anaphylactic reactions and VAED, and post-authorization observational and active surveillance safety studies (Table 6). There are also ongoing clinical trials.
+Table 6: Summary of Safety Concerns and Planned Pharmacovigilance Activities*
+Safety Concern
+Actions Proposed
+Important Identified Risks
+Anaphylaxis
+• Routine pharmacovigilance
+• Data capture aid
+Communication of important identified risk via label (Sections 4 - Contraindications, 5.1 - Management of Acute Allergic Reactions, Section 6 - Adverse reactions - and 6.2 - Post Authorization Experience)
+• Completion of C4591001: Phase 1/2/3, placebo-controlled, randomized, observer-blind, dose-finding study to evaluate the safety, tolerability, immunogenicity, and efficacy of SARS-CoV-2 mRNA vaccine candidates against COVID-19 in healthy individuals
+• Three post-authorization safety studies to monitor safety of BNT1622 (C4591009, C4591011, C4591012)
+Myocarditis and Pericarditis • Routine pharmacovigilance
+• Three post-authorization safety studies to monitor safety of BNT162b2 (C4591009, C4591011, C4591012)
+FDA will also require a safety post-marketing study to further assess these serious risks
+| Important Potential Risks
+Vaccine-Associated
+• Routine pharmacovigilance
+Enhanced Disease (VAED),
+• Data capture aid
+including Vaccine-
+Completion of C4591001: Phase 1/2/3, placebo-
+Associated Enhanced
+controlled, randomized, observer-blind, dose-
+Respiratory Disease
+finding study to evaluate the safety, tolerability,
+(VAERD)
+immunogenicity, and efficacy of SARS-CoV-2 mRNA vaccine candidates against COVID-19 in healthy individuals
+• Four post-authorization safety studies to monitor safety of BNT1622 (C4591008, C4591009
+21
+
+Missing Information
+Use in pregnancy and lactation
+Vaccine effectiveness
+Use in pediatric individuals
+<12 vears of age
+C4591011, C4591012)
+• Routine pharmacovigilance
+• Completion of C4591015: A phase 2/3, placebo-controlled, randomized, observer blind study to evaluate the safety, tolerability, and immunogenicity of a SARS-CoV-2 RNA vaccine candidate (BNT162b2) against COVID-19 in healthy pregnant women 18 years of age and older
+• Three post-authorization safety studies to monitor safety of BNT162b2
+(C4591009, C4591011, C4591022
+[Pregnancy Registry study])
+• Routine pharmacovigilance
+• Completion of BNT162-01 cohort 13 (Phase 1/2 dose-escalation clinical trial): Immunogenicity of
+Pfizer-BioNTech COVID-19 Vaccine in immunocompromised subjects, including assessment of antibody responses and cell-mediated responses
+• Three post-authorization vaccine effectiveness studies (C4591014: Pfizer-BioNTech COVID-19
+BNT162b2 Vaccine Effectiveness Study - Kaiser
+Permanente Southern California
+• WI235284: determining RSV Burden and Outcomes in Pregnant Women and Older Adults Requiring Hospitalization. COVID-19
+Amendment for COVID VE/ Sub-study 6
+WI255886: Avon Community Acquired
+Pneumonia Surveillance Study: A Pan- pandemic
+Acute Lower Respiratory Tract Disease
+Surveillance Study
+• Routine pharmacovigilance
+• Completion of C4591001 ≥12 to 515 years of age: Phase 1/2/3, placebo-controlled, randomized, observer-blind, dose-finding study to evaluate the safety, tolerability, immunogenicity, and efficacy of SARS-CoV-2 mRNA vaccine candidates against COVID-19 in healthy individuals. Randomized placebo-controlled study in 2,000 participants (1,000 active recipients) of 2 doses of BNT162b2 at a
+21-day interval
+• Completion of C4591007 <12 years of age:
+Phase 1 open label dose-finding study to
+22
+
+evaluate safety, tolerability, and immunogenicity and phase 2/3 placebo-controlled, observer-blinded safety, tolerability, and immunogenicity study of a SARS-CoV-2 mRNA vaccine candidate against COVID-19 in healthy children <12 years of age
+• One post-authorization safety study to monitor safety of BNT162b2 (C4591009)
+*Adapted from sponsor's Pharmacovigilance Plan, Version 1.1 Table 46: Summary of Safety Concerns and Action Plans.
+7.3 Summary of Post-authorization Safety Surveillance Studies
+The sponsor proposes five post-authorization safety surveillance studies, which are summarized in the sections below. The sponsor also proposes three post-authorization vaccine effectiveness studies (C4591014, W1235284, WI255886):
+• C4591014: Pfizer-BioNTech COVID-19 BNT1622 Vaccine Effectiveness Study -
+Kaiser Permanente Southern California
+• WI235284: Determining RSV Burden and Outcomes in Pregnant Women and Older Adults Requiring Hospitalization; COVID-19 Amendment for COVID VE/ Sub-study 6
+• WI255886: Avon Community Acquired Pneumonia Surveillance Study: A Pan-pandemic Acute Lower Respiratory Tract Disease Surveillance Study
+Reviewer comment: The vaccine effectiveness study protocols were submitted to IND 19736/268 and are being reviewed by the CBER Biologics Effectiveness and Safety
+(BEST) team; see memorandums from CBER BEST team for study details and OBE assessment.
+7.3.1 C4591008: HERO Together: A post-Emergency Use Authorization observational cohort study to evaluate the safety of the Pfizer-BioNTech COVID-
+19 Vaccine in U.S. healthcare workers, their families, and their communities
+The primary objective of this study is to estimate the real-world incidence of safety events of interest and other clinically significant events among U.S. healthcare workers vaccinated with the Pfizer-BioNTech COVID-19 vaccine following EUA. Secondary objectives are to evaluate whether the vaccine recipients experience increased risk of safety events of interest and other clinically significant events post-vaccination and to estimate the incidence rates of safety events of interest and other clinically significant events among sub-cohorts, such as individuals who are pregnant or immunocompromised, and stratified by age.
+This prospective observational study will collect data based on participant self-report
+23
+
+(primarily using a secure web portal) at regular intervals for 24 months following vaccination. Events will be confirmed using medical records. This study aims to enroll at least 20,000 HCW who received a COVID-19 vaccine. Safety outcomes of interest area based on the priority list of AESI from the Brighton Collaboration's Safety Platform for Emergency Vaccines (SPEC) Project (https://brightoncollaboration.us/priority-list-aesi-covid/; accessed 12/13/2020) and include the following (* denotes events that will only be collected if individual hospitalized:
+• Neurologic: generalized convulsion/seizures, Guillain-Barré syndrome, aseptic meningitis, encephalitis/encephalomyelitis, other acute demyelinating diseases, transverse myelitis, multiple sclerosis, optic neuritis, Bell's palsy
+• Immunologic: anaphylaxis, vasculitides*, arthritis/arthralgia, multisystem inflammatory syndrome (in adults), Kawasaki disease, fibromyalgia, autoimmune thyroiditis
+• COVID-19: severe COVID-19 disease*, microangiopathy*, heart failure and cardiogenic shock*, stress cardiomyopathy*, coronary artery disease*, arrythmia*, deep vein thrombosis, pulmonary embolus, cerebrovascular stroke, limb ischemia*, hemorrhagic disease*, acute kidney injury*, liver injury, Chillblain-like lesions, single organ cutaneous vasculitis*, erythema multiforme*
+• Cardiac: myocarditis, pericarditis, acute myocardial infarction
+• Hematologic: thrombocytopenia, disseminated intravascular coagulation
+• Other: pregnancy outcomes, death, narcolepsy and cataplexy, non-anaphylactic allergic reactions
+Data analysis will include descriptive statistics of vaccination and baseline characteristics, number and incidence rate for each safety event of interest will be calculated overall and within subgroups of interest. Qualitative comparisons will be made using hospitalization rates among non-vaccinated HW enrolled in the HERO registry and external sources of background event rates. A self-matched comparative analysis will then be performed for events that appear to be associated with vaccination and that are amenable to self-matched analysis (e.g., adequate case counts, known risk interval).
+The proposed study milestones are:
+Interim report submission: June 30, 2021; December 31, 2021; June 30, 2022;
+December 31, 2022
+Final study report submission: December 31, 2023
+Reviewer comment: This study was proposed in the original EUA submission (EUA 27034/0) and the final study protocol was submitted to EUA 27034/68; OBE/DE reviewed the final study protocol and provided comments to the sponsor. In addition, the sponsor submitted an interim statistical analysis plan (SAP) and a protocol amendment (IND 19736/324) to expand the study population to include HCW families and community members, update recruitment strategies, and provide additional details
+24
+
+regarding the clinical event ascertainment process. The protocol amendment and SAP were reviewed by OBE/DE and are acceptable. Please see previous review memorandums for additional details.
+7.3.2 C4591009: A non-interventional post-approval safety study of the Pfizer--BioNTech COVID-19 mRNA vaccine in the United States
+The primary objective of this study is to estimate the relative risk (RR) or prevalence ratio of safety events of interest following receipt of at least one dose of the Pfizer-BioNTech COVID-19 vaccine in the overall study population and in pregnant women, in immunocompromised individuals, and in individuals with a history of COVID-19. Secondary objectives are to describe the proportion of individuals receiving at least one dose and a complete dose series, the timing and type of second dose of COVID-19 vaccine, and the baseline characteristics of individuals who receive at least one dose of the Pfizer-BioNTech COVID-19 vaccine compared to those who do not receive any COVID-19 vaccine doses.
+This is a retrospective cohort study comparing vaccinated individuals with concurrent unexposed comparators using claims and electronic health record data from partners in the Sentinel System. Safety events of interest will be aligned with events being monitored in the rapid cycle analysis of COVID-19 vaccines in the FDA's BEST system and CDC's VSD. The study will estimate incidence rates or incidence/prevalence proportions for each safety event of interest for matched exposed and unexposed cohorts; comparative analyses will also estimate hazard ratios or incidence rate ratios and 95% Cl within propensity score-matched cohorts. Individuals of all ages will be included in the descriptive analysis of vaccine utilization while the safety analysis will be limited to individuals within the age-indicated population for the Pfizer-BioNTech COVID-19 vaccine. The study period will extend a minimum of three years post-EUA.
+The proposed study milestones are:
+Final protocol submission: August 31, 2021
+Monitoring report submission: October 31, 2022
+Interim report submission: October 31, 2023
+Final study report submission: October 31, 2025
+Reviewer comment: This study was proposed in the EU submission to expand the Pfizer-BioNTech COVID-19 vaccine indication to pediatric individuals age 12-15 years (EUA 27034/132); a study protocol synopsis was submitted with the BLA.
+25
+
+7.3.3 C4591011: Active safety surveillance of the Pfizer-BioNTech COVID-19 vaccine in the U.S. Department of Defense population following Emergency Use Authorization
+The primary objective of this study is to assess whether individuals and sub-cohorts of interest (i.e., pregnant women, immunocompromised, elderly, individuals with specific comorbidities, individuals receiving only one dose of the Pfizer-BioNTech COVID-19 vaccine, and individuals with prior SARS-CoV-2 infection) in the Department of Defense (DoD) military health system (MHS) experience increased risk of safety events of interest following receipt of the Pfizer-BioNTech COVID-19 vaccine.
+Secondary objectives are to characterize utilization patterns of the Pfizer-BioNTech
+COVID-19 vaccine among individuals within the DoD MHS.
+This active safety surveillance study will utilize a rapid-cycle, longitudinal, observational cohort study design to assess real-world safety of the Pfizer-BioNTech COVID-19 vaccine using a self-controlled risk interval design and a cohort design with two comparator populations (2018/2019 season influenza vaccine recipients and unvaccinated matched controls). Safety events of interest are aligned with AESs from the Brighton Collaboration's SPEAC Project, FDA, and CDC's Advisory Committee on Immunization Practices (ACIP) enhanced safety monitoring recommendations. A stepwise data analysis process will include signal detection, evaluation, and verification.
+The study will use coding and medical record data from the DoD MHS Data Repository and will be conducted for 30-months post-EUA.
+The proposed study milestones are:
+Interim report submissions: June 30, 2021; December 31, 2021; June 30, 2022;
+December 31, 2022
+Final study report submission: December 31, 2023
+Reviewer comment: This study was proposed in the original EUA submission (EUA 27034/0). The final study protocol was submitted to EUA 27034/68 and reviewed by the
+CBER BEST team. An IR response (EUA 27034/186) indicated that the start date for C4591011 is delayed due to a change in study collaborators and the first interim report will be submitted by December 31, 2021 rather than June 30, 2021. Please see previous review memorandums for additional details.
+7.3.4 C4591012: Post-emergency use authorization active safety surveillance study among individuals in the Veteran's Affairs Health System receiving Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) vaccine
+The primary obiective of this study is to assess whether individuals and sub-cohorts of interest (i.e., immunocompromised, elderly, individuals with specific comorbidities, individuals receiving only one dose of the Pfizer-BioNTech COVID-19 vaccine, and individuals with prior SARS-CoV-2 infection) in the Veterans Health Administration
+26
+
+(VHA) system experience increased risk of safety events of interest following receipt of the Pfizer-BioNTech COVID-19 vaccine. Secondary obiectives are to characterize utilization patterns of the Pfizer-BioNTech COVID-19 vaccine among individuals within the VHA.
+This active safety surveillance study will utilize a rapid-cycle, longitudinal, observational cohort study design to assess real-world safety of the Pfizer-BioNTech COVID-19 vaccine using a self-controlled risk interval design and an active comparator design (2014/2015 through 2018/2019 seasonal influenza vaccine recipients). Safety events of interest are aligned with AESs from the Brighton Collaboration's SPEAC Project, FDA, and CDC's ACIP enhanced safety monitoring recommendations. A stepwise data analysis process will include signal detection, evaluation, and verification. The study will use coding and medical record data from the VHA Corporate Data Warehouse which is an integrated electronic medical record system and will be conducted for 30-months post-EUA.
+The proposed study milestones are:
+Interim report submissions: June 30, 2021; December 31, 2021; June 30, 2022;
+December 31, 2022
+Final study report submission: December 31, 2023
+Reviewer comment: This study was proposed in the original EUA submission (EUA
+27034/0). The final study protocol was submitted to EUA 27034/68 and reviewed by the
+CBER BEST team. An IR response (EUA 27034/186) indicates that the protocol will be revised to incorporate CBER BEST team comments regarding the addition of a contemporary unvaccinated comparator cohort for signal evaluation; a revised protocol will be submitted by August 31, 2021. Please see previous review memorandums for additional details.
+7.3.5 C4591022: Pfizer-BioNTech COVID-19 Vaccine exposure during pregnancy: A non-interventional post-approval safety study of pregnancy and infant outcomes in the Organization of Teratology Information Specialists (OTIS)/Mother To Baby
+Pregnancy Registry
+The primary objective of this pregnancy registry study is to assess whether pregnant women in the Organization of Teratology Information Specialists (OTIS) Pregnancy Registry receiving the Pfizer-BioNTech COVID-19 vaccine experience increased risk of pregnancy and infant safety outcomes. The secondary objective is to characterize utilization patterns of the Pfizer-BioNTech COVID-19 vaccine among pregnant women in the OTIS registry.
+This prospective, observational cohort pregnancy registry study will utilize two comparator groups: 1) pregnant women who received an influenza or Tap (tetanus, diphtheria, and acellular pertussis) vaccine during pregnancy and 2) pregnant women who received no vaccines during pregnancy. The study aims to enroll 1800 pregnant women over a 3-year recruitment period. Pregnancy and infant safety outcomes will include major congenital malformations, spontaneous abortion, stillbirth, preterm
+27
+
+delivery, small for gestational age, and small for age postnatal growth to one year of age. Data will be collected using maternal interviews, medical record review, and a pregnancy exposure diary. Data analysis will include descriptive statistics, birth prevalence rates and incidence rates, and risk estimates.
+The proposed study milestones are:
+Final protocol submission: July 1, 2021
+Interim report submissions: January 31, 2022; January 31, 2023; January 31, 2024;
+January 31, 2025
+End of data collection: December 31, 2024
+Final study report submission: December 1, 2025
+Reviewer comment: This pregnancy registry study will be a post-marketing commitment
+(PMC).
+8 DE Assessment of Sponsor's Pharmacovigilance Plan
+8.1 Important Identified Risk: Anaphylaxis
+The risk of anaphylaxis was recognized early in the post-authorization time period and information was added to the EUA Fact Sheets for healthcare providers and recipients and caregivers. One BNT162b2-related-SAE of anaphylactoid reaction occurred in a clinical trial (C4591001) participant who originally received placebo and then received BNT162b2 after unblinding. This individual had an ongoing medical history of drug hypersensitivity and food and seasonal allergies and had onset 2-days post-1st dose of BNT162b2; she self-administered an epinephrine pen and symptoms resolved the same day. In addition, the sponsor's summary of post-authorization A reports identified 1,002 cases of anaphylaxis that met the Brighton Collaboration (BC) definition level 1 (highest level of certainty) through 4 (reported event with insufficient evidence to meet case definition), including nine fatal events. A VAERS search for reports of anaphylaxis returned 1,034 reports, including 524 serious reports and 12 death reports; there were no patterns suggestive of any new safety signals.
+The important identified risk of anaphylaxis, which can be fatal or life-threatening, will be monitored through routine pharmacovigilance activities, including a data capture aid to identify relevant clinical information, and post-authorization safety studies. This safety concern has labeling proposed in the following sections of the USPI
+• Section 4 Contraindications
+• Section 5 Warnings and Precautions, 5.1 Management of Acute Allergic Reactions
+• Section 6 Adverse Reactions
+Reviewer comment: The proposed PVP is adequate to monitor the risk of anaphylaxis.
+28
+
+8.2 Important Identified Risk: Myopericarditis and Pericarditis
+During the post-authorization period, myocarditis and pericarditis following administration of the Pfizer-BioNTech COVID-19 Vaccine was reported to VAERS.
+Myocarditis and pericarditis emerged as a safety signal in VAERS, and there are ongoing analyses for further characterization of these risks. CDC issued clinical considerations regarding myocarditis and pericarditis after receipt of mRNA COVID-19 vaccines among adolescents and young adults in May 2021. Myocarditis and pericarditis following mRNA COVID-19 vaccines was discussed at the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) and CDC Advisory Committee on Immunization Practices (ACIP) meetings in June 2021. The EUA Fact Sheet was revised on June 25, 2021 to add a Warning for myocarditis and pericarditis and the PVP was amended to include myocarditis and pericarditis as important identified risks. The sponsor's PVP indicates that a mechanism of action has not been established for how the vaccine could cause myocarditis and pericarditis, however potential hypotheses are related to an immune stimulated response, a general systemic inflammatory response, or a hypersensitivity response. The revised PVP (Version 1.1) also included post-authorization data for myocarditis and pericarditis among individuals 16 years of age and older through June 18, 2021. As per the sponsor, there was a total of 823 reports, including 490 reports of myocarditis and 372 reports of pericarditis. A VAERS search for reports of myopericarditis returned 1,023 reports (1,012 were U.S. reports), including 809 serious reports (seven were death reports concerning six unique individuals). As described in the O/E analysis, given a 7-day risk window (Tables 3 and
+4), the reporting rate and R is elevated in age groups under 30 years, with more cases occurring after dose 2. The reporting rate and RR was higher among males than females for almost all age groups.
+Monitoring for myocarditis and pericarditis is ongoing and includes the following activities:
+Continued passive surveillance using VAERS
+Vaccine Safety Datalink (VSD) analyses for safety signals
+- Ongoing Sponsor passive surveillance using worldwide adverse events data
+Ongoing Sponsor active surveillance studies
+In addition, a safety post-marketing requirement (PMR) under FDAAA is warranted to further characterize the serious risk of myopericarditis.
+This safety concern has labeling proposed in the following sections of the USPI:
+• Section 5 Warnings and Precautions
+• Section 6 Adverse Reactions
+Reviewer comment: The sponsor's proposed PVP and FDA required post-marketing study is adequate to monitor and further assess the risk of myocarditis and pericarditis including long-term follow up. Please see PVP addendum memo for review of the safety PMR.
+29
+
+8.3 Important Potential Risk: Vaccine-Associated Enhanced Disease (VAED), including Vaccine-Associated Enhanced Respiratory Disease (VAERD)
+Vaccine-associated enhanced disease (VAED) is a modified and/or severe presentation of an infectious disease in individuals exposed to a wild-type pathogen following receipt of a vaccine designed to prevent infection (Munoz, 2021). The clinical manifestations of VAED are within the spectrum of natural disease and are difficult to separate from vaccine failure; there are no specific biomarkers or histopathologic findings for VAED (Munoz, 2021). In addition, there can be multiple pathophysiologic pathways that could lead to VAED/VAERD in general, such as immune complex mediated enhanced disease, cellular immunity in enhanced respiratory disease, antibody mediated enhanced disease, cytokine activation, or vaccine-induced enhancement of infection acquisition (Munoz, 2021). The sponsor cites VAED as a theoretical risk based on animal models of related betacoronaviruses, including SARS-CoV-1 and MERS-CoV, and disease enhancement that was seen in vaccinated children following infection with natural virus after receipt of inactivated respiratory syncytial virus vaccine. Data from the blinded placebo-controlled follow-up period in Study C4591001 show one confirmed case of post-vaccination severe COVID-19 compared to 31 confirmed cases in the placebo group. No post-authorization A reports have been identified as cases of VAED/VAERD. The important potential risk of VAED will be monitored through routine pharmacovigilance activities, including a data capture aid to identify relevant clinical information, and post-authorization safety studies.
+Reviewer comment: The favorable balance of confirmed cases of severe COVID-19 in BNT162b2 vs placebo recipients in Study C4591001 is reassuring. The proposed PVP is adequate to monitor the potential risk of VAED and VAERD.
+8.4 Missing Information: Use in pregnancy and lactation
+Pregnant women were excluded from the pivotal clinical trial and the safety profile of the Pfizer-BioNTech COVID-19 vaccine in pregnant or lactating women is not known. Post-authorization data from the sponsor's safety database and a VAERS search did not identify any patterns suggesting new safety concerns. Missing information regarding the use of the product during pregnancy and lactation will be monitored through routine pharmacovigilance activities, a clinical trial, and post-authorization safety studies, including a Pregnancy Registry study which will be a PMC. The lack of safety data will be communicated in product labeling (Section 8.1 Pregnancy and 8.3 Lactation).
+Reviewer comment: The proposed PVP is adequate to monitor for use in pregnancy and lactation.
+8.5 Missing Information: Vaccine effectiveness
+Real-world vaccine effectiveness of the Pfizer-BioNTech COVID-19 vaccine outside of clinical trials and in larger and more diverse populations is not known. Post-
+30
+
+authorization data from the sponsor's safety database identified 16 cases of vaccination failure out of 42,086 total AE cases reported cumulatively to February 28, 2021. The sponsor's review of these cases did not reveal any new safety signals associated with the lack of vaccine effectiveness. In addition, a VAERS search returned 1,788 reports that included the PT vaccination failure (n=254) and/or drug ineffective (n=1,565); 31 reports contained both PTs; there were no patterns suggestive of any safety signals.
+Missing information regarding real-world vaccine effectiveness will be monitored through routine pharmacovigilance activities and post-authorization real-world vaccine effectiveness studies. Data on vaccine efficacy in clinical trials will be communicated in product labeling (Section 14 Clinical Studies).
+Reviewer comment: The proposed PVP is adequate to monitor vaccine effectiveness.
+8.6 Missing Information: Use in pediatric individuals <12 years of age
+Pediatric individuals <12 years of age were excluded from the pivotal clinical trial and the safety profile in this population is not known. Post-authorization data from the sponsor's safety database revealed 34 cases concerning 132 AEs; review of PTs did not reveal new safety concerns. A VAERS search returned 273 reports concerning individuals <12 years of age and did not suggest any patterns concerning for any new safety signals. Missing information regarding pediatric individuals <12 years of age will be monitored through routine pharmacovigilance activities and a post-authorization safety study. There are also ongoing clinical trials. The lack of safety data will be communicated in product labeling (Section 8.4 Pediatric Use).
+Reviewer comment: The proposed PVP is adequate to monitor use in individuals <12 years of age.
+9 DE Conclusions
+Based on review of available data, there is a new safety signal for myopericarditis from post-authorization safety surveillance which warrants a FDAAA Title IX PMR safety study to assess the important identified risk of myopericarditis. Please see PVP addendum memo for review of the safety PMR. The sponsor's proposed Pregnancy Registry study (C4591022) will be a PMC. In addition, the safety of BNT162b2 can be monitored through routine PV activities, risk communication through labeling, and the additional post-authorization safety studies proposed by the sponsor.
+10 DE Recommendations
+Should the product be approved, based on the review of the clinical trial safety data, and the post-authorization safety data, OBE/DE recommends the following actions:
+• Routine pharmacovigilance in accordance with adverse event reporting regulations under 21 CFR 600.80, as per the sponsor's proposed PVP.
+31
+
+• Post-marketing requirement (PMR) safety study under Section 505(o) of the
+FDCA (amended by FDAAA, Title IX, Section 901), to assess the serious risk of myopericarditis. (Please see PVP addendum memo for review of the safety PMR.)
+• Post-marketing commitment (PMC) safety study for a pregnancy registry
+(C4591022) to assess whether pregnant women receiving the Pfizer-BioNTech
+COVID-19 vaccine experience an increased risk of pregnancy and infant safety outcomes compared to two comparator groups.
+• Voluntary post-marketing studies: Post-EUA studies that continue as voluntary studies will be followed through updates in periodic safety update reports (PSURs).
+OBE/DE also recommends inclusion of the following AEs to the USPI, Section 6.2 Post-marketing Experience: dizziness and dyspnea.
+At this time, the available safety data do not suggest a safety concern that would require a REMS. Please see the final version of the package insert submitted by the sponsor for the final agreed-upon language for the label.
+11 References
+Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine - United States, December 14-23, 2020. MMWR Morb Mortal Wkly Rep 2021;70:46-51. DOl: http://dx.doi.org/10.15585/mmwr.mm70021
+Gee J, Marquez P, Su J, et al. First Month of COVID-19 Vaccine Safety Monitoring - United States, December 14, 2020-January 13, 2021. MMWR Morb Mortal Wkly Rep
+2021;70:283-288. DOl: http://dx.doi.org/10.15585/mmwr.mm70083
+Gubernot D, Jazwa A, Niu M, Baumblatt J, U.S. Population-Based background incidence rates of medical conditions for use in safetv assessment of COVID-19 vaccines. Vaccine. 2021 Jun 23;39(28): 3666-3677. PMID: 34088506.
+Magnus MC, Wilcox AJ, Morken NH, Weinberg CR, Haberg SE. Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study. BMJ.
+2019;364:1869.
+Munoz FM, Cramer JP, Dekker CL, Dudley MZ, Graham BS, Gurwith M, Law B, Perlman S, Polack FP, Spergel JM, Van Braeckel E, Ward BJ, Didierlaurent AM, Lambert PH; Brighton Collaboration Vaccine-associated Enhanced Disease Working Group. Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2021 May
+21;39(22):3053-3066. do: 10.1016/j.vaccine.2021.01.055. Epub 2021 Feb 23. PMID:
+33637387; PMCID: PMC7901381.
+32
+
+Myocarditis Brighton Collaboration Definition (Pandemic Emergency Response
+Process_Draft Release), Version 1.4.2; May 30, 2021. Available at:
+https://brightoncollaboration.us/wp-content/uploads/2021/07/Myocarditis-
+CD Version 1.4.2 30.May .2021 LOC ALL FINAL.POSTING.pdf
+Roth, G. A., Mensah, G., Johnson, C.O., Addolorato, G., Journal of the American College of Cardiology J Am Coll Cardiol. 2020 Dec 22; 76(25): 2982-3021. PMID:
+33309175.
+Rüggeberg JU, Gold MS, Bayas JM, Blum MD, Bonhoeffer J, Friedlander S, de Souza Brito G, Heininger U, Imoukhuede B, Khamesipour A, Erlewyn-Lajeunesse M, Martin S, Mäkelä M, Nell P, Pool V, Simpson N; Brighton Collaboration Anaphylaxis Working Group. Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2007 Aug 1;25(31):5675-84. doi:
+10.1016/j.vaccine.2007.02.064. Epub 2007 Mar 12. PMID: 17448577.
+Shimabukuro TT, Cole M, Su JR. Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US-December 14, 2020-January 18, 2021. JAMA. 2021 Mar
+16;325(11):1101-1102. do: 10.1001/jama.2021.1967. PMID: 33576785
+33
+

docs/Pharmacovigilance Plan Review-Addendum Memo - COMIRNATY.txt

@@ -0,0 +1,183 @@
+Department of Health and Human Services
+Food and Drug Administration (FDA)
+Center for Biologics Evaluation and Research (CBER)
+Office of Biostatistics and Epidemiology (OBE)
+Division of Epidemiology (DE)
+PHARMACOVIGILANCE PLAN REVIEW: ADDENDUM MEMORANDUM
+From:
+Meghna Alimchandani, MD
+Deputy Director, Division of Epidemiology (DE)
+Kerry Welsh, MD
+Medical Officer, Analytic Epidemiology Branch (AEB)
+To:
+Through:
+Subject:
+Sponsor:
+Product:
+BLA Number:
+Proposed Indication:
+Submission Date:
+Action Due Date:
+Ramachandra Naik, PhD
+Chair, Review Committee
+Office of Vaccines Research and Review (OVRR), CBER, FDA
+Manette Niu, MD
+Branch Chief, AEB
+DE, OBE, CBER, FDA
+Narayan Nair, MD
+Division Director, DE
+OBE, CBER, FDA
+Review of Pharmacovigilance Plan - Addendum memo
+Pfizer
+COMIRNATY; BNT162b2 (Pfizer-BioNTech COVID-19
+Vaccine)
+125742/0
+Active immunization to prevent COVID-19 disease caused by SARS-CoV-2 in individuals >16 years of age.
+May 18, 2021
+January 16, 2022
+1
+
+1 Objectives and Scope
+The sponsor's proposed pharmacovigilance plan (PVP), clinical safety database and post-authorization safety data were reviewed in the OBE/DE Pharmacovigilance Plan
+Review Memorandum, dated August 6, 2021 (OBE/DE primary reviewer: Deborah Thompson, MD). This addendum memo serves to provide review updates, including additional VAERS analvsis for adverse events of special interest, and new information on sponsor proposed postmarketing safety studies, and final OBE/DE recommendations for postmarket safety monitoring for COMIRNATY.
+2 Vaccine Adverse Event Reporting System Data
+FDA post-authorization safety data was previously summarized in section 6 of OBE/DE
+Pharmacovigilance Plan Review Memorandum, dated August 6, 2021. A COVID-19
+Vaccine Safety Update1 from the European Medicines Agency (EMA) prompted further
+VAERS analysis of the following adverse events of special interest (AESI): ervthema multiforme; glomerulonephritis and nephrotic syndrome; menstrual disorders.
+• Erythema multiforme (EM), Stevens-Johnson Syndrome, and toxic epidermal necrolysis:
+A query? of the VAERS database on August 16, 2021, retrieved 194 reports of
+which there were 53 U.S. reports. Among U.S. reports (n = 53), there were 12
+serious reports including 1 death:
+• The patient that died (VAERS ID 1034116) was a 58 year old female who presented with 3 - 4 days of extensive rash with skin sloughing 11 days after vaccination. Skin biopsy was compatible with toxic epidermal necrolvsis. She died ®® davs after vaccination.
+Cases involved 29 females, 23 males and sex was unknown in one case. Median age was 56 years (range 13 - 98 years, unknown for 5 cases). Interval to onset of symptoms post vaccination was 2 days (range 0 - 45 days, unknown for 3 cases).
+• Glomerulonephritis and nephrotic syndrome:
+A query of the VAERS database on August 16, 2021, retrieved 175 reports of
+which there were 57 U.S. reports. Among U.S. reports (n = 57), there were 35
+serious reports. There were no deaths. Cases involved 24 females, 32 males and sex was not reported in one case. Median age was 40 years (range 12 - 88
+1 https://www.ema.europa.eu/en/documents/covid-19-vaccine-safety-update/covid-19-vaccine-safety-update-spikevax-previouslv-covid-19-vaccine-moderna-11-august-2021 en.odf
+2 Preferred Terms (PTs) for querv: ERYTHEMA MULTIFORME-STEVENS-JOHNSON SYNDROME:TOXIC EPIDERMAL NECROLYSIS
+3 PTs for query: ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE; C3 GLOMERULOPATHY; FIBRILLARY GLOMERULONEPHRITIS; FOCAL SEGMENTAL GLOMERULOSCLEROSIS: GLOMERULONEPHRITIS: GLOMERULONEPHRITIS ACUTE:GLOMERULONEPHRITIS CHRONIC:GLOMERULONEPHRITIS MEMBRANOPROLIFERATIVE:GLOMERULONEPHRITIS MEMBRANOUS:GLOMERULONEPHRITIS MINIMAL LESION•GLOMERULONEPHRITIS PROLIFERATIVE-GLOMERULONEPHRITIS RAPIDLY PROGRESSIVE:GOODPASTURES SYNDROME:GRANULOMATOSIS WITH POLYANGIITIS:HENOCH-SCHONLEIN PURPURA: HENOCH-SCHONLEIN PURPURA NEPHRITIS: IGA NEPHROPATHY:IGM NEPHROPATHY:MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS: MICROSCOPIC POLYANGIITIS:NEPHRITIC SYNDROME:NEPHRITIS ALLERGIC:NEPHRITIS:NEPHRITIS INTERSTITIAL: NEPHROTIC SYNDROME
+2
+
+years, unknown for 2 cases). Interval to onset of symptoms post vaccination was 2.5 days (range 0 - 48 days, unknown for 3 cases).
+• Menstrual disorders:
+A query of the VAERS database on August 16, 2021, retrieved 7249 reports of which there were 3327 U.S. reports. Twenty-eight U.S. reports were excluded because sex was reported as male, or sex was not reported. Among U.S. cases
+in females only (n = 3299), there were 85 serious reports. There were no deaths.
+Median age was 37 years (range 12 - 74 years, unknown for 107 cases).
+Interval to onset of symptoms post vaccination was median 3 days (range 0 - 154 days, unknown for 158 cases).
+Reviewer comment: Note that the above analysis is based on case counts retrieved from automated queries, and individual cases were not manually reviewed. Limitations of passive surveillance data include missinq/incomplete data and unconfirmed diagnoses. In the context of 201,577,973 doses of Pfizer-BioNTech COVID-19 Vaccine administered, there are no new safety signals identified from the above analysis of VAERS data at this time. Based on the above query results, there were few U.S.
+reports for erythema multiforme (n = 53 U.S.) and glomerulonephritis and nephrotic
+syndrome (n = 57 U.S. reports). Majority of the reports of menstrual disorders were non-
+serious reports. Menstrual disorders are common in the general population and can occur without an underlying medical condition. OBE/DE will continue safety monitoring for adverse events after COMIRNATY. We will review any additional information on these AESIs from EMA when available.
+3 Serious risks: myocarditis and pericarditis, and subclinical myocarditis
+Myocarditis and pericarditis: Post-authorization safety data (previously described in section 6 of OBE/DE Pharmacovigilance Plan Review Memorandum, dated August 6,
+2021) has identified serious risks for myocarditis and pericarditis after COMIRNATY, with increased risk in males under 30 years of age, particularly following the second dose, and onset of symptoms within 7 days following vaccination. Authorized EUA Fact Sheets were updated on June 25, 2021, to include a new Warning about myocarditis and pericarditis.
+Subclinical myocarditis: Incidence of subclinical myocarditis and potential long-term sequelae following COMIRNATY are unknown. A previous study® of smallpox vaccine
+4 PTs for query: ABNORMAL UTERINE BLEEDING;ABNORMAL WITHDRAWAL BLEEDING; ANOVULATORY CYCLE; BLEEDING ANOVULATORY;
+DELAYED MENARCHEDYSMENORRHOE;INTERMENSTRUALBLEEDING:MENSTRUALDISORDER:MENSTRUALDISCOMFORT:MENSTRUATION IRREGULAR;PREMENSTRUAL DYSPHORIC DISORDER;PREMENSTRUAL PAIN;PREMENSTRUAL SYNDROME;WITHDRAWAL BLEED; AMENORRHOEA;
+HYPOMENORRHOEA;MENSTRUATION DELAYED; OLIGOMENORRHOEA; HEAVY MENSTRUAL BLEEDING; MENOMETRORRHAGIA;
+POLYMENORRHAGIA; POLYMENORRHOEA
+5 CDC COVID Data Tracker accessed on August 18, 2021 https://covid.cdc.gov/covid-data-tracker/#vaccinations vacc-total-admin-rate-total
+6 Engler RJ, et al. A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination. PLoS One. 2015;10(3): e0118283
+
+suggested an incidence of possible subclinical myocarditis (based on cardiac troponin T elevations) 60-times higher than the incidence rate of overt clinical myocarditis.
+FDA information request dated July 28, 2021, asked the sponsor to propose postmarketing observational safety study(ies) to assess myocarditis and pericarditis following administration of COMIRNATY to quantify the magnitude of risk by age, sex, and dose; include follow up cases (e.g., via a registry) for recovery status and long-term sequelae; and propose plans to characterize subclinical cases of myocarditis. The sponsor's proposed plans were reviewed (responses to Information Requests dated July 28, 2021, and August 10, 2021) and recommendations for proposed safety postmarketing requirements/commitments (PMs/PMs) as well as CBER Sentinel Sufficiency assessment were presented to the CBER Safety Working Group (SWG) on
+August 12, 2021.
+4 Sponsor proposed post-authorization/postmarketing safety studies
+The safety surveillance studies proposed by the Sponsor were previously reviewed in section 7.3 of OBE/DE Pharmacovigilance Plan Review Memorandum, dated August 6,
+2021. Additional information provided by the sponsor is summarized below.
+Studies to assess risks of myocarditis, pericarditis and subclinical myocarditis
+• C4591021 and C4591021 substudy (EU): Post Conditional Approval Active
+Surveillance Study Among Individuals in Europe
+• C4591021 is a retrospective cohort study and the C4591021 substudy is a natural history cohort study within a retrospective cohort study. The substudy plans to collect follow-up for treatment for myocarditis and pericarditis, clinical outcomes, and recovery. The data source comprises of electronic healthcare databases in Netherlands, Norway, United Kingdom, Italy and Spain. The sponsor estimates that the EU databases will capture approximately 4.1 million individuals ≤ 30 years of age with exposure to COMIRNATY. The final protocol for study C4591021 was approved by the EMA on June 24, 202, and this protocol was submitted to FDA for review on August 11, 2021 and is currently under review.?
+Prospective cohort registry study for long term follow-up, in collaboration with Pediatric Heart Network (PHN). PHN is a multi-center consortium of hospitals across U.S. and Canada that conducts research for congenital and pediatric-acquired heart disease. The National Institutes of Health (NIH)/National Heart, Lung and Blood Institute (NHLBI) provides funding for PHN. The sponsor identified approximately 130 patients (as of August 2021), who presented to PHN
+https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118283
+Note that review of study protocols are documented in separate protocol review memorandums.
+
+sites after receiving a COVID-19 vaccine and were diagnosed with myocarditis.
+The sponsor states that, "additional patients continue to present and could be enrolled." Projected sample size and statistical analysis plan will be provided upon submission of the final study protocol on November 30, 2021. In accordance with FDA recommendations, the sponsor has agreed to follow subjects prospectively for 5 years. The objectives of the study include:
+• Characterize the clinical course of acute post-vaccine myocarditis
+Characterize potential long-term sequelae and quality of life
+• Compare long-term effects of post-vaccine myocarditis with those of nonvaccine myocarditis, including myocarditis arising in COVID-infected persons
+• Identify possible risk factors for post-vaccine myocarditis (including age, sex, race, ethnicity, obesity, and other factors)
+• Plans by Sponsor to characterize subclinical cases of myocarditis:
+• The sponsor has expressed challenges in proposing a potential prospective study of subclinical myocarditis because of the absence of a definition of subclinical myocarditis and unknown background incidence of troponin abnormalities. As an initial step, the sponsor plans to determine the background rate of abnormal troponin levels by analyzing troponin I levels in samples of stored sera (drawn <1 year ago) in 12-30-year-old individuals participating in BNT162b2 studies, prior to receipt of BNT162b2 (i.e., either at baseline, or at any visit for placebo recipients).
+Three thousand samples, stratified in the 12-17, 18-24 and 25-30 years age group, will be analyzed (there is a 95% probability of observing one abnormal result amongst the overall sample if the background rate of abnormality is 0.1%). The sponsor anticipates this analysis to be completed by the end of December 2021.
+o The sponsor has proposed modifications to the following two trials to
+obtain a serum sample for storage and potential future troponin testing, at baseline and 2-5 days after the second or third dose of BNT162b2:
+* Study C4591007: proposed addition of 750 participants 5 to <12 years of age (randomized 2:1 to receive BNT162b2 10 ug or placebo) and 500 participants 12-15 years of age (open label receipt of BNT162b2 30 ug).
+C4591031 substudy: proposed addition of a new substudy of 1000 subiects with documented receipt of 2 prior 30 ug doses of BNT162b2 (the second dose received at least 6 months ago), 16 to 30 years of age (randomized 1:1 in a crossover design to receive
+30 Mg BNT162b2 or placebo at baseline and the alternative 4 weeks later).
+• As per the sponsor, "Assuming that subclinical myocarditis can be defined on the basis of elevated troponin I, and that the baseline analysis indicates that such a study is feasible, we will consider C4591031 to be the
+
+prospective study to assess the incidence of subclinical myocarditis following vaccination in individuals ≥16 years. If the sample size of 1000 is insufficient, it will be increased through a protocol amendment."
+5 CBER Safety Working Group (SWG) concurrence with proposed safety postmarketing requirements/commitments (PMRs/PMCs)
+Based on review of available data, there are known risks for myocarditis and pericarditis and an unexpected serious risk for subclinical myocarditis, which warrant PMR safety studies to assess these serious risks. The CBER Sentinel Program was deemed to be insufficient to assess the serious risks of myocarditis and pericarditis, and subclinical myocarditis for the following reasons (please also see Sentinel Sufficiency memorandum):
+• At the time of BLA approval, the data sources in the CBER Sentinel Program are not sufficient to identify the outcomes due to lack of sufficient power to assess the magnitude of risk in patients 12-30 years of age.
+• In addition, CBER Sentinel Program is not sufficient to follow up cases for recovery status and long-term sequelae of myocarditis and pericarditis, or for identification and characterization of subclinical myocarditis cases.
+Furthermore, the FDA and applicant have agreed upon safety studies as PMCs to (a) assess safety in pregnant women and, (b) an active surveillance study in the Veteran's Affair Health System database, which includes sub-cohorts of interest (i.e., immunocompromised, elderly, individuals with specific comorbidities, individuals receiving only one dose Pfizer vaccine, and individuals with prior SARS-CoV-2 infection).
+During a meeting on August 12, 2021, the CBER Safety Working Group concurred with the review team's proposed PMRs/PMCs:
+• Postmarketing requirements (PM) under Section 505(o) of Federal Food, Drug, and Cosmetic Act (FDCA) to assess known serious risks of mvocarditis and pericarditis and an unexpected serious risk for subclinical myocarditis:
+1. Epidemiologic studies using large electronic healthcare databases to evaluate the occurrence of myocarditis and pericarditis
+a) US - Sentinel system (C4591009)
+b) EU - active surveillance study (C4591021 and C4591021 substudy)
+2. Registry for long-term follow-up (in collaboration with Pediatric Heart
+Network)
+3. Prospective study to assess the incidence of subclinical myocarditis following vaccination
+• Postmarketing commitments (PMCs):
+6
+
+1. Pregnancy registry study to assess pregnancy and infant outcomes after exposure to COMIRNATY during pregnancy among pregnant women aged 18 years or older& who reside in the US or Canada. (C4591022)
+2. Randomized controlled trial (RCT) in pregnant women (C4591015)
+3. Active safety surveillance study among persons in the Veteran's Affairs
+Health System (C4591012)
+The sponsor was notified of the above PMs/PMCs in an Information Request (IR) dated August 13, 2021.
+Updates since August 12, 2021 SWG meeting:
+• During the SW meeting, there were questions raised regarding the feasibility of completing the RCT in pregnant women (C4591015), as planned, considering CDC's recommendation° of COVID-19 vaccination for all people 12 years and older, including people who are pregnant. In further communication with the sponsor, Pfizer described this as a global study that included sites outside the U.S. The Sponsor acknowledged challenges with enrollment due to recommendations for immunization of pregnant women in most participating countries, which may preclude them from reaching the full target enrollment for 700 subjects. As of August 13, 2021, enrollment included 259 subjects, and the sponsor anticipated enrollment for approximately 450 subjects by December
+2021. The Sponsor's Internal Review Committee met on August 5, 2021, to review reactogenicity and safety data through 7 days after the second dose and recommended that the study continue. At this time, Pfizer plans (b) (4)
+Upon further discussion between OVRR and OBE, it was decided not to include the RCT in pregnant women as a PMC at this time. The study will continue under IND. OBE defers to OVRR as the lead reviewer for this clinical trial.
+• The SWG had concurred on the need for PMR(s) to further assess subclinical myocarditis, but additional details on study design were not available at the time of the SW meeting. Since the SW meeting, OVRR had further communication with the sponsor and, the sponsor proposed protocol modifications to two clinical trials (studies C4591007 and C4591031) to assess subclinical myocarditis. OBE defers to OVRR as the lead reviewer for these clinical trial PMRs:
+• A prospective assessment of the incidence of subclinical myocarditis following administration of the second dose of COMIRNATY in a subset of participants 5 through 15 years of age enrolled in Study C4591007
+& The pregnancy registry will be in collaboration with the Organization of Teratology Information Specialists
+(OTIS) /MotherToBaby Pregnancy Registry. The final protocol was submitted on July 1, 2021, is currently under review.
+9 https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html#anchor 1628692562866
+
+• Study C4591031 substudy to prospectively assess the incidence of subclinical myocarditis following administration of a third dose of
+COMIRNATY in a subset of participants 16 to 30 years of age
+• OBE and OVRR are in agreement with the following PMC for a vaccine effectiveness study: Study C4591014, entitled "Pfizer-BioNTech COVID-19
+BNT162b2 Vaccine Effectiveness Study - Kaiser Permanente Southern
+California." DE defers to OBE/OD as the lead reviewer of real-world evidence
+(RWE) for vaccine effectiveness.
+• OVRR included the following clinical trial as a PMC: An evaluation of the immunogenicity and safety of lower dose levels of COMIRNATY in individuals 12 through <30 years of age enrolled in Study C4591007. OBE defers to OVRR as the lead reviewer for this clinical trial PMC.
+6 DE Recommendations
+Should the product be approved, based on the review of the clinical trial safety data, and the post-authorization safety data, OBE/DE recommends the following pharmacovigilance activities:
+• Routine pharmacovigilance in accordance with adverse event reporting regulations under 21 CF 600.80, as per sponsor's proposed PVP (version 1.1).
+• Postmarketing requirement (PMR) safety studies under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to assess the known serious risks of myocarditis and pericarditis and an unexpected serious risk for subclinical myocarditis:
+1. Study C4591009, entitled "A Non-Interventional Post-Approval Safety
+Study of the Pfizer-BioNTech COVID-19 mRNA Vaccine in the United States," to evaluate the occurrence of myocarditis and pericarditis following administration of COMIRNATY.
+2. Study C4591021, entitled "Post Conditional Approval Active Surveillance
+Study Among Individuals in Europe Receiving the Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) Vaccine," to evaluate the occurrence of myocarditis and pericarditis following administration of COMIRNATY.
+3. Study C4591021 substudy to describe the natural history of myocarditis and pericarditis following administration of COMIRNATY.
+4. A prospective cohort study with at least 5 years of follow-up for potential long-term sequelae of myocarditis after vaccination (in collaboration with Pediatric Heart Network).
+
+The following clinical trials to assess subclinical myocarditis will be under the lead review of OVRR:
+5. A prospective assessment of the incidence of subclinical myocarditis following administration of the second dose of COMIRNATY in a subset of participants 5 through 15 years of age enrolled in Study C4591007.
+6. Study C4591031 substudy to prospectively assess the incidence of subclinical myocarditis following administration of a third dose of
+COMIRNATY in a subset of participants 16 to 30 years of age.
+• Postmarketing commitment (MC) safety studies agreed upon by FDA and applicant:
+1. Study C4591022, entitled "Pfizer-BioNTech COVID-19 Vaccine Exposure during Pregnancy: A Non-Interventional Post- Approval Safety Study of Pregnancy and Infant Outcomes in the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry."
+2. Study C4591012, entitled "Post-emergency Use Authorization Active
+Safety Surveillance Study Among Individuals in the Veteran's Affairs Health System Receiving Pfizer-BioNTech Coronavirus Disease 2019
+(COVID-19) Vaccine."
+• Voluntary postmarketing studies: The sponsor has agreed to provide updates regarding post-EUA studies that continue as voluntary studies post-licensure in periodic safety update reports (PSURs).
+1. C4591011: Active safety surveillance of the Pfizer-BioNTech COVID-19 vaccine in the U.S. Department of Defense population following
+Emergency Use Authorization
+2. C4591008: HERO Together: A post-Emergency Use Authorization observational cohort study to evaluate the safety of the Pfizer-BioNTech
+COVID-19 Vaccine in U.S. healthcare workers, their families, and their
+communities
+At this time, the available safety data do not suggest a safety concern that would require a Risk Evaluation and Mitigation Strategy (REMS).
+Please see the approval letter for study milestone dates.
+Please see the final version of the package insert submitted by the sponsor for the final agreed-upon lanquage for the label.
+C
+

docs/Real World Evidence BLA Memo - COMIRNATY.txt

@@ -0,0 +1,134 @@
+FDA U.S. FOOD & DRUG
+ADMINISTRATION
+Department of Health and Human Services
+Food and Drug Administration
+Center for Biologics Evaluation and Research (CBER)
+Office of Biostatistics and Epidemiology (OBE)
+REAL WORLD EVIDENCE BLA MEMORANDUM
+From:
+Yun Lu, PhD
+Mathematical Statistician
+Analytics and Benefit-Risk Assessment Team (ABRA)
+Office of Biostatistics and Epidemiology (OBE)
+CBER, FDA
+To:
+Ramachandra Naik, PhD Chair of the Review Committee Office of Vaccines Research and Review
+Through:
+Richard Forshee, PhD Acting Deputy Director, OBE CBER, FDA
+Subject:
+Review of Pharmacovigilance Plan, Real World Post-Authorization Effectiveness Protocol C4591014, Post-Authorization Safety Protocols C4591009, C4591021,
+Amendment 30, Amendment 42, Amendment 51
+Sponsor:
+BioNTech RNA Pharmaceuticals GmbH/Pfizer, Inc.
+Product:
+COMIRNATY; Pfizer-BioNTech COVID-19 Vaccine*
+Application Type/Number:
+BLA STN 125742/0
+Proposed Indication:
+Prevention of COVID-19 in individuals 16 years of age and older
+Submission Date:
+May 18, 2021
+*The product was also referred to as BNT162b2 in the clinical development
+
+1 OBJECTIVE
+The purpose of this review is to assess the adequacy of the real world post-authorization vaccine effectiveness protocols C4591014, post-authorization vaccine safety protocols C4591009 and C4591021 for Pfizer-BioNTech coronavirus disease
+2019 (COVID-19) Vaccine COMIRNATY.
+Materials Reviewed
+• Pharmacovigilance Plan, Version 1.1 (ST 125742/0.20; received July 29, 2021)
+• Response to CBER 28 July 2021 Information Request Regarding Post-marketing Safety Study(ies) (ST 125742/0.30; received August 3, 2021)
+• Response to CBER 10 August 2021 Information Request Regarding Post-marketing Safety Studies (STN 125742/0.42; received August 11, 2021)
+• Response to CBER 13 August 2021 Information Request Regarding Safety-Related
+Postmarketing Requirement/Postmarketing Commitment Studies (ST
+125742/0.51; received August 16, 2021)
+• C4591009 Synoposis: A Non-Interventional Post-Approval Safety Study of the
+Pfizer-BioNTech COVID-19 mRNA Vaccine in the United States.
+• C4591021 protocol: Post Conditional Approval Active Surveillance Study Among Individuals in Europe Receiving the Pfizer-BioNTech Coronavirus Disease 2019
+(COVID-19) Vaccine
+• C4591014 protocol: Pfizer-BioNTech COVID-19 BNT162b2 Vaccine Effectiveness
+Study - Kaiser Permanente Southern California
+2 PRODUCT INFORMATION
+2.1 Product Description
+The Pfizer-BioNTech COVID-19 Vaccine COMIRNATY contains a nucleoside-modified messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The product is a frozen suspension for intramuscular injection.
+The product is administered as a series of two doses (0.3 mL) each 21 days apart by intramuscular injection.
+2.2 Proposed Indication
+The proposed indication for Pfizer-BioNTech COVID-19 Vaccine COMIRNATY in the United States is for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and older.
+3 POST-AUTHORIZATION SAFETY AND EFFECTIVENESS STUDIES
+In Response to CBER 28 July 2021 Information Request Regarding Post-marketing Safety Study(ies) (STN 125742/0.30; received August 3, 2021), the sponsor provided required number of cases to detect Myocarditis risk under
+2
+
+different assumptions of background rates. The sponsor also compared four post-authorization safety studies C4591009 (US), C4591011 (US), C4591012 (US), and C4591021 (EU) to assess increased risk of safety events of interest, including myocarditis/pericarditis.
+Reviewer comment: Among the four proposed post-authorization safety studies, two studies C4591009 (US) and C4591021(EU) have relatively large source population. The estimated number of individuals <30 years administered Pfizer vaccine is approximately 14.1 million in C4591009 and approximately 4.1 million in C4591021. It would be useful to include these two safety studies as postmarketing requirements (PMRS).
+Please provide protocols for the C4591021 study and C4591021 substudy.
+The sponsor submitted C4591009 protocol synopsis, and the protocol is expected to be finalized by August 31, 2021.
+Below are the comments for C4591009 protocol synopsis:
+1. The primary analysis in the post-authorization safety study C4591009 protocol synopsis uses a concurrent unexposed cohort. People without vaccination codes could receive their COVID vaccinations outside of the system, and exposure misclassification could bias the results. The self-controlled methods such as self-controlled risk interval (SCRI) are less susceptible to bias due to exposure misclassification. SCRI with a post-vaccination control window was proposed as a sensitivity analysis.
+Please clarify how you plan to assess the magnitude of exposure misclassification for the concurrent unexposed cohort and quantify the bias. If the magnitude of the exposure misclassification is large, please consider using the SCRI as the primary analysis. The proposed SCRI control window has the same length as the risk interval, which may decrease the risk of time-varying confounding bias but could result in more limited person time for some AESIs thus impacting the power of the SCRI analysis. Since SCRI allows the control window to have a different length than the risk window, please consider using a longer control window (e.g., multiples of the risk window) in the primary analysis, while maintaining the shorter control window for a sensitivity analysis. Please provide length of risk interval for each AESI.
+2. Table 1 on Page 5 of the Response to Information Request provided the required number of cases to detect myocarditis under different assumptions with a self-controlled case series (SCCS) analysis. The study C4591009 protocol synopsis proposed a SCRI analysis. SCCS samples cases only, SCRI samples vaccinated individuals only, and the control interval could differ between these two study designs even with the same length of risk interval. Please clarify the length and definition of control interval in the Table 1 sample size calculation. The choice of risk window is critical for SCRI. Because the onset of myocarditis was typically
+3
+
+within several days after mRNA COVID-19 vaccination, please add a 7-day risk window to the SCRI analysis in addition to the proposed 14-day and 21-day risk window. Please also provide the sample size calculation for a 7-day risk window for myocarditis.
+For study C4591009 protocol synopsis, the sample size calculation on Page 14 was based on a true RR=1. Please recalculate the sample size under alternative RRS.
+In Response to CBER 10 August 2021 Information Request Regarding Post-marketing Safety Studies (ST 125742/0.42; received August 11, 2021), the sponsor addressed questions regarding study C4591009 and provided protocol for study C4591021.
+Reviewer comment:
+Below are the comments for sponsor's response regarding C4591009(US):
+1. The sponsor addressed exposure misclassification issue in the full C4591009 protocol (to be submitted by August 31, 2021) with pre-specified feasibility assessment. If vaccine coverage estimates differ meaningfully from the
+"benchmarking" estimates, the sponsor may consider the SCRI or the cohort design with historical unexposed comparators as the primary study designs and/or consider linkage to immunization registries if feasible.
+The sponsor's response is acceptable.
+The COVID pandemic could have short-term and long-term impact on people's health seeking behavior. For historical unexposed comparators, please clarify how you plan to evaluate the temporal trend of time varying confounders.
+Page 12 of the C4591009 protocol synopsis mentioned ICD-9-CM and ICD-10-CM codes. ICD-10-CM was effective as of Oct 1, 2015. Please clarify whether historical unexposed comparators before Oct 1, 2015 will be used. There are differences between the ICD-9-CM and ICD-10-CM codes, and bias could be introduced. Please clarify how you plan to address the differences between the ICD-9-CM and ICD-10-CM sustem.
+2. The length of the control window in the SCRI analyses will be assessed separately for each outcome and the risk intervals for each safety event of interest will be provided in Section 9.3.2.1 of the full C4591009 protocol.
+The sponsor's response is acceptable.
+3. The sponsor will incorporate a 7-day risk period for myocarditis into the protocols.
+The sponsor's response is acceptable.
+4
+
+4. The sponsor provided study size estimates for 1:1 matching for true RR=1, 1.2 and
+1.4 in Appendix 1.
+The sponsor's response is acceptable.
+The sponsor submitted C4591021(EU) protocol. Below are the comments:
+1. Page 21. Section 9.1.1.1. Matching process.
+The sponsor proposed "a 1:1 matching without replacement using a 'rolling cohort' design". A vaccinated individual will be censored if his/her unvaccinated match is vaccinated later.
+If rapid vaccine rollout happens and a large number of individuals receive vaccines within a short period of time, many vaccinated individuals may get censored. This will have a negative impact on the person time. Please clarify how you plan to address this potential issue.
+2. Page 23. Section 9.1.2. Self-controlled risk interval (SCRI) design.
+Figure 1 illustrated a SCRI example with a risk window of 42 days and a control window of 42 days. Please clarify how the risk interval and control interval are defined for a fully vaccinated individual. For example, for a person who receives the and dose 21 days after the ist dose, the ist dose and the and dose risk intervals overlap. Is the risk window 42 days or 42+21=63 days? Is the control window 42 days or 42+21=63 days?
+3. Page 29. Section 9.3.2.1. Safety outcomes
+Table 1, Heparin-induced thrombocytopenia (HIT) - like event has a risk interval of 15 days. For a person who receives the 2nd dose 21 davs after the 1st dose, the ist dose risk interval and the and dose risk interval do not overlap. Please clarify the HIT-like event risk and control windows for people who receive two doses.
+4. Page 29. Section 9.3.2.1. Safety outcomes
+Table 1. Cardiovascular system. Myocarditis is one of the AESIs. The risk window was listed as "any". Please specify the length of risk window for myocarditis. Only cohort study was proposed in the Table. Please consider adding SCRI for myocarditis.
+5. Page 32, 9.3.3. Covariate definition
+"Age will be categorised as age categories in line with published background incidence rates from ACCESS (0-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70-79,
+80+)"
+5
+
+Myocarditis is one of the AESIs. Please consider refining the age category 0-19 to include an adolescent age group, such as 10-19 years old.
+6. Page 47, 9.5. Study size
+The protocol mentioned that "The study will be conducted in a source population of 38.9 million individuals captured in the electronic healthcare data sources.
+39
+Seven data sources are included in the protocol with a total source population of 38.9 million. The data will be analyzed separately by data source. The number of active individuals ranges from 1 million in Pedianet/Health Search Database (IT) to 16 million in Clinical Practice Research Datalink and Hospital Episode Statistics (UK). Some data sources may not have enough study size to detect rare AESIs.
+In the Pharmacovigilance Plan, the Sponsor planned three real world post-authorization vaccine effectiveness studies to determine the effectiveness of COMIRNATY when administered outside of the clinical setting: one non-interventional study C4591014 and two low-interventional studies WI235284 and WI255886.
+Reviewer comment:
+WI235284 COVID-19 vaccine effectiveness (VE) Substudy 6 will enroll healthy women who present at Emory University Hospital or Emory University Hospital Midtown for delivery, regardless of respiratory syncytial virus or COVID-19 status. A test negative case-control design is proposed.
+Study WI255886 will be conducted in Bristol, England with approximately 630,000 adults in surveillance population. Real world VE estimates for COVID-19 vaccines will be assessed using a test negative design case control analysis.
+Study C4591014 will estimate the VE of 2-doses of Pfizer's COVID-19 vaccine against acute respiratory illness requiring hospitalization due to SARS-CoV-2 infection among
+Kaiser Permanente Southern California (KPSC) members ≥16 years of age. Two parallel study designs are proposed: a test-negative case-control design and a retrospective cohort design.
+Among the three proposed real world post-authorization vaccine effectiveness studies, Study C4591014 has the largest source population. KPSC has significant proportions of adolescent and young adult populations. It would be useful to include this effectiveness study as a postmarketing commitment (PMC) and include individuals 12 through 15 years of age.
+In Response to CBER 13 August 2021 Information Request Regarding Safety-Related Postmarketing Requirement/Postmarketing Commitment Studies (ST 125742/0.51; received August 16, 2021), the sponsor addressed questions regarding study C4591014.
+
+Reviewer comment:
+The sponsor agreed to include individuals 12 through 15 years of age in Study
+C4591014.
+The sponsor's response is acceptable.
+4 OBE REAL WORLD EVIDENCE RECOMMENDATIONS
+Postmarketing requirement (PMR) safety studies under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to assess the known serious risks of myocarditis and pericarditis, using real world evidence study design:
+1. Study C4591009, entitled "A Non-Interventional Post-Approval Safety Study of the Pfizer-BioNTech COVID-19 mRNA Vaccine in the United States."
+2. Study C4591021, entitled "Post Conditional Approval Active Surveillance Study
+Among Individuals in Europe Receiving the Pfizer-BioNTech Coronavirus
+Disease 2019 (COVID-19) Vaccine."
+3. Study C4591021 substudy to describe the natural history of myocarditis and pericarditis following administration of COMIRNATY.
+OBE will review the final protocols for C4591009 and C4591021 substudy when available (please see approval letter for study milestone dates). The final protocol for Study C4591021 was submitted August 11, 2021 [under ST 125742.0.42] and is currently under review1
+Postmarketing commitment (PMC) vaccine effectiveness study agreed upon by FDA and the sponsor:
+1. Study C4591014, entitled "Pfizer-BioNTech COVID-19 BNT162b2 Vaccine
+Effectiveness Study - Kaiser Permanente Southern California." Include individuals 12 through 15 years of age.
+Note that PMR/PMC studies, in addition to the above listed studies, have been described in OBE/Division of Epidemiology pharmacovigilance plan (PVP) review memo and addendum memo.
+1 Note that the FDA review for this protocol will be documented in a separate protocol review memorandum. Additionally, study C4591021 is also a post-conditional approval study for the European Medicines Agency (EMA) and the protocol was approved by the EMA on June 24, 2021.
+

docs/Statistical Review - COMIRNATY.txt

@@ -0,0 +1,1088 @@
+Application Type
+STN
+CBER Received Date
+PDUFA Goal Date
+Division/ Office
+Committee Chair
+Clinical Reviewers)
+Project Manager
+Priority Review
+Reviewer Names)
+Review Completion Date /
+Stamped Date
+Supervisory Concurrence
+Applicant
+Established Name
+(Proposed) Trade Name
+Pharmacologic Class
+Formulation(s), including
+Adjuvants, etc
+Dosage Form(s) and Route(s) of
+Administration
+Dosing Regimen
+Indication(s) and Intended
+Population(s)
+Statistical Review
+STN: 125742/0
+BLA, Original Application
+125742/0
+May 18, 2021
+January 16, 2022
+DVRPA /OVRR
+Ramachandra Naik
+Ann Schwartz; Susan Wollersheim Mike Smith; Laura Gottschalk Yes Lei Huang
+Tsai-Lien Lin, Branch Chief, VEB, DB,
+John A. Scott, Director, DB, OBE
+BioNTech Manufacturing GmbH (in partnership with Pfizer, Inc.)
+COVID-19 Vaccine, mRNA
+COMIRNATY
+Vaccine
+After preparation, each 0.3 mL dose contains 30ug modified mRNA encoding
+SARS-CoV-2 spike glycoprotein
+Injectable Suspension, Intramuscular
+Two 0.3 mL doses, 3 weeks apart Active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older.
+Page i
+
+Statistical Review
+STN: 125742/0
+Table of Contents
+Glossary....
+1. Executive Summary..
+2. Clinical and Regulatory Background
+3. Submission Ouality and Good Clinical Practices ...............
+3.1 Submission Quality and Completeness........
+3.2 Compliance With Good Clinical Practices And Data Integrity.
+4. Significant Efficacy/Safety Issues Related to Other Review Disciplines............
+5
+5. Sources of Clinical Data and Other Information Considered in the Review ........... 5
+5.1 Review Strategy......
+5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review.........
+5.3 Table of Studies/Clinical Trials...
+6. Discussion of Individual Studies/Clinical Trials.
+6.1 Study C4591001.
+6.1.1 Objectives.
+6.1.2 Design Overview.
+6.1.3 Population
+6.1.4 Study Treatments or Agents Mandated by the Protocol
+6.1.6 Sites and Centers
+6.1.7 Surveillance/Monitoring.
+6.1.8 Endpoints and Criteria for Study Success
+6.1.9 Statistical Considerations & Statistical Analysis Plan
+6.1.10 Study Population and Disposition
+6.1.11 Efficacy Analyses.....
+6.1.12 Safety Analyses.
+7. Integrated Overview of Efficacy...........
+10
+10
+12
+16
+. 25
+• 25
+8. Integrated Overview of Safety.......
+........ 25
+9. Additional Statistical Issues...........
+........... 25
+10. Conclusions..........
+10.1 Statistical Issues and Collective Evidence .........
+10.2 Conclusions and Recommendations..
+............. 25
+......... 25
+....... 26
+Page ii
+
+Statistical Review
+STN: 125742/0
+GLOSSARY
+BIMO
+BNT16262
+CDC
+CI
+COVID-19
+EUA
+HHS
+HIV
+IM
+IR
+LNP modRNA
+NAAT pV
+RT-PCR
+SARS-CoV-2
+VE
+VRBPAC
+WHO
+Bioresearch Monitoring
+PfizerBioNTech COVID-19 Vaccine
+Centers for Disease Control and Prevention
+Confidence interval coronavirus disease 2019
+Emergency Use Authorization
+Health and Human Services human immunodeficiency virus intramuscular
+Information request lipid nanoparticle nucleoside-modified messenger RNA nucleic acid amplification-based test person-years
+reverse transcription-polymerase chain reaction severe acute respiratory syndrome coronavirus 2 vaccine efficacy
+Vaccines and Related Biological Products Advisory Committee
+World Health Organization
+1. EXECUTIVE SUMMARY
+Pfizer submitted a Biologics License Application (BLA 125742/0) on May 18, 2021 to seek licensure of the Pfizer-BioNTech COVID-19 Vaccine (BNT16262) for active immunization to prevent Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. The BLA is supported by safety, efficacy, and immunogenicity data from two ongoing studies (C4591001 and BNT-162-01). This statistical review focuses on the analyses of efficacy data collected during the blinded, placebo-controlled follow-up in the Phase 2/3 portion of Study C4591001.
+Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blinded Phase 1/2/3 study being conducted in the United States, Argentina, Brazil, Germany, South Africa, and Turkey. In the Phase 2/3 portion of the study, 44,165 subjects aged 16 and above were randomized 1:1 to receive two doses of BNT162b2 or placebo 21 days apart.
+Randomization was stratified by age group. Starting December 14, 2020, following issuance of an Emergency Use Authorization (EUA), participants 16 years of age and older were systematically unblinded when eligible per local recommendations and offered BNT1622 vaccination if they had been randomized to placebo.
+In the updated efficacy analvsis for cases accrued during blinded placebo-controlled follow-up (cutoff date: March 13, 2021) of Study C4591001 in participants 16 years of age and older, the estimated vaccine efficacy (VE) against confirmed COVID-19
+Page 3
+
+Statistical Review
+STN: 125742/0
+occurring at least 7 days after Dose 2 was 91.1% (95% CI: 88.8%, 93.1%), with 77 COVID-19 cases in the BNT1622 group compared to 833 cases in the placebo group among participants without evidence of SARS-CoV-2 infection before and during the vaccination regimen; the estimated vaccine efficacy (VE) against confirmed COVID-19
+occurring at least 7 days after Dose 2 was 90.9% (95% CI: 88.5%, 92.8%), with 81 COVID-19 cases in the BNT1622 group compared to 854 cases in the placebo group among participants with or without evidence of SARS-CoV-2 infection before and during the vaccination regimen.
+With respect to efficacy against severe COVID-19 cases occurring at least 7 days after Dose 2, the estimated VE was 95.3% (95% CI: 71.0%, 99.9%), with 1 and 21 cases in the BNT1622 and placebo groups, respectively, among participants without evidence of SARS-CoV-2 infection; the VE result was the same among participants with or without evidence of SARS-CoV-2 infection.
+Overall, the updated efficacy analysis results show that BNT1622 provided high VE in preventing symptomatic COVID-19 and severe COVID-19 cases.
+2. CLINICAL AND REGULATORY BACKGROUND
+Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2, a novel coronavirus that emerged in late 2019 in patients with pneumonia of unknown cause. On January 31, 2020, the United States Secretary of Health and Human Services (HHS) made the declaration that COVID-19 constitutes a nationwide public health emergency. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic.
+The BNT16262 vaccine, developed by BioNTech Manufacturing GmbH in partnership with Pfizer, Inc., was granted Fast Track Designation on July 7, 2020 for individuals ≥18 years of age. An Emergency Use Authorization (EUA) was granted in the U.S. on December 11, 2020 for individuals >16 years of age (EUA 27034). An amendment to the EUA was submitted on May 10, 2021 to support emergency use in participants 12 to 15 years of age.
+3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
+3.1 Submission Quality and Completeness
+The submission was adequately organized and integrated to accommodate the conduct of a complete statistical review.
+3.2 Compliance With Good Clinical Practices And Data Integrity
+Please refer to Haecin Chun's Bioresearch Monitoring (BIMO) review memo.
+Page 4
+
+Statistical Review
+STN: 125742/0
+4. SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
+DISCIPLINES
+Please refer to other review disciplines' memos.
+5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW
+5.1 Review Strategy
+This memo focuses on the statistical review of clinical efficacy data. Please refer to Dr.
+Ye Yang's memo for the statistical review of clinical safety data, and to Dr. Xinyu Tang's memo for the statistical review of non-clinical data.
+To demonstrate efficacy of BNT162b2, the applicant provided the efficacy results from the interim analysis (cutoff date: November 4, 2020), the final analysis (cutoff date:
+November 14, 2020), and an updated analysis for cases accrued during blinded placebo-controlled follow-up (cutoff date: March 13, 2021) for Study C4591001. As the efficacy results from the interim and final analyses supported the issuance of an EU and have been reviewed under EUA 27034, this statistical review primarily focuses on the updated efficacy results.
+5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review
+The following documents submitted to the BLA are reviewed:
+125742/0 (submitted on 5/6/2021)
+Module 2. Common Technical Document Summaries
+• Clinical Overview
+• Summary of Clinical Efficacy
+Module 5. Clinical Study Reports
+• C4591001 Statistical Analysis Plan
+C4591001 Interim 6-Month Report
+125742/0.3 (submitted on 5/19/2021)
+Module 1.11.3 Clinical Information Amendment
+• Response to FDA 18 May 2021 IR
+125742/0.17 (submitted on 7/26/2021)
+Module 1.11.3 Clinical Information Amendment
+• Response to CBER Clinical 22 July 2021 Info Request
+125742/0.18 (submitted on 7/28/2021)
+Module 1.11.3 Clinical Information Amendment
+• Response to CBER 22 July 2021 Info Request
+125742/0.27 (submitted on 8/2/2021)
+Page 5
+
+Statistical Review
+STN: 125742/0
+Module 1.14.1 Draft Labeling
+125742/0.28 (submitted on 8/02/2021)
+Module 1.11.3 Clinical Information Amendment
+• Response to CBER Clinical 22 July 2021 Information Request
+125742/0.32 (submitted on 8/05/2021)
+Module 1.11.3 Clinical Information Amendment
+• Response 22 Jul 2021 - Follow-up #3
+Module 5 Clinical Study Reports
+• C4591001 - 508 Efficacy Tables
+125742/0.38 (submitted on 8/09/2021)
+Module 1.14.1 Draft Labeling
+Module 5 Clinical Study Reports
+• C4591001 - Source Vaccine Efficacy Tables
+125742/0.49 (submitted on 8/16/2021)
+Module 1.14.1 Draft Labeling
+Module 5 Clinical Study Reports
+• C4591001 - Follow Up Table (with and without evidence of infection)
+5.3 Table of Studies/Clinical Trials
+Data from two ongoing clinical studies were submitted to support the licensing application for BNT16262 and are summarized in Table 1 below. The pivotal data are derived from a single study, C4591001, which is a multi-center, Phase 1/2/3, randomized, double-blinded, placebo-controlled safety, immunogenicity, and efficacy study; the second study, BNT162-01, is a Phase 1 safety and immunogenicity study evaluating various vaccine candidates and dose levels.
+Page 6
+
+Statistical Review
+STN: 125742/0
+Table 1. Clinical Trials Supporting Licensure of the Pfizer-BioNTech COVID-19 Vaccine
+Study Number/ Description
+BNT162b2 (30 jug)*
+Placebo
+Country
+participants
+participants
+(N)
+(N)
+C4591001
+Phase 1/2/3 randomized, placebo-
+Phase 1ª: 24
+Phase 1a. 6
+Argentina, Brazil, controlled, observer-blind; to
+Phase 2/3b: 22085
+Phase 2/3b: 22080
+Germany, S.
+evaluate safety, immunogenicity
+Africa, Turkey, and efficacy of COVID-19 US.A.
+vaccine
+BNT162-01
+Phase 1/2 randomized, open-label; 24
+0
+Germany
+to evaluate safety and
+immunogenicity, dose escalation
+N= total number of randomized participants 16 years of age and older, as of March 13, 2021 Placebo:
+Study
+Status
+Ongoing
+Ongoing
+saline.
+- Studies C4591001 and BNT162-01 started in April 2020 (first participant, first visit).
+* Phase 1 studies included additional participants vaccinated with other dose levels and other mRNA vaccine candidates.
+a Phase 1: enrolled individuals 18-85 years of age
+b Phase 2/3: Phase 2: enrolled individuals >18 years of age (stratified as 18 to 55 years and 56 to 85 years); Phase 3: enrolled individuals ≥16 years of age (stratified as 16-55 years and >55 years of age).
+Source: Summarized by reviewer based on information provided in Module 2 - Clinical Overview.
+6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS
+6.1 Study C4591001
+Title: Phase 1/2/3, Placebo-Controlled, Randomized, Observer-Blind, Dose-Finding Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-CoV-
+2 RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
+First Subject First Visit: April 29, 2020
+Data Cut-off: Mach 13, 2021
+6.1.1 Objectives
+The objectives and endpoints are presented below are for the Phase 2/3 portion of the study. The objectives for the Phase 1 portion are described in Section 6.1.2 (Design Overview).
+Primary efficacy obiectives
+1. To evaluate the efficacy of BNT1622 against confirmed COVID-19 occurring from 7 days after Dose 2 in participants without evidence of SARS-CoV-2 infection before vaccination.
+Endpoint: COVID-19 disease based on laboratory-confirmed nuclei acid amplification-based test (NAAT) in participants with no serological or virological evidence (up to 7 davs after Dose 2) of past SARS-CoV-2 infection.
+Page 7
+
+Statistical Review
+STN: 125742/0
+2. To evaluate the efficacy of BNT16262 against confirmed COVID-19 occurring from 7 days after Dose 2 in participants with and without evidence of SARS-CoV-2 infection before vaccination.
+Endpoint: COVID-19 disease based on laboratory-confirmed NAAT
+Secondary efficacy objectives
+• To evaluate the efficacy of BNT1622 against confirmed COVID-19 occurring from 14 days after Dose 2 in
+o participants without evidence of SARS-CoV-2 infection before vaccination
+(Dose 1)
+o participants with and without evidence of SARS-CoV-2 infection before
+vaccination (Dose 1)
+Endpoint: COVID-19 disease based on laboratory-confirmed NAAT
+• To evaluate the efficacy of BNT1622 against severe COVID-19 occurring from 7 days and from 14 days after Dose 2 in
+• participants without evidence of SARS-CoV-2 infection before vaccination o participants with and without evidence of SARS-CoV-2 infection before
+vaccination
+Endpoint: Severe COVID-19 disease
+• To describe the efficacy of BNT162b2 against confirmed COVID-19 (CDC-defined symptoms) occurring from 7 days and from 14 days after Dose 2 in o participants without evidence of SARS-CoV-2 infection before vaccination o participants with and without evidence of infection before vaccination
+Endpoint: COVID-19 disease (CDC-defined symptoms) based on laboratory-confirmed NAAT
+6.1.2 Design Overview
+Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blinded Phase 1/2/3 study being conducted in the U.S., Argentina, Brazil, Germany, South Africa and Turkey. Initially the study was designed as a Phase 1/2 study in healthy adults in the U.S. for vaccine candidate and dosage selection, as well as evaluation of immunogenicity and preliminary efficacy. The protocol was expanded to include a Phase 2/3 portion of the study to evaluate clinical disease efficacy endpoint in individuals 12 years of age and older in the U.S. and additional sites outside of the U.S. This review will focus on data collected from participants 16 years of age and older.
+The Phase 1 portion of the study was designed to identify a preferred vaccine candidate(s) and vaccine dose level(s) for further development based on safety, tolerability, and immunogenicity. To this end, two age groups were evaluated in separate
+Page 8
+
+Statistical Review
+STN: 125742/0
+cohorts: younger adults 18 through 55 years of age (N=45) and older adults 65 through 85 years of age (N=45). The study population included healthy men and women and excluded participants at high risk of SARS-CoV-2 infection or with serological evidence of prior or current SARS-CoV-2 infection. Two different vaccine candidates were evaluated, and younger participants received escalating dose levels Evaluation of escalating dose levels in the older age group (65 through 85 years), were based on recommendations from an internal review committee that reviewed safety and immunogenicity data. For each vaccine candidate and dose level, participants were randomized 4:1, such that 12 participants received the vaccine candidate and 3 participants received placebo. Review of the safety and immunogenicity from Phase 1, in combination with data from Study BNT162-01 (see Section 6.2 of this review), supported the final vaccine candidate and dose level (BNT1622 at 30 ug, given 21 days apart) to proceed into Phase 2/3.
+In Phase 2/3, participants were initially enrolled with stratification by age (younger adults: 18 through 55 years of age; older adults: over 55 years of age) and a goal of 40% enrollment in the older adult age group. Adolescents 16-17 years of age (and subsequently 12-15 years of age) were added to the protocol later, based on review of safety data in younger adults enrolled in the ongoing study. The study population for Phase 2/3 includes participants at higher risk for acquiring COVID-19 and at higher risk of severe COVID-19 disease, such as participants working in the healthcare field, participants with autoimmune disease, and participants with chronic but stable medical conditions such as hypertension, asthma, diabetes, and infection with HIV, hepatitis B or hepatitis C. Participants were randomized 1:1 to receive 2 doses of either BNT16262 or placebo, 21 days apart. The Phase 2 portion of the study evaluated reactogenicity and immunogenicity for 360 participants enrolled early, and these participants also contribute to the overall efficacy and safety data in the Phase 3 portion.
+The ongoing Phase 3 portion of the study is evaluating the safety and efficacy of
+BNT1622 for the prevention of COVID-19 disease occurring at least 7 days after the second dose of vaccine. Efficacy is being assessed throughout a participant's follow-up in the study through surveillance for potential cases of COVID-19. If, at any time, a participant develops acute respiratory illness, an illness visit occurs. Assessments for illness visits include a nasal (midturbinate) swab, which is tested at a central laboratory using a reverse transcription-polymerase chain reaction (RT-PCR) test (e.g., Cepheid;
+FDA authorized under EUA), or other sufficiently validated NAAT, to detect SARS-CoV-2. The central laboratory NAAT result is used for the case definition, unless it is not possible to test the sample at the central laboratory. In that case, the following NAAT results are acceptable: Cepheid Xpert Xpress SARS-CoV-2, Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001), and Abbott Molecular/RealTime SARS-
+CoV-2 assay (EUA200023/A001).
+The study design included a planned interim analysis of the first primary efficacy endpoint at pre-specified numbers of COVID-19 cases (at least 62, 92, and 120 cases), and all primary and secondary efficacy endpoints were analyzed in the final efficacy analysis after at least 164 COVID-19 cases were accrued (see Statistical Analysis section,
+Page 9
+
+Statistical Review
+STN: 125742/0
+below). Participants are expected to participate for a maximum of approximately 26 months.
+Starting December 14, 2020, following issuance of the Emergency Use Authorization for the Pfizer-BioNTech COVID-19 Vaccine, study participants 16 years of age and older have been unblinded to their treatment assignment when eligible per local recommendations, and offered BNT1622 vaccination if they had been randomized to placebo.
+The study was unblinded in stages as each participant was either individually unblinded upon eligibility for vaccination outside the study or had concluded their 6-month post-Dose 2 study visit. Every participant 16 years of age and older who participated in the Phase 2/3 study was given the opportunity to receive BNT16262 no later than the 6-month timepoint after the second study vaccination. Participants who originally received placebo but then went on to receive BNT1622 were moved to a new visit schedule to receive both doses of BNT162b2, 3 weeks apart.
+6.1.3 Population
+comorbidities.
+Individuals 12 years of age and older including those with stable infections and common
+6.1.4 Study Treatments or Agents Mandated by the Protocol
+Study C4591001 (Phase 1) evaluated a 2-dose series of investigational vaccine or placebo (0.9% normal saline) administered at a 21-day interval. Subiects were randomized to receive one of three levels of investigational RNA vaccine candidates (or placebo) for active immunization against COVID-19. The investigational RNA vaccine candidates included:
+• BNT1621 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the
+RBD): dose levels 10 Mg, 20 Mg, 30 Mg, 100 kg
+• BNT16262 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2
+S): dose levels 10 ug, 20 ug, 30 Mg
+Based upon the preliminary results, the vaccine candidate selected for further evaluation in the Phase 2/3 studies was BNT16262 BNT162 RNA-LN vaccine utilizing modRNA
+(6) (4) mcg/0.5 mL] at a dose of 30 Mg.
+6.1.6 Sites and Centers
+The study was conducted in a total of 153 sites: 131 in the U.S., 9 in Turkey, 6 in Germany, 4 in South Africa, 2 in Brazil, and 1 in Argentina.
+6.1.7 Surveillance/Monitoring
+Please refer to Drs. Susan Wollersheim and Ann Schwartz's clinical review memo.
+Page 10
+
+Statistical Review
+STN: 125742/0
+6.1.8 Endpoints and Criteria for Study Success
+Please refer to Section 6.1.1 for efficacy endpoints.
+Study success criteria:
+In Phase 2/3, the assessment of VE is based on posterior probability of VE >30% and VEr>30%, where VEi represents VE for prophylactic BNT16262 against confirmed COVID-19 in participants without evidence of infection before vaccination, and VE2 represents VE for prophylactic BNT162b2 against confirmed COVID-19 in all participants after vaccination. Only the first primary endpoint was analyzed at interim analyses. The criteria for success at an interim analysis are based on the posterior probability, i.e. Pr(VE>30%|data) at the current number of cases. Efficacy will be declared if the posterior probability is higher than the success threshold, where the success threshold for each interim analysis was calibrated to maintain a familywise type I error rate of 2.5%. If the first primary objective is met, the second primary objective will be evaluated at the final analysis.
+6.1.9 Statistical Considerations & Statistical Analysis Plan
+The statistical analyses for the Phase 1 portion were descriptive.
+For Phase 2/3, the evaluable efficacy population, which included all randomized participants who received all study interventions as randomized within the predefined window and had no other important protocol deviations as determined by the clinicians, was the primary analysis population for all efficacy analyses. Additional analyses based on the all-available efficacy population, which included all randomized subjects who received either at least 1 dose of vaccine or placebo (Dose 1 all-available set) or 2 doses (Dose 2 all-available set), were also performed.
+The VE is defined as VE = 100 × (1 - IRR), where IRR is calculated as the ratio of the confirmed COVID-19 illness rate in the vaccine group to the corresponding illness rate in the placebo group. Assuming a true VE of 60%, 164 COVID-19 cases would provide 90% power to conclude true VE >30%. Because the analyses are based on the number of cases rather than the number of participants, the total number of participants enrolled in Phase 2/3 would vary depending on the incidence of COVID-19 at the time of enrollment, the true underlying VE, and a potential early stop for efficacy or futility. Four interim analyses were planned to be performed after accrual of at least 32, 62, 92, and 120 cases. However, for operational reasons, the first IA was not performed until 94 cases were accrued, followed by the final analysis with 170 cases.
+VE was evaluated using a beta-binomial model and the posterior probability of VE being
+>30% was assessed. A minimally informative beta prior, beta (0.700102, 1), was
+proposed for 0 = r(1-VE)/(1+r(1-VE)), where r is the ratio of surveillance time in the
+BNT162b2 group over that in the placebo group. For participants with multiple confirmed cases, only the first case contributed to the VE calculation. The two primary efficacy endpoints were evaluated sequentially to control the familywise type I error rate at 2.5% (one-sided). For the primary endpoint analysis, missing efficacy data were not imputed; only participants with known disease status were included. A sensitivity
+Page 11
+
+Statistical Review
+STN: 125742/0
+analysis was performed by imputing missing values with the assumption of missing at random (MAR). Secondary endpoints were evaluated similarly to the primary endpoints.
+After the final efficacy analyses at 170 cases, updated efficacy analyses on primary and secondary efficacy endpoints were performed with additional data accrued. The point estimate of VE in the blinded follow-up period and associated 2-sided 95% CI were derived using the Clopper-Pearson method, adjusting for surveillance time. The posterior probability, Pr(VE>30%|data), was also provided.
+6.1.10 Study Population and Disposition
+6.1.10.1 Populations Enrolled/Analyzed
+Participants 18 through 55 years of age and 56 years of age and older began enrollment into Phase 2/3 from July 27, 2020 and participants 16 through 17 years of age began enrollment from September 16, 2020.
+6.1.10.1.1 Demographics
+The population for the updated analysis of vaccine efficacy endpoint (March 2021 data cutoff) included 42,436 participants 16 years of age and older (21,136 in the BNT16262 group and 21,300 in the placebo group), with or without evidence of prior infection with SARS-CoV-2 through 7 days after the second dose. Table 2 presents the specific demographic characteristics in the studied population.
+The evaluable efficacy population who received BNT1622 included 48.6% females, 81.9% White, 9.5% African American, 4.4% Asian, and <3% from other racial groups;
+25.6% of participants were Hispanic/Latino. The median age was 51 years. One or more comorbidities that increase the risk of severe COVID-19 disease were present among 46% of participants. Evidence of prior SARS-CoV-2 infection was observed in 3% of participants. Geographically, <2% of participants lived in Germany, Turkey and South Africa, 6.8% lived in Brazil, 12.7% lived in Argentina, and 76.4% of participants lived in the U.S.
+Page 12
+
+Statistical Review
+STN: 125742/0
+Table 2. Demographics and Other Baseline Characteristics, Participants 16 Years of Age and Older, With or Without Evidence of Infection Prior to 7 Days After Dose 2, Evaluable Efficacy Population (Data Cutoff March 13, 2021)
+BNT162b2 (30 ug)
+(Na=21136
+Characteristic
+nb (%)
+Placebo
+(N°=21300)
+nb (%)
+Total
+(Na=42436)
+nb (%)
+Sex: Female
+Sex: Male
+Age at Vaccination: Mean years (SD)
+Age at Vaccination: Median (years)
+Age at Vaccination: Min, max (years)
+Age Group: 16 to <18 years
+Age Group: 18 to 55 years
+Age Group: >55 years
+Age Group: ≥65 years
+Race: American Indian or Alaska Native
+Race: Asian
+Race: Black or African American
+Race: Native Hawaiian or Other Pacific Islander
+Race: White
+Race: Multiracial
+Race: Not reported
+Ethnicity: Hispanic or Latino
+Ethnicity: Not Hispanic or Latino
+Ethnicity: Not reported
+Obesity: Yes
+Obesity: No
+Comorbidities: Yesd
+Comorbidities: No
+Baseline evidence of prior SARS-CoV-2 infection:
+Negative™
+Positive®
+Missing
+Country: Argentina
+Country: Brazil
+Country: Germany
+Country: South Africa
+Country: Turkey
+Baseline evidence of prior SARS-CoV-2 infection:
+Baseline evidence of prior SARS-CoV-2 infection:
+10280 (48.6)
+10856 (51.4)
+49.8 (16.0)
+51.0
+(16, 89)
+370 (1.8)
+12120 (57.3)
+8646 (40.9)
+4407 (20.9)
+204 (1.0)
+929 (4.4)
+2009 (9 5)
+56 (0.3)
+17304 (81.9)
+545 (2.6)
+89 (0.4)
+5403 (25 6)
+15628 (73.9)
+105 (0.5)
+7239 (34.2)
+13897 (65.8)
+9712 (46.0)
+11424 (54.0)
+20365 (96.4)
+627 (3.0)
+144 (0.7)
+2686 (12.7)
+1437 (6.8)
+240 (1.1)
+391 (1.8)
+241 (1.1)
+10579 (49.7) 20859 (49.2)
+10721 (50.3) 21577 (50.8)
+49.7 (16.0)
+49.7 (16.0)
+51.0
+51.0
+(16, 91)
+(16, 91)
+362 (1.7)
+732 (1.7)
+12252 (57.5) 24372 (57.4)
+8686 (40.8) 17332 (40.8)
+4429 (20.8)
+8836 (20.8)
+190 (0.9)
+394 (0.9)
+924 (4.3)
+1853 (4.4)
+2036 (9.6)
+4045 (9.5)
+32 (0.2)
+88 (0.2)
+17487 (82.1) 34791 (82.0)
+519 (2.4)
+1064 (2.5)
+112 (0.5)
+201 (0.5)
+5409 (25.4) 10812 (25.5)
+15778 (74.1) 31406 (74.0)
+113 (0.5)
+218 (0.5)
+7386 (34 7) 14625 (34 5)
+13914 (65.3) 27811 (65.5)
+9736 (45.7) 19448 (45.8)
+11564 (54.3) 22988 (54.2)
+20511 (96.3) 40876 (96.3)
+669 (3.1) 1296 (3.1)
+120 (0.6)
+264 (0.6)
+2710 (12.7)
+1432 (6.7)
+243 (1.1)
+392 (1.8)
+238 (1.1)
+5396 (12.7)
+2869 (6.8)
+483 (1.1)
+783 (1.8)
+479 (1.1)
+Page 13
+
+BNT162b2 (30 Mg)
+(Na=21136)
+nb (%)
+Placebo
+(N°=21300)
+n' (%)
+Statistical Review
+STN: 125742/0
+Total
+(N°=42436)
+nb (%)
+Characteristic
+Country: United States of America
+16141 (76.4)
+16285 (76.5) 32426 (76.4)
+Abbreviation: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
+Note: HIV-positive subjects are included in this summary but not included in the analyses of the overall study obiectives.
+a. N= number of subjects in the specified group, or the total sample. This value is the denominator for the percentage calculations.
+Note: The analysis was based on treatment group as randomized. b.
+n = Number of subjects with the specified characteristic.
+C.
+Subiects who had BMI >30 kg/m?.
+Number of subiects who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as subjects who had at least one Charlson comorbidity index category or BMI >30 kg/m?.
+e. Positive N-binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
+f. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
+Source: Table F of C4591001-508-efficacy-tables submitted to ST 125742/0.32.
+6.1.10.1.2 Medical/Behavioral Characterization of the Enrolled Population
+Please refer to Drs. Susan Wollersheim and Ann Schwartz's clinical review memo.
+6.1.10.1.3 Subject Disposition
+The disposition of all Phase 2/3 participants 16 years of age and older is presented in Table 3. During the blinded placebo-controlled follow-up period, most participants randomized received Dose 1 (99.7%) and Dose 2 (98.0%).
+Table 3. Disposition of Participants 16 Years of Age and Older, Phase 2/3 Subjects, Efficacy Population (Data Cutoff March 13, 2021)
+BNT162b2
+(30 ug)
+n° (%)
+Randomized
+Dose 1 all-available efficacy population
+Subiects without evidence of infection before Dose 1
+Subjects excluded from Dose 1 all-available efficacy population
+Reason for exclusion°
+Did not receive at least 1 vaccination
+Data considered potentially unreliable due to lack of PI oversight identified as significant quality event
+22085 (100.0)
+22009 (99.7)
+21172 (95.9)
+76 (0.3)
+Placebo na (%)
+22080
+(100.0)
+Total n° (%)
+44165
+(100.0)
+22008
+44017
+(99.7)
+(99.7)
+21168
+42340
+(95.9)
+(95.9)
+72 (0.3) 148 (0.3)
+55 (0.2)
+21 (0.1)
+50 (0.2) 105 (0.2)
+22 (0.1) 43 (0.1)
+Page 14
+
+Statistical Review
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+BNT16262
+(30 ug)
+nª (%)
+Placebo na (%)
+Total na (%)
+Dose 2 all-available efficacy population
+21648 (98.0)
+21624
+43272
+(97.9)
+(98.0)
+Subjects without evidence of infection prior to 7 days after Dose 20536 (93.0)
+20487
+41023
+2
+(92.8)
+(92.9)
+Subjects excluded from Dose 2 all-available efficacy population
+437 (2.0)
+456 (2.1) 893 (2.0)
+Reason for exclusion°
+Did not receive 2 vaccinations
+374 (1.7)
+Data considered potentially unreliable due to lack of PI oversight
+21 (0.1)
+430 (1.9) 804 (1.8)
+22 (0.1) 43 (0.1)
+identified as significant quality event
+Unblinded prior to 7 days after Dose 2
+44 (0.2）
+11 (0.0) 55 (0.1)
+Evaluable efficacy (7 days) population
+21136 (95.7)
+Subiects without evidence of infection prior to 7 days after Dose 20064 (90.8)
+2
+Subjects excluded from evaluable efficacy (7 days) population
+Reason for exclusion
+Randomized but did not meet all eligibility criteria
+Data considered potentially unreliable due to lack of PI oversight identified as significant quality event
+Did not receive all vaccinations as randomized or did not receive
+Dose 2 within the predefined window (19-42 days after Dose 1)
+Unblinded prior to 7 days after Dose 2
+Had other important protocol deviations on or prior to 7 days after Dose 2
+949 (4.3)
+21300
+42436
+(96.5)
+(96.1)
+20197
+40261
+(91.5)
+(91.2)
+780 (3.5) 1729 (3.9)
+32 (0.1)
+21 (0.1)
+30 (0.1) 62 (0.1)
+22 (0.1) 43 (0.1)
+718 (3.3) 729 (3.3) 1447 (3.3)
+44 (0.2)
+240 (1.1)
+11 (0.0) 55 (0.1)
+58 (0.3) 298 (0.7)
+Note: HIV-positive subjects are included in this summary but not included in the analyses of the overall study obiectives.
+Note: The analysis was based on treatment group as randomized.
+а.
+n = Number of subjects with the specified characteristic.
+b. These values are the denominators for the percentage calculations.
+c. Subjects may have been excluded for more than 1 reason.
+Source: Table D of C4591001-508-efficacy-tables submitted to ST 125742/0.32.
+Reviewer Comment
+1. There were more protocol deviations leading to exclusion from analvses in the BNT162b2 group than in the placebo group. The majority of protocol deviations were in the category of investigational products, including dosing/administration error and investigational product deemed not suitable for use. Protocol deviations in other categories appeared balanced across the two treatment groups. The additional analysis on the all-available efficacy population may be regarded as a sensitivity analysis and showed very similar efficacy results.
+2. The Dose I all-available efficacy population excluded 43 subjects (21 in the BNT162b2 group and 22 in the placebo group) due to a specific protocol
+Page 15
+
+Statistical Review
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+deviation, i.e. data considered potentially unreliable due to lack of PI oversight identified as a significant quality event, while the Dose I all-available set is defined as all randomized participants who received at least I vaccination in the SAP. I conducted a sensitivity analysis without excluding these 43 subjects for efficacy analyses using the Dose I all-available population, when applicable, and it showed minimal impact on VE results.
+6.1.11 Efficacy Analyses
+6.1.11.1 Analyses of Primary Endpoints
+The Interim and Final Analyses
+At the interim analysis, there were 4 confirmed COVID-19 cases in the BNT1622 group and 90 confirmed cases in the placebo group among subjects without evidence of prior SARS-CoV-2 infection prior to 7 days after Dose 2, resulting in a VE point estimate of 95.5% (95% credible interval: 88.8%, 98.4%) and a 99.99% posterior probability for the true VE being >30%, which met the prespecified success criterion of posterior probability
+>99.5%. The median follow-up duration for subjects included in the first interim efficacy analysis was slightly less than the planned 2 months. In the final analysis, the case split between the BNT162b2 and placebo groups was 8:162 (VE: 95.0%; 95% credible interval: 90.3%, 97.6%) among subjects without evidence of prior SARS-CoV-2 infection prior to 7 days after Dose 2, and 9:169 (VE: 94.6%; 95% credible interval:
+89.9%, 97.3%) among subjects with and without evidence of prior SARS-CoV-2 infection prior to 7 days after Dose 2. The final analysis extended the median follow-up for these subjects to greater than 2 months, and the results indicate that the conclusions from the first interim efficacy analysis would not change when including additional follow-up to November 14, 2020. This pre-specified primary efficacy analysis was the basis for issuance of the Emergency Use Authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine on December 10, 2020.
+Reviewer Comment
+1. The efficacy results presented above included 88 subjects 12-15 years of age (46 in the BNI162b2 group and 42 in the placebo group). Since none of these 12-15 years old subjects developed protocol defined cases and the number of subjects is small relative to the evaluable population, the efficacy results excluding these subjects are very similar to the results including them. Based on my calculation, VE for 16 years and older subjects is 94.6% (95% credible interval: 90.3%, 97.6%).
+2. The interim and final analyses were reviewed under EUA 27034, and hence the review is not replicated for this BLA submission.
+Updated Efficacy Analyses
+Updated efficacy analyses were performed with additional confirmed COVID-19 cases accrued during blinded placebo-controlled follow-up through March 13, 2021,
+Page 16
+
+Statistical Review
+STN: 125742/0
+representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population.
+For participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, the updated VE against confirmed COVID-19 occurring at least 7 days after Dose 2 was 91.1%. The case split was 77 COVID-19 cases in the BNT16262 group compared to 833
+COVID-19 cases in the placebo group (Table 4).
+Table 4. Updated Efficacy of BNT162b2 Against Confirmed COVID-19 From 7 Days
+After Dose 2 in Participants Without Evidence of Prior SARS-CoV-2 Infection
+- Evaluable Efficacy Population, 16 Years and Older (Data Cutoff March 13, 2021)
+BNT16262
+Placebo
+(Na=19993)
+(Na=20118)
+Cases nib
+Cases nib
+Surveillance Time°
+Surveillance Time
+Pre-specified Age Group
+(n2d)
+(n2d)
+Vaccine Efficacy %
+(95% CHe
+All participants
+77
+833
+6.092
+5.857
+91.1
+(88.8. 93.1)
+(19711)
+(19741)
+16 to 55 years
+52
+568
+3.593
+3.439
+91.2
+(88.3, 93.5)
+(11517)
+(11533)
+>55 years and older
+25
+265
+2.499
+2.417
+90 9
+(86.2. 94.2)
+(8194)
+(8208)
+Abbreviations: N-binding = SARS-CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test;
+SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
+Note: Subiects who had no serological or virological evidence (prior to 7 davs after receipt of the last dose) of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT (nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+a. N= number of subjects in the specified group. b.
+n = Number of subjects meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d. n2 = Number of subjects at risk for the endpoint.
+e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+Source: Table H of C4591001-508-efficacv-tables submitted to STN 125742/0.32.
+Reviewer Comment
+1. One subject (C4591001 (b) (6)
+) reported "covid-19 antibody test
+positive" in medical history but was included in the VE analvis in participants without evidence of prior infection in Table 4. An information request (IR) was sent on July 22, 2021. In the IR response submitted on July 26, 2021, the applicant clarified that "without evidence of prior infection" was based only on the NAAT tests at Visits I and 2 and the N-binding assay results due to the
+Page 17
+
+Statistical Review
+STN: 125742/0
+potential uncertainty of a medical history entry without knowledge of circumstances, assay performed, etc. Because this subject received placebo and was not a case, inclusion of subject would result in no real change to the VE estimate.
+2. A total of 9 participants in the placebo group with COVID-19 symptoms starting on the same day of unblinding with PCR confirmation either on the same day or a few days after, were included in these analyses as positive cases.
+3. Initially, there was one additional case reported in the placebo group, for Subject
+C4591001 (b) (6)
+This subject reported three COVID symptom
+episodes: from October 8, 2020 to October 16, 2020, November 2, 2020 to December 11, 2020, and December 17, 2020 to January 16, 2021 (referred to as Episodes A, B and C, respectively). The PCR tests were negative for the first two episodes and positive for Episode C. Since the three episodes were more than 4 days apart, they should be treated as separate episodes per the statistical analysis plan (SAP). Hence, this subject should be considered to be a case with an onset on December 17, 2020, one day after the unblinding on December 16, 2020, and should be excluded from the analysis. In the IR response submitted on July 26, 2021, the applicant explained that Episodes B and C were merged into one episode as this subject was hospitalized from (b) (6)
+to (b) (6)
+, connecting Episodes B and C. We did not agree with the merging of the two episodes, because hospitalization is not a symptom or criterion pre-specified in the protocol for COVID-19 definition and there were no other data that could corroborate that this hospitalization was due to COVID-19. The applicant agreed to remove this case and updated efficacy tables were submitted on August 5, 2021.
+4. The set of subjects used for efficacy analyses excluded those who had reported
+COVID symptoms but had missing or unknown PC results at any time. It may be reasonable to exclude subjects who had reported COVID symptoms but had missing/unknown PCR results prior to 7 days after Dose 2 for efficacy analyses in participants without evidence of prior infection. However, subjects who reported symptoms and had missing/unknown PCR results after 7 days post Dose 2 were also excluded from the risk set, while they were at risk for the efficacy endpoint (lab-confirmed COVID-19 starting from 7 days post Dose 2). An IR was sent to the applicant on July 22, 2021. In the IR response submitted on July 26, 2021, the applicant explained that subjects who reported symptoms and had missing/unknown PC results do not have a chance to be counted in the numerator and inclusion of these subjects may result in an underestimation of the incidence rate. Since the percentages of such subjects were small and slightly higher in the placebo group, excluding them from the analyses likely had minimal impact on VE results. Per our request, the applicant also provided a sensitivity analysis under the missing at random (MAR) assumption, where missing efficacy endpoints were imputed based on predicted probability from logistic regression model using the fully conditional specification method for a total of 648 subjects (279 in BNT162b2 group and 369 in placebo group) in the evaluable population who reported COVID-19 symptoms from 7 days post Dose 2 but had missing/unknown PCR results. As a supplementary sensitivity analysis, the
+Page 18
+
+Statistical Review
+STN: 125742/0
+applicant also applied a conservative approach to the model by assuming a higher than the observed case rate when imputing missing efficacy endpoints from participants in the BNTI62b2 group only, to reflect potentially unknowable missing not at random effects that are unfavorable for efficacy result of the study.
+As shown in Table 5, the average VE after imputation was 90.76% under the MAR assumption, which is consistent with the efficacy results reported in Table 4. The sensitivity analyses under the missing-not-at-random assumptions show that the efficacy results are robust, e.g. at least a 16-fold increase of positivity rate in the BNTI62b2 group is required for the average VE to fall below 70%, which we do not consider to be a plausible scenario.
+Table 5. Sensitivity and Robustness Analysis of Missing Laboratory Results for Vaccine Efficacy - First COVID-19 Occurrence From 7 Days After Dose 2 - Subjects Without
+Evidence of Infection Prior to 7 Days After Dose 2 - Evaluable Efficacy (7 Days)
+Population
+Assumed
+Missing Data
+Mechanism
+Infection Rates
+Average Positive Based on Existing Median Median of
+Rate (%) Across and Imputed
+Posterior
+Lower
+all Imputations
+Values
+Probability Limit of
+(BNT162b2:
+(BNT162b2:
+of
+95% CI for Median
+Average
+Placebo)a
+Placebo)b
+VE>30%
+VE
+VE (%) VE (%)
+MAR
+MNARI
+MNAR2
+MNAR3
+MNAR4
+MNAR5
+4.0:28.5
+10.1:28 5
+23.3:285
+45.3:28.5
+69.1:28.5
+85.9:28.5
+4.21:45.31
+5.01:45.31
+6.76:45.31
+9.69:45.31
+100.00
+100.00
+100.00
+100.00
+12.85:45.31
+15.08:45.31
+100.00
+100.00
+88.56
+86.55
+82.30
+75.36
+67.71
+62.36
+90 78
+88.97
+85.12
+78.79
+71.78
+66.81
+90.76
+88.98
+85.14
+78.69
+71.75
+66.85
+Abbreviations: MAR = missing at random; MNAR = missing not at random; VE = vaccine efficacy.
+Note: Each row of this table represents summary results from 500 imputations that were generated using
+SAS PROC MI Fully Conditional Specification (FCS) method. Each imputation filled in the missing laboratory results based on a logistic regression model at the subject level, under the assumed missing data mechanism.
+a. Average positive rate for each vaccine group was calculated as the mean of positive rates across all imputations among subjects with missing data after each imputation. Under the MAR assumption, the imputation model assumes the probability of positive cases for each vaccine group to be the same as observed from subjects with no missing data in that group. Under each MNAR assumption, while keeping the imputation model for placebo group unchanged, an increase in the positive rate for the BTN16262 group was assumed to reflect a potential conservative and unknowable MNAR scenario for efficacy results of the study.
+b. Infection rate in each vaccine group was the number of cases divided by a total number of subjects in that vaccine group times 1000.
+Source: Adapted from Table I of response-22jul2021-followup submitted to STN 125742/0.28.
+For participants with and without evidence of SARS-CoV-2 infection before and during vaccination regimen, the updated VE against confirmed COVID- 19 occurring at least 7 days after Dose 2 was 90.9%, with 81 and 854 cases in the BNT1622 and placebo groups, respectively (Table 6).
+Page 19
+
+Statistical Review
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+Table 6. Updated Efficacy of BNT16262 Against Confirmed COVID-19 From 7 Days
+After Dose 2 in Participants With or Without Evidence of Prior SARS-CoV-2 Infection
+- Evaluable Efficacy Population, 16 Years and Older (Data Cutoff March 13, 2021)
+BNT16262
+Placebo
+(Nª=21047)
+(NA=21210)
+Cases
+Cases
+nib
+nib
+Surveillance Time° Surveillance Time Vaccine Efficacy %
+Pre-specified Age Group
+(n24)
+(n20)
+(95% CI)°
+All participants
+81
+854
+6.340
+6.110
+90.9
+(88.5, 92.8)
+(20533)
+(20595)
+16 to 55 years
+56
+584
+3.766
+3.619
+90.8
+(87.9, 93.1)
+(12088)
+(12142)
+>55 years and older
+25
+270
+2.573
+2.492
+91.0
+(86.5, 94.3)
+(8445)
+(8453)
+Abbreviations: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
+N = number of subjects in the specified group.
+b. n1 = Number of subjects meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all subjects within each
+group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 o the
+end of the surveillance period.
+d. n2 = Number of subiects at risk for the endpoint.
+e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adiusted for
+surveillance time.
+Source: Table I of C4591001-508-efficacy-tables submitted to STN 125742/0.32.
+VE in participants in the all-available efficacy population was similar to results in the evaluable efficacy population (Table 7). The VE for the prevention of COVID-19 disease after Dose 1 is 87.6%, in the all-available efficacy population. Based on the number of cases accumulated after Dose 1 and before Dose 2, there seems to be some protection against COVID- 19 disease following one dose (VE=56.4%); however, these data do not provide information about longer term protection beyond 21 days after a single dose.
+Page 20
+
+Statistical Review
+STN: 125742/0
+Table 7. Primary Efficacy Endpoint - Participants 16 Years of Age and Older - Dose 1 All-Available Efficacy Population (Data Cutoff March 13, 2021)
+BNT162b2
+Placebo
+(N°=21909)
+(Na=21908)
+Cases
+Cases
+nib
+nib
+Surveillance Time Surveillance Time Vaccine Efficacy %
+Efficacy Endpoint Subgroup
+(n29)
+(n29)
+(95% CI)e
+First COVID-19 occurrence after Dose 1
+After Dose 1 to before Dose 2
+Dose 2 to 7 days after Dose 2
+≥7 Days after Dose 2
+128
+8.155
+(21385)
+43
+1.273
+(21385)
+3
+0 403
+(21049)
+82
+6 479
+(21019)
+998
+7.874
+(21315)
+98
+1.266
+(21315)
+30
+0.401
+(20952)
+870
+6.207
+(20901)
+87.6
+(85.1, 89.8)
+56.4
+(37.0, 70.3)
+90.0
+(68.0, 98.1)
+91.0
+(88.7, 92.9)
+Abbreviation: VE = vaccine efficacy.
+a. N= number of subjects in the specified group. b.
+n1 = Number of subjects meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID-19 case accrual is from Dose 1 to the end of the surveillance period. d.
+n2 = Number of subiects at risk for the endpoint.
+e.
+Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adiusted for surveillance time.
+Source: Table O of C4591001-508-efficacy-tables submitted to ST 125742/0.32.
+Reviewer Comment
+As mentioned, the Dose I all-available efficacy population excluded 43 subjects with a protocol deviation of data being considered potentially unreliable due to lack of PI oversight identified as a significant quality event. In my additional analysis with these subjects included, the case split for the first COVID-19 occurrence after dose I is
+129:1003, resulting in an estimated VE of 87.6% (95% CI: 85.1%, 89.7%). Hence, the exclusion of these subjects likely had minimal impact on the VE results.
+6.1.11.2 Analyses of Secondary Endpoints
+Protocol-Defined Severe cases
+Undated efficacy analvses of the secondary efficacy endpoint for the use of BNT16262 for the prevention of severe COVID-19 were also evaluated. Vaccine efficacy against severe COVID-19 is presented in Table 8 for participants without prior SARS-CoV-2 infection. In the updated analysis, among participants without evidence of prior infection, the estimated VE against severe COVID-19 disease occurring at least 7 days after Dose 2 was 95.3% (71.0%, 99.9%), with one subject who received BNT16262 and 21
+Page 21
+
+Statistical Review
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+participants who received placebo experiencing severe disease. The same number of severe cases were reported among participants with or without evidence of prior infection and the estimated VE was the same (95.3%). These updated analyses of the secondary vaccine efficacy with a larger number of severe cases now shows more definitive evidence of protection against severe COVID-19 disease offered by BNT16262 (the data from the November 14, 2020 cut-off were limited to 4 total severe cases).
+Table 8. First Severe COVID-19 Occurrence From 7 Days After Dose 2 - Subiects
+Without Evidence of Infection Prior to 7 Days After Dose 2 - Participants 16 Years of Age and Older - Evaluable Efficacy Population (Data Cutoff March 13, 2021)
+BNT16262
+Placebo
+(Na=19993)
+(N°=20118)
+Cases
+Cases
+nib
+nib
+Surveillance
+Surveillance
+Time©
+Time©
+Secondary Efficacy Endpoint
+(n2d)
+(n2d)
+Vaccine
+Efficacy %
+(95% CI)e
+First severe COVID-19 occurrence from 7 days after Dose 2 in participants without evidence of prior SARS-CoV-2 infection
+1
+6.103
+(19711)
+21
+5.971
+(19741)
+95.3
+(71.0, 99.9)
+Abbreviations: N-binding = SARS-CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test;
+SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
+Note: Subiects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS-CoV-2 infection (ie, N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
+a. N= number of subjects in the specified group. b.
+n1 = Number of subjects meeting the endpoint definition.
+C.
+Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d. n2 = Number of subiects at risk for the endpoint.
+e.
+Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+Source: Table M of C4591001-508-efficacy-tables submitted to ST 125742/0.32.
+In the all-available efficacy population, 31 participants had severe COVID-19 disease after Dose 1 (one subject who received BNT16262 and 30 participants who received placebo) as summarized in Table 9.
+Page 22
+
+Statistical Review
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+Table 9. First Severe COVID-19 Occurrence After Dose 1 - Participants 16 Years of Age and Older - Dose 1 All-Available Efficacy Population (Data Cutoff March 13, 2021)
+BNT162b2
+Placebo
+(Na=21909)
+(N°=21908)
+Cases
+Cases
+nib
+nib
+Surveillance Time Surveillance Time Vaccine Efficacy %
+Secondary Efficacy Endpoint
+(n2d)
+(n2)
+(95% CIe
+First severe case occurrence after Dose 1
+1
+8.181
+(21385)
+After Dose 1 to before Dose 2
+1.285
+(21385)
+Dose 2 to 7 days after Dose 2
+>7 Days after Dose 2
+0.403
+(21056)
+1
+6 493
+(21029)
+30
+8.032
+(21316)
+6
+1.293
+(21316)
+1
+0 402
+(20962)
+23
+6.337
+(20940)
+96.7
+(80.3, 99.9)
+100.0
+(14.6, 100.0)
+100.0
+NA
+95.8
+(73.9, 99.9)
+Abbreviation: VE = vaccine efficacy.
+a. N= number of subjects in the specified group. b.
+n1 = Number of subjects meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID-19 case accrual is from Dose 1 to the end of the surveillance period d.
+n2 = Number of subiects at risk for the endpoint.
+e.
+Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adiusted for surveillance time.
+Source: Table N of C4591001-508-efficacy-tables submitted to STN 125742/0.32.
+Severe Case Based on CDC-Definition
+Vaccine efficacy against severe COVID-19 based on the CDC definition is presented for participants with or without prior SARS-CoV-2 infection (Table 10) as the COVID-19 case counts in participants without prior SARS-CoV-2 infection were the same as those in participants with or without prior SARSCoV2 infection in both the vaccine and placebo groups.
+Page 23
+
+Statistical Review
+STN: 125742/0
+Table 10. First Severe COVID-19 Occurrence Based on CDC-Definition From 7 Days
+After Dose 2 - Subiects With or Without Evidence of Infection Prior to 7 Days After Dose 2 - Participants 16 Years of Age and Older - Evaluable Efficacy Population (Data
+Cutoff March 13, 2021)
+Efficacy Endpoint
+BNT162b2
+(N°=21047)
+Cases nib
+Surveillance
+Time (n20)
+Placebo
+(N°=21210)
+Cases nib
+Surveillance
+Time© (n29
+Vaccine
+Efficacy %
+(95% CIe
+First severe COVID-19 occurrence based on CDC-definition from 7 days after Dose 2
+0
+6.345
+(20513)
+31
+6.225
+(20593)
+100.0
+(87.6, 100.0)
+Abbreviations: VE = vaccine efficacy.
+N = number of subjects in the specified group.
+b. n1 = Number of subjects meeting the endpoint definition.
+c. Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
+d. n2 = Number of subjects at risk for the endpoint.
+e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+Source: Adapted from Table ADCI9EF_VE_SEV_7PD2_CDC_EVALofC4591001-ve-tables submitted to
+STN 125742/0.38.
+6.1.11.3 Subpopulation Analyses
+VE point estimates for the primary endpoint in participants without evidence of prior infection were comparable across sex, age groups (16 to 55 years and >55 years), race, ethnicity, and country, excluding categories with too few cases to analyze. Additional subgroup analyses were performed for the second vaccine efficacy endpoint (i.e.
+COVID-19 for participants with and without evidence of infection prior to vaccination) because this endpoint may generalize better to the population who may receive the vaccine, as baseline evidence of prior infection may not be known by all people who might receive the vaccine. VE point estimates were generally high (>84%) across the subgroups examined (i.e. sex, age, race, ethnicity, comorbidity, baseline SARS-CoV-2 status, and country with the exception of participants identified as positive or unknown for baseline SARS-CoV-2 status and with un-reported ethnicity, for which there were too few COVID-19 cases to interpret efficacy data for these subgroups.
+6.1.11.4 Dropouts and/or Discontinuations
+Dropouts and discontinuations are generally balanced across the groups. There were 352 (1.6%) participants in the BNT162b2 group and 528 (2.4%) participants in the placebo group who discontinued from the vaccination period (Dose 1 to 1 month after Dose 2).
+Most participants completed the visit at 1 month post-Dose 2 (>96.4%). Few participants in the BNT1622 and placebo groups were withdrawn from the study (1.6% and 2.2%,
+Page 24
+
+Statistical Review
+STN: 125742/0
+respectively), and most were due to withdrawals by the participant, or they were lost to follow-up without other cause given.
+Starting December 14, 2020, following issuance of the Emergency Use Authorization for the Pfizer-BioNTech COVID-19 Vaccine, study participants 16 years of age and older have been unblinded to their treatment assignment when eligible per local recommendations, and offered BNT16262 vaccination if they had been randomized to placebo. The length of blinded follow-up appears to be balanced between the BNT16262 and placebo groups. During the blinded placebo-controlled follow-up period, 52.4% of participants in the BNT1622 group and 52.6% of participants in the placebo group in the evaluable efficacy population with or without evidence of infection prior to 7 days after dose 2 had follow-up time between ≥4 months to <6 months after Dose 2, and 8.4% in the BNT16262 group and 6.1% in the placebo group had follow up ≥6 months.
+6.1.11.5 Exploratory and Post Hoc Analyses
+Not Applicable.
+6.1.12 Safety Analyses
+Please refer to Dr. Ye Yang's memo for the statistical review of the clinical safety data of
+Study C4591001.
+7. INTEGRATED OVERVIEW OF EFFICACY
+Data supporting the effectiveness of the vaccine were primarily generated in Study
+C4591001. Consequently, no pooled efficacy analyses were performed.
+8. INTEGRATED OVERVIEW OF SAFETY
+Please refer to Dr. Ye Yang's memo for the statistical review of the clinical safety data.
+9. ADDITIONAL STATISTICAL ISSUES
+Not Applicable.
+10. CONCLUSIONS
+10.1 Statistical Issues and Collective Evidence
+In the updated efficacy analysis for cases accrued during blinded placebo-controlled follow-up (cutoff date: March 13, 2021) of Study C4591001 in participants 16 years of age and older, the estimated vaccine efficacy (VE) against confirmed COVID-19
+occurring at least 7 days after Dose 2 was 91.1% (95% CI: 88.8%, 93.1%), with 77 COVID-19 cases in the BNT162b2 group compared to 833 cases in the placebo group among participants without evidence of SARS-CoV-2 infection before and during the vaccination regimen; the estimated vaccine efficacy (VE) against confirmed COVID-19
+occurring at least 7 days after Dose 2 was 90.9% (95% CI: 88.5%, 92.8%), with 81 COVID-19 cases in the BNT1622 group compared to 854 cases in the placebo group
+Page 25
+
+Statistical Review
+STN: 125742/0
+among participants with or without evidence of SARS-CoV-2 infection before and during the vaccination regimen.
+With respect to efficacy against severe COVID-19 cases occurring at least 7 days after Dose 2, the estimated VE was 95.3% (95% CI: 71.0%, 99.9%), with 1 and 21 cases in the BNT1622 and placebo groups, respectively, among participants without evidence of SARS-CoV-2 infection; the VE result was the same among participants with or without evidence of SARS-CoV-2 infection.
+10.2 Conclusions and Recommendations
+Overall, the updated efficacy analysis results show that BNT1622 provided high VE in preventing symptomatic COVID-19 and severe COVID-19 cases that is consistent with the VE results reported in the interim and final analyses.
+Page 26
+

docs/Statistical Review -- COMIRNATY.txt

@@ -0,0 +1,266 @@
+Statistical Review
+STN: 125742/0
+Application Type
+Original BLA
+STN
+125742/0
+CBER Received Date
+May 18, 2021
+PDUFA Goal Date
+January 16, 2022
+Division / Office
+OVRR
+Committee Chair
+Ramachandra Naik
+Product Reviewer
+Xiao Wang
+Project Manager Mike Smith and Laura Gottschalk
+Priority Review
+Yes
+Reviewer Name
+Xinyu Tang
+Review Completion Date / Stamped
+Date
+Lei Huang, Concurring Reviewer, VEB, DB, OBE
+Concurrence
+Tsai-Lien Lin, Branch Chief, VEB, DB, OBE
+John A. Scott, Director, DB, OBE
+BioNTech Manufacturing GmbH in partnership
+Applicant with Pfizer, Inc.
+Established Name
+COVID-19 Vaccine, mRNA
+Trade Name
+COMIRNATY@
+Pharmacologic Class
+Vaccine
+After preparation, each 0.3 mL dose contains 30 ug
+Formulation, including Adjuvants, etc.
+modified mRNA encoding SARS-CoV-2 spike glycoprotein
+Dosage Form and Route of
+Administration
+Dosing Regimen
+Injectable Suspension, Intramuscular Two 0.3 mL doses, 3 weeks apart
+Active immunization to prevent coronavirus disease
+2019 (COVID-19) caused by severe acute
+Indication and Intended Population respiratory syndrome coronavirus 2 (SARS-CoV-2)
+in individuals 16 years of age and older
+Page i
+
+Statistical Review
+STN: 125742/0
+Table of Contents
+GlossarY ..........
+3
+1. Executive Summary...
+2. Regulatory Background.
+3. Sources of Data and Other Information Considered in the Review .....
+4. Review of the Method Validation of the SARS-CoV-2 mNeonGreen Virus
+Microneutralization Assay ...........
+4.1 Introduction...............
+4.2 Experimental Design .......
+4.3 Statistical Analysis..
+4.4 (b) (4) Linearity...
+4.4 Precision......
+4.5 Limits of Quantitation.....
+4.6 Assav Intermediate Precision.....
+4.7 Limit of Detection..
+4.8 Extravariability of Replicates.
+11
+..... 11
+5. Review of the Report for Co-validation of Test Method TM100010380 -
+Determination of the (b) (4)
+of PF-07302048 (BNT162b2 Construct,
+Drug Product) by (b) (4)
+11
+5.1 Introduction............
+5.2 Validation Outline...........
+5.3 Precision - Repeatability
+5.4 Precision - Reproducibility
+5.5 Specificity......
+5.6 Detection Limit
+.................... 11
+.......... 12
+.................. 13
+14
+15
+15
+5.7 Robustness........
+........................... 17
+6. Conclusions................
+17
+Page ii
+
+Statistical Review
+STN: 125742/0
+GLOSSARY
+BLA
+CI
+COVID-19
+DL dLIA
+DP
+DPC
+DS
+GMT
+IR
+LLOO
+IM
+IND
+ENP
+LOD (b) (4)
+mRNA
+(b) (4)
+biologics license application confidence interval
+Coronavirus Disease 2019 detection limit direct Luminex assay drug product drug product control drug substance geometric mean titer information request lower limit of quantitation intramuscular
+Investigational New Drug application lipid nanoparticle limit of detection
+messenger RNA
+RSD
+SARS-CoV-2
+SARS-CoV-2 mNG NT
+SIN
+TDV
+ULOQ
+VCA
+relative standard deviation
+severe acute respiratory syndrome coronavirus-2
+SARS-CoV-2 mNeonGreen virus microneutralization assay signal-to-noise
+Titer Determining Value upper limit of quantitation variance components analysis
+1. Executive Summary
+BioNTech and Pfizer submitted an original Biologics License Application (BLA) on May 18, 2021 for BNT1622. BNT162b2 is a prophylactic vaccine that prevents Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2
+(SARS-CoV-2). The proposed indication is active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals ≥16 years of age. The proposed dosage is 30 g via intramuscular (IM) injection following a dosing regimen of two 0.3-mL doses given three weeks apart.
+This review memo focuses on the statistical review of the non-clinical aspects of this submission, including the validation of the clinical immunogenicity assay as well as the in-vitro potency assay. Specifically, this review memo covers:
+• the validation of the SARS-CoV-2 mNeonGreen virus microneutralization assay
+(SARS-CoV-2 mNG NT) for the detection of serum antibodies capable of neutralizing SARS-CoV-2 (VR-MVR-10083), and
+• the validation of Test Method TM100010380 v5.0 for determination of the (b) (4)
+of PF-07302048 (BNT16262 construct, Drug Product) by (b) (4)
+(VAL100147509)
+Page 3
+
+Statistical Review
+STN: 125742/0
+based on the validation reports submitted in Module 5.3.1.4 of BLA125742/0.0 and Module 3.2.R of BLA125741/0.19, which have not been reviewed previously.
+With respect to the validation of the SARS-CoV-2 mNG NT assay, results from the validation study suggest acceptable accuracy and precision. The limit of detection (LOD), lower limit of quantitation (LLOQ), and upper limit of quantitation (ULOQ) were determined to be (b) (4)
+, respectively. The LOD study demonstrated an
+acceptable false positive rate but did not evaluate the false negative rate at the LOD.
+Because this assay was not used in the determination of serostatus in clinical studies included in this BLA submission, the unknown false negative rate does not impact the approval of this BLA. However, the false negative rate may be a concern in the future, depending on future use of this assay.
+With respect to the validation of Test Method TM100010380 v5.0 (referred to as the (b) (4)
+assay hereafter), results from the validation study suggest acceptable
+specificity and robustness to b) (4)
+. The detection limit (DL) was determined to be b) (4)
+The repeatability and
+reproducibility of the assay were estimated to be (b) (4)
+relative standard deviation
+(RSD), respectively. Since the (b) (4)
+assay was validated as a limit test, the
+repeatability and reproducibility results were evaluated for information only.
+In conclusion, I consider both the SARS-CoV-2 mNG NT and (b) (4) adequate for their intended uses in support of this BLA.
+assays
+2. Regulatory Background
+The Investigational New Drug Application (IND19736) for BNT16262 was submitted on April 29, 2020. Fast Track Designation was granted on July 7, 2020 for individuals 18 years of age and older. On December 11, 2020, Emergency Use Authorization (EUA
+27034) of BNT16262 for active immunization to prevent COVID-19 in individuals 16 years of age and older was granted (EUA product identified as Pfizer-BioNTech COVID-
+19 Vaccine). BioNTech and Pfizer submitted this BLA on May 18, 2021 for BNT162b2.
+The following documents regarding clinical assays were submitted in Module 5.3.1.4 of
+BLA125741/0.0:
+• Report on Method Validation of a Cepheid Xpert® Xpress PC Assay to Detect SARS-CoV-2 (VR-MVR-10080, Version 3.0),
+• Method Validation Report for the Elecsys Anti-SARS-CoV-2 Assay (VR-MVR-10081, Version 2.0),
+• Qualification Report for a (b) (4)
+Direct Luminex Assay (dLIA) for Quantitation
+of IgG Antibodies to SARS-CoV-2 S1 Protein in Human Sera (VR-MQR-10211,
+Version 2.0),
+• Oualification Report for a b) (4)
+Direct Luminex Assay (dLIA) for Ouantitation
+of IgG Antibodies to SARS-CoV-2 RBD Protein in Human Sera (VR-MQR-10212,
+Version 2.0),
+Page 4
+
+Statistical Review
+STN: 125742/0
+• Oualification of the SARS-CoV-2 mNeonGreen Virus Microneutralization Assay
+(VR-MQR-10214, Version 2.0), and
+• Method Validation of the SARS-CoV-2 mNeonGreen Virus Microneutralization
+Assay (VR-MVR-10083, Version 1.0).
+All these qualification and validation reports have been reviewed during the IND stage, except for the validation report for the SARS-CoV-2 mNG NT assay, which is covered in this review memo.
+The following document regarding the potency assay was submitted in Module 3.2.R of
+BLA125741/0.19:
+• Report for Co-Validation of Test Method TM100010380 - Determination of the
+of PF-07302048 (BNT162b2 Construct, Drug Product) by (b) (4)
+(VAL100147509, Version 1.0).
+This validation report has not been previously reviewed during the IND stage and is covered in this review memo as well.
+3. SOURCES OF DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW
+The following documents submitted to the BLA are reviewed:
+• Method Validation of the SARS-CoV-2 mNeonGreen virus microneutralization assay used for the detection of serum antibodies capable of neutralizing SARS-CoV-2 (VR-MVR-10083, Version 1.0) (BLA125742/0.0, dated February 9, 2021, received May 6, 2021),
+• Report for Co-Validation of Test Method TM100010380 - Determination of the (4)
+of PF-07302048 (BNT162b2 Construct, Drug Product) by (b) (4)
+(VAL100147509, Version 1.0) (BLA125742/0.19, Module 3.2.R, dated
+July 16, 2021, received July 28, 2021).
+• Response to 04 Aug 2021 FDA Information Request (IR) (BLA125742/0.34, Module
+1.11.1, dated August 6, 2021, received August 6, 2021), and
+• Validation of Analytical Procedure - (b) (4)
+(BLA125742/0.34,
+Module 3.2.P.5.3, dated August 6, 2021, received August 6, 2021).
+The following document submitted to the IND is also referred to when reviewing the validation of the SARS-CoV-2 mNG NT assay:
+• Validation Protocol for the SARS-CoV-2 mNeonGreen Virus Microneutralization
+Assay (VR-MVP-10074, Version 2.0) (IND19736/157, Module 5.3.1.4, dated December 2, 2020, received December 4, 2020).
+4. REVIEW OF THE METHOD VALIDATION OF THE SARS-CoV-2 MNEONGREEN
+VIRUS MICRONEUTRALIZATION ASSAY
+4.1 Introduction
+The SARS-CoV-2 mNG NT assay is a biofunctional assay that measures neutralizing antibodies against SARS-CoV-2. This assay is described in Test Method VR-TM-10298
+Briefly, (b) (4)
+Page 5
+
+Statistical Review
+STN: 125742/0
+(b) (4)
+This validation study evaluated assay (b) (4) linearity, precision, limit of detection, and intermediate precision. The ) (4) linearity and precision results were used to define the limits of quantitation and extravariability criterion.
+4.2 Experimental Design
+Validation of the SARS-CoV-2 mNG NT assay was performed as described in the validation protocol (VR-MVP-10074). (b) (4)
+(b) (4)
+Page 6
+
+4 pages have been determined to be not releasable: (b)(4)
+
+(b) (4)
+5.1 Introduction
+Test Method TM100010380 Determination (b) (4)
+(b) (4)
+Statistical Review
+STN: 125742/0
+PF-07302048
+Page 11
+
+Statistical Review
+STN: 125742/0
+(b) (4)
+5.2 Validation Outline
+This validation report contains the results of validation study conducted according to the following method validation protocols:
+• VAL100138078, V1.0 Protocol for co-validation of test method TM100010380, which was the original method validation protocol to evaluate repeatability, reproducibility, specificity, and detection limit,
+• INX100459445, V1.0 Amendment for protocol for co-validation of test method
+TM100010380, which was an amendment to original method validation protocol
+VAL100138078 to evaluate the robustness of (b) (4)
+during reproducibility studies.
+In routine tests, the assay is analyzed (b) (4)
+Page 12
+
+4 pages have been determined to be not releasable: (b)(4)
+
+Statistical Review
+STN: 125742/0
+(b) (4)
+6. CONCLUSIONS
+This review memo focuses on the validation of the SARS-CoV-2 mNG NT assay for the detection of serum antibodies capable of neutralizing SARS-CoV-2 and the validation of the (b) (4) potency assay, TM100010380 v5.0, for determination of the (b) (4)
+of PF-07302048 by (b) (4)
+With respect to the validation of the SARS-CoV-2 mNG NT assay, results from the validation study suggest acceptable accuracy and precision. The LOD, LLOQ, and ULOO were determined to be b) (4)
+, respectively. The LOD study
+demonstrated (b) (4)
+With respect to the validation of the (b) (4)
+assay, results from the validation
+study suggest acceptable specificity and is robust to (b) (4)
+. The detection limit (DL) was determined to be (b) (4)
+The
+repeatability and reproducibility of the assay were estimated to be (b) (4)
+, respectively. Since the (b) (4)
+assay was validated as
+a limit test, the repeatability and reproducibility results were evaluated for information only.
+In conclusion, I consider both the SARS-CoV-2 mNG NT and (b) (4) adequate for their intended uses in support of this BLA.
+assays
+Page 17
+

docs/Statistical Review-COMIRNATY.txt

@@ -0,0 +1,1200 @@
+Statistical Review
+STN: 125742/0
+Application Type
+BLA, Original Application
+STN
+125742/0
+CBER Received Date
+May 18, 2021
+PDUFA Goal Date
+January 16, 2022
+Division/ Office
+DVRPA/OVRR
+Committee Chair
+Ramachandra Naik
+Clinical Reviewers)
+Ann Schwartz; Susan Wollersheim
+Project Manager
+Michael Smith; Laura Gottschalk
+Priority Review
+Yes
+Reviewer Name
+Ye Yang, Mathematical Statistician, DB/VEB
+Review Completion Date /
+Stamped Date
+Concurrence
+Lei Huang, Concurring Reviewer, DB/VEB
+Supervisory Concurrence
+Tsai-Lien Lin, Branch Chief, DB/VEB
+Supervisory Concurrence
+John Scott, Director, DB
+Applicant
+Established Name
+(Proposed) Trade Name
+Dosage Form(s) and Route(s) of
+Administration
+Dosing Regimen
+Indication(s) and Intended
+Population(s)
+BioNTech Manufacturing GmbH (in partnership with Pfizer, Inc.)
+COVID-19 Vaccine, mRNA
+COMIRNATY
+Injectable Suspension, Intramuscular
+Two 0.3 mL doses, three weeks apart
+Active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older
+Page i
+
+Statistical Review
+STN: 125742/0
+Table of Contents
+Glossary....
+3
+1. Executive Summary..
+2. Clinical and Regulatory Background
+3. Submission Ouality and Good Clinical Practices ..............
+5
+3.1 Submission Quality and Completeness ....
+3.2 Compliance With Good Clinical Practices And Data Integrity
+4. Significant Efficacy/Safety Issues Related to Other Review Disciplines............
+5
+5. Sources of Clinical Data and Other Information Considered in the Review. .......... 5
+5.1 Review Strategy .........
+5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review.
+5.3 Table of Studies/Clinical Trials...
+6. Discussion of Individual Studies/Clinical Trials ..
+6.1 Study C4591001......
+6.1.1 Objectives.
+6.1.2 Design Overview.
+6.1.3 Population
+6.1.4 Study Treatments or Agents Mandated by the Protocol
+6.1.6 Sites and Centers
+6.1.7 Surveillance/Monitoring.
+6.1.8 Endpoints and Criteria for Study Success
+6.1.9 Statistical Considerations & Statistical Analysis Plan
+6.1.10 Study Population and Disposition
+6.1.11 Efficacy Analyses.....
+6.1.12 Safety Analyses.
+7. Integrated Overview of Efficacy...........
+8
+9
+9
+.. 15
+8. Integrated Overview of Safety.......
+........ 15
+9. Additional Statistical Issues...........
+........... 15
+10. Conclusions..........
+10.1 Statistical Issues and Collective Evidence..............
+10.2 Conclusions and Recommendations..
+............. 15
+15
+........... C
+Page ii
+
+Statistical Review
+STN: 125742/0
+GLOSSARY
+ADaM
+AE
+BIMO
+BLA
+BNT16262
+COVID-19
+EUA
+HIV
+RT-PCR
+SAE
+SAP
+SARS-CoV-2
+SDTM
+Analysis Data Model
+Adverse Event
+Bioresearch Monitoring
+Biologics License Application
+Pfizer-BioNTech COVID-19 Vaccine
+Coronavirus Disease 2019
+Emergency Use Authorization
+Human Immunodeficiency Virus
+Reverse Transcription-Polymerase Chain Reaction
+Serious Adverse Event
+Statistical Analysis Plan
+Severe Acute Respiratory Syndrome Coronavirus 2
+Study Data Tabulation model
+Page 3
+
+Statistical Review
+STN: 125742/0
+1. Executive Summary
+Pfizer submitted a Biologics License Application (BLA 125742.0) on May 18, 2021 to seek licensure of the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) for active immunization to prevent Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. The BLA is supported by safety, efficacy, and immunogenicity data from two ongoing studies (C4591001 and BNT-162-01). This statistical review focuses on safety data from subjects aged 16 years and above in the Phase 2/3 part of Study C4591001 collected up to the March 13, 2021 data cut-off.
+Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blinded Phase 1/2/3 study being conducted in the United States, Argentina, Brazil, Germany, South Africa, and Turkey. In the Phase 2/3 portion of the study, 44,165 subjects aged 16 and above were randomized 1:1 to receive two doses of BNT16262 or placebo 21 days apart.
+Randomization was stratified by age group (younger adults 18 through 55 years of age and older adults >55 years of age; adolescents 16 to 17 were later added via a protocol amendment) with 40.6% of the final study population being older adults. Since December 14, 2020, following issuance of the EUA, participants 16 years of age and older were systematically unblinded when eligible per local recommendations and offered
+BNT1622 vaccination if they had been randomized to placebo.
+For all 44,047 randomized participants who received at least one dose of the study intervention, unsolicited adverse events (AEs) and serious AEs (SAEs) were collected from Dose 1 up to the March 13, 2021 data cut-off. A reactogenicity subset of approximately 4,900 participants per arm who received at least one dose of the study intervention recorded local reactions, systemic events, and antipyretic/pain medication usage from Day 1 through Day 7 after each dose.
+No major statistical issues were identified for the safety data during review. A higher percentage of subjects in the BNT16262 group reported solicited local and systemic reactions than placebo recipients in both the younger (16 to 55 years) and older (>55 years) adult age groups after both doses. There was an imbalance in the frequencies of unsolicited AEs in the vaccine group, driven largely by increased reactogenicity. In addition, one report of pericarditis was identified in a 66-year-old male participant 28 days after receiving Dose 2 of BNT16262. There were no reports of myocarditis in the vaccine arm up to the data cut-off. There were no major imbalances in reported SAEs, AEs leading to withdrawal, or deaths between the treatment groups at one month and up to six months after the second dose or unblinding/data cut-off.
+2. Clinical and Regulatory Background
+The Pfizer-BioNTech COVID-19 Vaccine (BNT1622) was granted Fast Track
+Designation for individuals ≥18 years of age on July 7, 2020, and was authorized under an Emergency Use Authorization (EUA) on December 11, 2020 for individuals ≥16 years of age. The EUA was amended to include individuals ≥12 years of age on May 10, 2021.
+Pfizer submitted a BLA on May 18, 2021 to seek licensure of the vaccine for active
+Page 4
+
+Statistical Review
+STN: 125742/0
+immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and older.
+3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
+3.1 Submission Quality and Completeness
+The submission was adequately organized for conducting a complete statistical review without unreasonable difficulty.
+3.2 Compliance With Good Clinical Practices And Data Integrity
+Please refer to Haecin Chun's Bioresearch Monitoring inspections review memo.
+4. SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
+DISCIPLINES
+Please refer to reviews of other review disciplines.
+5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW
+5.1 Review Strategy
+This statistical review focuses on safety data from subiects aged 16 years and above in the Phase 2/3 part of Study C4591001 collected up to the March 13, 2021 data cut-off.
+5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review
+The following documents submitted to the BLA are reviewed:
+125742/0 (submitted on 5/6/2021)
+Module 2. Common Technical Document Summaries
+• Clinical Overview
+• Summary of Clinical Safety
+Module 5. Clinical Study Reports
+125742/0/1 (submitted on 5/18/2021)
+Module 1. Administrative Information and Prescribing Information
+125742/0/3 (submitted on 5/19/2021)
+Module 1. Administrative Information and Prescribing Information
+• Response to May 18, 2021 Information Request
+125742/0/26 (submitted on 8/2/2021)
+Module 1. Administrative Information and Prescribing Information
+• Response to July 29, 2021 Information Request
+125742/0/37 (submitted on 8/9/2021)
+Page 5
+
+Statistical Review
+STN: 125742/0
+Module 5. Clinical Study Reports
+• C4591001 - 508 Safety Tables
+5.3 Table of Studies/Clinical Trials
+Data from two ongoing clinical studies were submitted to support the BLA for BNT162b2 and are summarized in Table 1 below. Study C4591001 is a multi-center, Phase 1/2/3, randomized, double-blinded, placebo-controlled safety, immunogenicity, and efficacy study and Study BNT162-01 is a Phase 1 safety and immunogenicity study evaluating various vaccine candidates and dose levels.
+Table 1. Clinical Trials Supporting Licensure of the Pfizer-BioNTech COVID-19 Vaccine
+Study Number/ Country
+Description
+BNT162b2 (30 Mg)
+participants (N)
+Placebo participants (N)
+C4591001
+Argentina, Brazil, Germany, S.
+Africa, Turkey, U.S.A.
+Phase 1/2/3 randomized, placebo-controlled, observer-blind; to evaluate safety, immunogenicity and efficacy of COVID-19 vaccine
+Phase 1: 24 (U.S.A.)
+Phase 2/3: 22085
+Argentina: 2887
+Brazil: 1452
+Germany: 250
+South Africa: 401
+Turkey: 251
+U.S.A: 16844
+Phase 1: 24 (Germany)
+Phase 1: 6 (U.S.A.)
+Phase 2/3: 22080
+Argentina: 2889
+Brazil: 1448
+Germany: 250
+South Africa: 399
+Turkey: 249
+U.S.A.: 16845
+0
+BNT162-01
+Germany
+Phase 1/2 randomized, open-label: to evaluate safety and immunogenicity,
+Source: Summarized by the reviewer based on information provided in Module 2. Clinical Overview.
+6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS
+Study
+Status
+Ongoing
+Ongoing
+6.1 Study C4591001
+Title of Study: A Phase 1/2/3, Placebo-Controlled, Randomized, Observer-Blind, Dose-Finding Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-COV-2 RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
+First Subject First Visit: April 29, 2020
+Data Cut-off: Mach 13, 2021
+6.1.1 Obiectives
+Primary Safety Objective (Phase 2/3):
+• To characterize the safety profile of prophylactic BNT16262 in all participants randomized in Phase 2/3
+6.1.2 Design Overview
+Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blinded Phase 1/2/3 study being conducted in the United States, Argentina, Brazil, Germany, South Africa, and Turkey. In the Phase 2/3 portion of the study, 43,998 subjects were planned
+Page 6
+
+Statistical Review
+STN: 125742/0
+to be randomized 1:1 to receive two doses of BNT162b2 or placebo 21 days apart.
+Randomization was stratified by age group (younger adults 18 through 55 years of age, older adults >55 years of age) with a goal of 40% enrollment among older adults.
+Eligibility was later expanded to include adolescents 16 to 17 years of age.
+Efficacy was assessed throughout the study via surveillance for potential cases of
+COVID-19. Participants who developed acute respiratory illness were tested for SARS-CoV-2 infection using reverse transcription-polymerase chain reaction (RT-PCR) in an illness visit. The study included planned interim analyses of the primary efficacy endpoint at 62, 92, and 120 cases, and a final analysis of all primary and secondary efficacy endpoints after at least 164 COVID-19 cases were accrued. Participants were to be followed for a maximum of 26 months. Efficacy assessments and results are covered in detail in Dr. Lei Huang's statistical review memo.
+Since December 14, 2020 following issuance of the EUA, participants 16 years of age and older were systematically unblinded and, when eligible per local recommendations, offered BNT1622 vaccination no later than the 6-month timepoint after the second study vaccination if they had been randomized to placebo.
+A subset of at least 6,000 participants (the reactogenicity subset, planned to be the first 6,000 or more patients randomized) were to record local reactions, systemic events, and antipyretic/pain medication usage from Day 1 through Day 7 after each dose. For all participants, unsolicited adverse events (AEs) and serious AEs (SAEs) were collected from Dose 1 up to the March 13, 2021 data cut-off.
+6.1.3 Population
+The Phase 2/3 study population consisted of participants 12 years of age and older at higher risk for acquiring COVID-19 (including, but not limited to, use of mass transportation, relevant demographics, and frontline essential workers).
+6.1.4 Study Treatments or Agents Mandated by the Protocol
+The study interventions were 30ug of BNT1622 and saline placebo.
+6.1.6 Sites and Centers
+A total of 153 sites across the United States (131), Turkey (9), Germany (6), South Africa, (4), Brazil (2) and Argentina (1) participated in the study.
+6.1.7 Surveillance/Monitoring
+Please refer to Drs. Susan Wollersheim and Ann Schwartz's clinical review memo.
+6.1.8 Endpoints and Criteria for Study Success
+The safety endpoints for all subiects include the occurrence of As and SAEs from Dose 1 up to one month post Dose 2 or unblinding (whichever is earlier), and from Dose 1 up to six months post Dose 2 or unblinding. For the reactogenicity subset, safety endpoints additionally include the occurrence of local reactions (redness, swelling, and injection
+Page 7
+
+Statistical Review
+STN: 125742/0
+site pain) and systemic reactions (fever, fatigue, headache, chills, vomiting, diarrhea, and muscle and joint pain) within seven days of each dose.
+6.1.9 Statistical Considerations & Statistical Analysis Plan
+Solicited safety analyses were based on subiects in the reactogenicity subset who received at least one dose of the study intervention and responded yes or no to any reaction within seven days of each dose. Unsolicited safety analyses were based the Safety Population, which consisted of all subjects randomized in the Phase 2/3 study who received at least one dose of study intervention, analyzed according to the intervention received. Safety endpoints were summarized descriptively by computing the number and percentage of participants within the analysis set who reported at least one event
+6.1.10 Study Population and Disposition
+6.1.10.1 Populations Enrolled/Analyzed
+Table 2 shows the disposition of randomized subjects >16 years of age in the Phase 2/3 portion of the study. A total of 44,165 subjects were randomized. The percentages of subiects who received each dose were similar between the vaccine and placebo groups.
+More subjects withdrew from the study in the placebo group than in the vaccine group.
+Table 2. Subiect Disposition
+BNT162b2
+Placebo
+Total
+N=22085
+N=22080
+N=44165
+n (%)
+n (%)
+n (%)
+Randomized
+Not vaccinated
+Vaccinated
+Dose 1
+Dose 2
+Withdrawn from the study
+Lost to follow-up
+Withdrawal by subiect
+Protocol deviation
+Death
+Adverse event
+Physician decision
+No longer meets eligibility criteria
+Pregnancy
+Medication error without AE
+Withdrawal by parent/guardian
+Other
+22085 (100.0) 22080 (100.0) 44165 (100.0)
+55 (0 2)
+50 (0 2)
+105 (0 2)
+22030 (99.8)
+22030 (99.8)
+44060 (99.8)
+22030 (99.8)
+22030 (99.8)
+44060 (99.8)
+21675 (98.1)
+21650 (98.1)
+43325 (98.1)
+343 (1.6)
+484 (2.2)
+827 (1.9)
+174 (0.8)
+191 (0 9)
+365 (0 8)
+122 (0.6)
+226 (1.0)
+348 (0.8)
+11(<0.1)
+24 (0.1)
+35 (0.1)
+16 (0.1)
+15 (0.1)
+31 (0.1)
+9 (<0.1)
+8 (<0.1)
+17(<0.1)
+3 (<0.1)
+6 (<0.1)
+9 (<0.1)
+1 (<0 1)
+4 (<0.1)
+5 (<0.11
+0
+1 (<0.1)
+1 (<0.1)
+1 (<0.1)
+1<0.1)
+1 (<0.1)
+1 (<0.1)
+5 (<0.1)
+9 (<0.1)
+14(<0.1)
+Source: Adapted from Table 31 of Summary of Clinical Safetv.
+6.1.10.1.1 Demographics
+Table 3 presents demographic characteristics for the Safety Population. Demographic characteristics were generally similar with regard to age, gender, race, and ethnicity
+Page 8
+
+Statistical Review
+STN: 125742/0
+among participants who received BNT162b2 and those who received placebo. Overall, among all the participants who received either BNT162b2 or placebo, 50.9% were male and 49.1% were female, 82.0% were White, 9.6% were Black or African American, 4.3% were Asian, and 1.0% were American Indian or Alaska Native.
+Table 3. Demographics Characteristics of the Safety Population
+BNT162b2
+N=22026 n (%)
+Placebo
+N=22021 n (%)
+Total
+N=44047 n (%)
+Sex
+Male
+Female
+Race
+White
+Black/African-American
+American Indian/Alaskan Native
+Asian
+Native Hawaiian/Other Pacific Islander
+Multiracial
+Not Reported
+Ethnicity
+Hispanic/Latino
+Non-Hispanic/Non-Latino
+Not Reported
+Country
+Argentina
+Brazil
+Germany
+South Africa
+Turkey
+USA
+Age Group
+16-55 Years
+>55 Years
+Age
+Mean (Standard Deviation)
+Median
+Minimum. Maximum
+Source: Table 4 of Summary of Clinical Safetv.
+11322 (51.4)
+11098 (50.4)
+22420 (50.9)
+10704 (48.6)
+10923 (49.6)
+21627 (49.1'
+18056 (82.0)
+18064 (82.0)
+36120 (82.0)
+2098 (9.5)
+2118 (9.6)
+4216 (9.6)
+221 (1.0)
+217 (1.0)
+438 (1.0)
+952 (4.3)
+942 (4.3)
+1894 (4.3)
+58 (0.3)
+32 (0.1)
+90 (0.2)
+550 (2.5)
+533 (2.4)
+1083 (2.5)
+91 (0.4)
+115 (0.5)
+206 (0.5)
+5704 (25.9)
+5695 (25.9)
+11399 (25.9)
+16211 (73.6) 16212 (73.6)
+32423 (73.6)
+111 (0.5)
+114 (0.5)
+225 (0.5)
+2883 (13.1)
+2881 (13.1)
+1452 (6.6)
+1448 (6.6)
+249 (1.1)
+250 (1.1)
+401 (1.8)
+399 (1.8)
+249 (1.1)
+249 (1_1)
+16792 (76.2)
+16794 (76.3)
+5764 (13.1)
+2900 (6.6)
+499 (1.1)
+800 (1.8)
+498 (1.1)
+33586 (76.3)
+13069 (59.3)
+8957 (40.7)
+13095 (59.5)
+8926 (40.5)
+26164 (59.4)
+17883 (40.6)
+49.7 (16.0)
+51.0
+(16, 89)
+49.6 (16.1)
+51.0
+(16, 91)
+49.7 (16.0)
+51.0
+(16, 91)
+6.1.11 Efficacy Analyses
+Please refer to Dr. Lei Huang's statistical review memo.
+6.1.12 Safety Analyses
+Solicited Local and Systemic Reactions
+Tables 4 and 5 present the frequency by severity of each solicited local and systemic reaction within seven days of each dose for the 16-to-55 and 56-and-above vear-old age
+Page 9
+
+Statistical Review
+STN: 125742/0
+groups, respectively. In general, incidence of any redness, swelling, injection site pain, fever, fatigue, headache, chills, new or worse muscle pain, and new or worse joint pain was higher among vaccine recipients than among placebo recipients. There were no notable differences between vaccine and placebo recipients or between vaccine Dose 1 and Dose 2 for vomiting or diarrhea.
+For both age groups, injection site pain was the most frequent solicited local adverse reaction. After Dose 2, the younger age group reported any pain more frequently than the older age group (78.3% vs 66.1%). A similar pattern was observed after Dose 1.
+Frequencies of any injection site redness and swelling were generally similar after each dose and for both age groups.
+Among BNT16262 recipients 16 to 55 years of age, the mean duration (not shown in tables) of pain at the injection site after Dose 2 was 2.5 days (range 1 to 70 days), 2.2 days for redness (range 1 to 9 days), and 2.1 days for swelling (range 1 to 8 days).
+Among BNT16262 recipients 56 years of age and older the mean duration of pain at the injection site after Dose 2 was 2.4 days (range 1 to 36 days), 3.0 days for redness (range 1 to 34 days), and 2.6 days for swelling (range 1 to 34 days).
+The frequency and severity of systemic AEs were generally higher in the younger age group. Within each age group, the frequency and severity of systemic AEs were higher after Dose 2 than Dose 1, except for vomiting and diarrhea, which were generally similar regardless of dose. For both age groups, fatigue, headache and new/worsened muscle pain were the most common reactions after Dose 2.
+Table 4. Frequency of Solicited Reactions Within Seven Days of each Dose (16 to 55 Years)
+BNT162b2
+Placebo
+BNT162b2
+Dose 1
+Dose 1
+Dose 2
+N=2899
+N=2908
+N=2682
+n (%)
+n (%)
+n (%)
+Placebo
+Dose 2
+N=2684 n (%)
+Redness
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+Swelling
+Anv (>2.0 cm)
+Mild
+Moderate
+Severe
+Pain at the iniection site
+Anv
+Mild
+Moderate
+Severe
+156 (5.4)
+113 (3.9)
+36 (1.2)
+7 (0.2)
+-
+184 (6.3)
+124(4.3)
+54(1.9)
+6 (0.2)
+28 (1.0)
+19 (0.7)
+6 (0.2)
+3 (0.1)
+-
+16 (0.6)
+6 (0.2)
+8 (0.3)
+2 (0.1)
+Fever
+>38.0°C
+>38 0°C to 38 4°C
+2426 (83.7)
+1464 (50.5)
+923 (31.8)
+39 (1.3)
+-
+119 (4.1)
+86 (3.0)
+414(14.2)
+391 (13.4)
+20 (0.7)
+3 (0.1)
+-
+25 (0.9)
+16 (0.6)
+151 (5.6)
+90 (3.4)
+50 (1.9)
+11 (0 4)
+-
+183 (6.8)
+110 (4.1)
+66 (2.5)
+7 (0.3)
+-
+2101 (78.3)
+1274 (47.5)
+788 (29.4)
+39 (1.5)
+-
+440 (16.4)
+254 (9.5)
+18 (0.7)
+12 (0.4)
+6 (0.2)
+0
+5 (0.2)
+3 (0.1)
+2 (0.1)
+312 (11.6)
+284 (10.6)
+28 (1.0)
+0
+11 (0.4)
+5 (0.2)
+Page 10
+
+>38.4°C to 38.9°C
+>38 9°C to 40 0°C
+>40 0°C
+BNT162b2
+Dose 1
+N=2899 n (%)
+25 (0.9)
+8 (0.3)
+0
+Placebo
+Dose 1
+N=2908 n (%)
+5 (0.2)
+4 (0.1)
+Fatigue
+Any
+Mild
+Moderate
+Severe
+BNT162b2
+Dose 2
+N=2682 n (%)
+146 (5.4)
+39 (1.5)
+1 (0.0)
+-
+1649 (61.5)
+558 (20.8)
+949 (35.4)
+142 (5.3)
+Headache
+Anv
+Mild
+Moderate
+Severe
+1431 (49.4)
+760 (26.2)
+630 (21.7)
+41(1.4)
+-
+1262 (43.5)
+785 (27.1)
+444(15.3)
+33(1.1)
+960 (33.0)
+570 (19.6)
+372 (12.8)
+18 (0.6)
+-
+975 (33.5)
+633 (21.8)
+318 (10.9)
+24 (0.8)
+1448 (54.0)
+699 (26.1)
+658 (24.5)
+91 (3.4)
+Chills
+Any
+Mild
+Moderate
+Severe
+479 (16.5)
+338 (11.7)
+126 (4.3)
+15 (0.5)
+Vomiting
+Any
+Mild
+Moderate
+34 (1.2)
+29 (1.0)
+5 (0.2)
+Severe
+199 (6.8)
+148 (5.1)
+49 (1.7)
+2 (0.1)
+-
+36 (1.2)
+30 (1.0)
+5 (0.2)
+1 (0.0)
+Placebo
+Dose 2
+N=2684 n (%)
+4 (0.1)
+2 (0.1)
+0
+-
+614 (22.9)
+317 (11.8)
+283 (10.5)
+14 (0.5)
+-
+652 (24.3)
+404 (15.1)
+230 (8.6)
+18 (0.7)
+-
+114 (4.2)
+89 (3 3)
+23 (0.9)
+2 (0.1)
+-
+30 (1.1)
+20 (0.7)
+10 (0.4)
+0
+Diarrhea
+Any
+Mild
+Moderate
+Severe
+New or worsened muscle vain
+Anv
+Mild
+Moderate
+Severe
+309 (10.7)
+251 (8.7)
+55 (1.9)
+3 (0.1)
+-
+664 (22.9)
+353 (12.2)
+296 (10.2)
+15 (0.5)
+323 (11.1)
+264 (9.1)
+58 (2.0)
+1 (0.0)
+-
+329 (11.3)
+231 (7.9)
+96 (3.3)
+2 (0.1)
+1015 (37.8)
+477 (17 8)
+469 (17.5)
+69 (2.6)
+-
+58 (2.2)
+42 (1 6)
+12 (0.4)
+4 (0.1)
+-
+269 (10.0)
+219 (8.2)
+44 (1.6)
+6 (0.2)
+-
+1055 (39.3)
+441 (16.4)
+552 (20.6)
+62 (2.3)
+205 (7.6)
+169 (6.3)
+35 (1.3)
+1 (0.0)
+-
+237 (8.8)
+150 (5.6)
+84 (3.1)
+3 (0.1)
+New or worsened joint pain
+Anv
+Mild
+Moderate
+Severe
+342 (11.8)
+200 (6.9)
+137 (4.7)
+5 (0.2)
+168 (5.8)
+112 (3.9)
+55 (1.9)
+1 (0.0)
+638 (23.8)
+291 (10 9)
+320 (11.9)
+27 (1.0)
+147 (5.5)
+82 (3.1)
+61 (2.3)
+4 (0.1)
+Use of antipvretic or pain medication
+805 (27.8)
+398 (13.7)
+1213 (45.2)
+320 (11.9)
+N=number of subjects responding yes or no for any reaction within seven days of dosing. n=number of subiects with the specified reaction.
+Source: Adapted from Table 14.68 of C4591001 Interim Clinical Study Report.
+Statistical Review
+STN: 125742/0
+Page 11
+
+Statistical Review
+STN: 125742/0
+Table 5. Frequency of Solicited Reactions Within Seven Days of each Dose (>55 Years)
+BNT162b2
+Placebo
+BNT162b2
+Placebo
+Dose 1
+Dose 1
+Dose 2
+Dose 2
+N=2008
+N=1989
+N=1860
+N=1833
+n (%)
+n (%)
+n (%)
+n (%)
+Redness
+-
+-
+-
+-
+Any (>2.0 cm)
+106 (5.3)
+20 (1.0)
+133 (7.2)
+14 (0.8)
+Mild
+71 (3.5)
+13 (0.7)
+65 (3.5)
+10 (0.5)
+Moderate
+30 (1.5)
+5 (0.3)
+58 (3.1)
+3 (0.2)
+Severe
+5 (0.2)
+2 (0.1)
+10 (0.5)
+1 (0.1)
+Swelling
+-
+-
+-
+Any (>2.0 cm)
+141 (7.0)
+23 (1.2)
+145 (7.8)
+13 (0.7)
+Mild
+87 (4.3)
+11 (0.6)
+80 (4.3)
+5 (0.3)
+Moderate
+52 (2.6)
+12 (0.6)
+61 (3.3)
+7 (0.4)
+Severe
+2 (0.1)
+0
+4 (0.2)
+1 (0.1)
+Pain at the injection site
+-
+-
+-
+Any
+1408 (70.1)
+185 (9.3)
+1230 (66.1)
+143 (7.8)
+Mild
+1108 (55.2)
+177 (8.9)
+873 (46.9)
+138 (7.5)
+Moderate
+296 (14.7)
+8 (0.4)
+347 (18.7)
+5 (0.3)
+Severe
+4 (0.2)
+10 (0.5)
+O
+Fever
+>38.0°C
+26 (1.3)
+8 (0.4)
+219 (11.8)
+4 (0.2)
+>38.0°C to 38.4°C
+23 (1.1)
+3 (0.2)
+158 (8.5)
+2 (0.1)
+>38.4°C to 38.9°C
+2 (0.1)
+3 (0.2)
+54 (2.9)
+1 (0.1)
+>38.9°C to 40.0°C
+1 (0.0)
+2 (0.1)
+7 (0.4)
+1 (0.1)
+>40.0°C
+0
+0
+Fatigue
+Any
+Mild
+Moderate
+Severe
+677 (33.7)
+415 (20.7)
+259 (12.9)
+3 (0.1)
+Grade 4
+Headache
+Anv
+Mild
+Moderate
+Severe
+-
+503 (25.0)
+381 (19.0)
+120 (6.0)
+2 (0.1)
+447 (22.5)
+281 (14.1)
+163 (8.2)
+3 (0.2)
+-
+363 (18.3)
+267 (13.4)
+93 (4.7)
+3 (0.2)
+Chills
+Anv
+Mild
+Moderate
+Severe
+Vomiting
+Any
+Mild
+Moderate
+130 (6.5)
+102 (5.1)
+28 (1.4)
+0
+-
+10 (0.5)
+9 (0.4)
+1 (0.0)
+69 (3.5)
+49 (2.5)
+19 (1.0)
+1 (0.1)
+9 (0.5)
+9 (0.5)
+0
+Severe
+-
+949 (51.0)
+391 (21.0)
+497 (26.7)
+60 (3.2)
+1 (0.1)
+-
+733 (39.4)
+464 (24.9)
+256 (13.8)
+13 (0 7\
+-
+435 (23 4)
+229 (12.3)
+185 (9.9)
+21 (1.1)
+-
+13 (0.7)
+10 (0.5)
+1 (0.1)
+2 (0.1)
+306 (16.7)
+183 (10.0)
+121 (6.6)
+2 (0.1)
+259 (14.1)
+189 (10.3)
+65 (3.5)
+5 (0.3)
+57 (3.1)
+45 (2.5)
+12 (0.7)
+0
+5 (0.3)
+5 (0.3)
+0
+Page 12
+
+Statistical Review
+STN: 125742/0
+Diarrhea
+Anv
+Mild
+Moderate
+Severe
+BNT162b2
+Dose 1
+N=2008 n (%)
+-
+168 (8.4)
+137 (6.8)
+27 (1.3)
+4 (0.2)
+Placebo
+Dose 1
+N=1989 n (%)
+BNT162b2
+Dose 2
+N=1860 n (%)
+Placebo
+Dose 2
+N=1833 n (%)
+130 (6 5)
+109 (5.5)
+20 (1.0)
+1 (0.1)
+152 (8.2)
+125 (6.7)
+25 (1.3)
+2 (0.1)
+102 (5.6)
+76 (4.1)
+22 (1.2)
+4 (0.2)
+New or worsened muscle pain
+Any
+Mild
+Moderate
+Severe
+New or worsened joint pain
+Anv
+Mild
+Moderate
+Severe
+274 (13.6)
+183 (9.1)
+90 (4.5)
+1 (0.0)
+-
+175 (8.7)
+119 (5.9)
+53 (2.6)
+3 (0.1)
+165 (8.3)
+111 (5.6)
+51 (2.6)
+3 (0.2)
+124 (6.2)
+78 (3.9)
+45 (2.3)
+1 (0.1)
+537 (28.9)
+229 (12.3)
+288 (15.5)
+20 (1.1)
+-
+353 (19.0)
+183 (9.8)
+161 (8.7)
+9 (0.5)
+99 (5.4)
+65 (3.5)
+33 (1.8)
+1 (0.1)
+-
+72 (3.9)
+44 (2.4)
+27 (1.5)
+1 (0.1)
+Use of antipyretic or pain medication
+382 (19.0)
+224 (11.3)
+688 (37.0)
+170 (9 3)
+N=number of subjects responding yes or no for any reaction within seven days of dosing. n=number of subjects with the specified reaction.
+Source: Adapted from Table 14.68 of C4591001 Interim Clinical Study Report.
+Reviewer Comment:
+• Three placebo recipients 16 to 55 years of age who reported fever of >42°C within seven days of the first or second dose were excluded from the analysis. As the subjects received placebo and these measurements were likely due to error, this is unlikely to affect safety conclusions.
+Unsolicited Safety
+Table 6 presents the numbers and percentages of subjects ≥16 years of age who reported any unsolicited AE, SAE, AE leading to withdrawal, or death after the first dose. These numbers are reported for three separate risk windows: a) Dose 1 to one month post Dose 2 or unblinding (whichever is first), b) Dose 1 to six months post Dose 2 or unblinding (whichever is first), and c (for placebo patients who received crossover vaccination) from crossover to March 13, 2021. The percentages of subjects reporting any SAE, AE leading to withdrawal, or death were generally similar between the vaccine and placebo groups from Dose 1 to one month after Dose 2 and from Dose 1 to six months after Dose 2 regardless of severity. A higher percentage of vaccine recipients reported any unsolicited AE after Dose 1 than placebo recipients. Four vaccine recipients reported SAEs up to six months post Dose 2 that were considered by the investigator to be related to the study intervention. In these analyses, 58.2% of study participants had at least four months of blinded follow-up after Dose 2.
+Page 13
+
+Statistical Review
+STN: 125742/0
+A total of 19,525 subiects originally randomized to placebo received at least one dose of
+BNT1622 after unblinding (Dose 3 and Dose 4) and before the March 13, 2021 data cutoff. Among these subjects, one (<0.1%) subject reported an SAE of anaphylactoid reaction after Dose 3 that was considered by the investigator to be related to the study intervention. Two subjects (<0.1%) died after receiving Dose 3, but neither were considered by the investigator to be related to the intervention.
+Table 6. Number of Subjects ≥16 Years of Age Reporting at Least One AE by Time Period
+BNT162b2
+Placebo
+BNT16262
+1MPD2a
+1MPD2a
+6MPD2®
+N=21926
+N=21921
+N=21926
+n (%)
+n (%)
+n (%)
+Anv AE
+6617 (30.2)
+3048 (13.9)
+6947 (31.7)
+Related
+5241 (23.9)
+1311 (6.0)
+5246 (23.9)
+Severe
+262 (1.2)
+150 (0.7)
+356 (1.6)
+Life-Threatening
+21 (0.1)
+26 (0.1)
+48 (0.2)
+Any SAE
+127 (0.6)
+116 (0.5)
+268 (1.2)
+Related
+3 (<0.1)
+4 (<0 1)
+Severe
+71 (0.3)
+66 (0 3)
+148(0.7)
+Life-Threatening
+21 (0.1)
+26 (0.1)
+48 (0.2)
+Any AE leading to withdrawal
+32 (0.1)
+36 (0.2)
+45 (0.2)
+Related
+13 (0.1)
+11 (0.1)
+13 (0.1)
+Severe
+10 (<0.1)
+10 (<0.1)
+10 (<0.1)
+Life-Threatening
+3 (<0.1)
+7 (<0.1)
+15 (0.1)
+Death
+3 (<0 1)
+5 (<0.1)
+15 (0.1)
+N=number of subjects who received at least one dose of the study intervention. n=number of subjects reporting at least one event.
+"Includes all events from Dose I up to the earlier of one month post Dose 2 or unblinding.
+Includes all events from Dose I up to the earlier of six months post Dose 2 or unblinding.
+Includes all events from crossover vaccination (Dose 3) to March 13, 2021.
+Includes all subiects randomized to placebo who received BNT1622 after unblinding.
+Source: Adapted from Tables 5, 7, and 14 of Summary of Clinical Safety.
+Placebo
+BNT162b2
+6MPD2b
+PD3C
+N=21921
+N=19525d
+n (%)
+_n (%)
+3568 (16.3) 4885 (25.0)
+1313 (6.0)
+4508 (23.1)
+256 (1.2)
+142 (0.7)
+54 (0.2)
+11 (0.1)
+268 (1.2)
+65 (0.3)
+1 (<0 1)
+1 (<0.1)
+156 (0.7)
+37 (0.2)
+54 (0.2)
+11 (0.1)
+51 (0.2)
+19(0.1)
+12 (0.1)
+12 (0.1)
+12 (0.1)
+2 (<0.1)
+16 (0.1)
+4 (<0.1)
+14 (0.1)
+2 (<0.1)
+Reviewer Comments:
+• The solicited and unsolicited AEs reported in the clinical study report were consistent with the Study Data Tabulation Model (SDTM) data.
+• The solicited and unsolicited AE analyses presented do not include the 200
+Human Immunodeficiency Virus (HIV)-positive participants. Similar safety results were observed in HIV-positive subjects.
+• The imbalance in the frequencies of unsolicited AEs is driven largely by increased reactogenicity in the vaccine arm, in that many events associated with reactogenicity (e.g. injection site pain, fatigue, etc.) occurring within days of vaccination were reported as unsolicited AEs.
+• Two subjects who received BNT162b2 and experienced an AE or SAE were not reported in the blinded follow-up safety analysis:
+1. One subject (C4591001 (b) (6)
+) received two doses of BNTI62b2
+and reported an SAE of acute hepatic failure on Day 100 that was not considered by the investigator to be related to the study intervention. The
+Page 14
+
+Statistical Review
+STN: 125742/0
+subject was unblinded and withdrew from the study on the same day that the SAE was reported. As the safety analyses included only events up to the day before unblinding (regardless of the reason for unblinding), this event was not considered to have occurred during blinded follow-up.
+2. One subject (C4591001 (b) (6)
+) received one dose of BNT162b2
+and reported a case of tinnitus with unknown start and end dates.
+I defer to the clinical reviewer regarding the interpretation of these events.
+• The applicant stated that 58.2% of subjects in the unsolicited safety analysis completed at least four months of follow-up post Dose 2. Of note, it appears that the applicant considered a month to be equivalent to 28 days. The median follow-up from Dose 2 to six months post Dose 2 or unblinding among ≥16-year-old participants in the Safety Population was approximately 120 days.
+Ten subjects (six vaccine and four placebo) who received at least one dose of the study intervention were excluded from the Safety Set due to "lack of PI [Principal Investigator] oversight," which was not documented in the Statistical Analvsis
+Plan. Among the six vaccine recipients, one non-serious AE of "excessive cerumen production" was reported that was not considered by the investigator to be related to the study intervention, and no SAEs were reported.
+Myocarditis and Pericarditis
+One report of pericarditis was identified in a 66-year-old male participant 28 days after receiving Dose 2 of BNT1622. One report of myocarditis was identified in a 25-year-old male participant in the placebo group five days after the second placebo dose.
+7. INTEGRATED OVERVIEW OF EFFICACY
+No integrated analysis of efficacy was performed.
+8. INTEGRATED OVERVIEW OF SAFETY
+No integrated analysis of safety was performed.
+9. ADDITIONAL STATISTICAL ISSUES
+There are no additional statistical issues.
+10. CONCLUSIONS
+10.1 Statistical Issues and Collective Evidence
+No major statistical issues were identified for the safety data during review. A higher percentage of subiects in the BNT16262 group reported solicited local and systemic reactions than placebo recipients in both the younger (16 to 55 years) and older (>55 years) adult age groups after each dose. There were no major imbalances in reported SAEs, AEs leading to withdrawal, or deaths between the treatment groups at one month and up to six months after the second dose or unblinding/data cut-off.
+Page 15
+
+Statistical Review
+STN: 125742/0
+10.2 Conclusions and Recommendations
+There is evidence of reactogenicity associated with BNT162b2; the overwhelming majority of events were of mild or moderate severity and short duration. There was no evidence of increased risk of unsolicited SAE or death associated with BNT162b2 in Study C4591001. I defer to Drs. Susan Wollersheim and Ann Schwartz's clinical review memo on the overall safety conclusion for BNT16262.
+Page 16
+

docs/Statistical-Review-COMIRNATY.txt

@@ -0,0 +1,1111 @@
+Statistical Review
+STN: 125742/45
+Application Type
+BLA Supplement
+STN
+125742/45
+CBER Received Date
+December 16, 2021
+PDUFA Goal Date
+June 17, 2022
+Division/ Office
+DVRPA/OVRR
+Committee Chair
+Ramachandra Naik
+Clinical Reviewers)
+Susan Wollersheim
+Project Manager
+Michael Smith; Laura Gottschalk
+Priority Review
+Yes
+Reviewer Name
+Ye Yang, Mathematical Statistician, DB/VEB
+Review Completion Date /
+Stamped Date
+Concurrence
+Lei Huang, Concurring Reviewer, DB/VEB
+Supervisory Concurrence
+Tsai-Lien Lin, Branch Chief, DB/VEB
+Applicant
+Established Name
+(Proposed) Trade Name
+Dosage Form(s) and Route(s) of
+Administration
+Dosing Regimen
+Indication(s) and Intended
+Population(s)
+BioNTech Manufacturing GmbH (in partnership with Pfizer, Inc.)
+COVID-19 Vaccine, mRNA
+COMIRNATY
+Injectable Suspension, Intramuscular
+Two 0.3 mL doses, three weeks apart
+Active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2
+(SARS-CoV-2) in individuals 12 through 15 years of age
+Page i
+
+Statistical Review
+STN: 125742/45
+Table of Contents
+Glossary....
+3
+1. Executive Summary..
+2. Clinical and Regulatory Background
+5
+3. Submission Ouality and Good Clinical Practices ..............
+5
+3.1 Submission Quality and Completeness ....
+3.2 Compliance With Good Clinical Practices And Data Integrity
+4. Significant Efficacy/Safety Issues Related to Other Review Disciplines............
+5
+5. Sources of Clinical Data and Other Information Considered in the Review...........
+5
+5.1 Review Strategy .........
+5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review ......
+5.3 Table of Studies/Clinical Trials...
+6. Discussion of Individual Studies/Clinical Trials ..
+6.1 Study C4591001......
+6.1.1 Objectives.
+6.1.2 Design Overview.
+6.1.3 Population
+6.1.4 Study Treatments or Agents Mandated by the Protocol
+6.1.6 Sites and Centers
+6.1.7 Surveillance/Monitoring.
+6.1.8 Endpoints and Criteria for Study Success
+6.1.9 Statistical Considerations & Statistical Analysis Plan
+6.1.10 Study Population and Disposition
+6.1.11 Efficacy Analyses.....
+6.1.12 Safety Analyses.
+7. Integrated Overview of Efficacy...........
+10
+17
+8. Integrated Overview of Safety.......
+17
+9. Additional Statistical Issues...........
+.............. 17
+10. Conclusions..........
+10.1 Statistical Issues and Collective Evidence..............
+10.2 Conclusions and Recommendations..
+17
+17
+........ Id
+Page ii
+
+Statistical Review
+STN: 125742/45
+GLOSSARY
+ADaM
+AE
+BIMO
+BLA
+BNT16262
+CI
+COVID-19
+EUA
+GMT
+GMR
+NAAT
+RT-PCR
+SAE
+SAP
+SARS-CoV-2
+SDTM
+SRR
+VE
+Analysis Data Model
+Adverse Event
+Bioresearch Monitoring
+Biologics License Application
+Pfizer-BioNTech COVID-19 Vaccine
+Confidence Interval
+Coronavirus Disease 2019
+Emergency Use Authorization
+Geometric Mean Titer
+Geometric Mean Titer Ratio
+Nucleic Acid Amplification Test
+Reverse Transcription-Polymerase Chain Reaction
+Serious Adverse Event
+Statistical Analysis Plan
+Severe Acute Respiratory Syndrome Coronavirus 2
+Study Data Tabulation model
+Seroresponse Rate
+Vaccine Efficacy
+Page 3
+
+Statistical Review
+STN: 125742/45
+1. Executive Summary
+The Pfizer-BioNTech COVID-19 Vaccine (BNT162b2, COMIRNATY) was licensed on August 23, 2021 for active immunization to prevent Coronavirus Disease 2019 (COVID-
+19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in individuals ≥16 years of age. Pfizer submitted a Biologics License Application Supplement (BLA; STN 125742/45) on December 16, 2021 to seek licensure of COMIRNATY for use in individuals 12 through 15 years of age. The BLA is supported by data from Study C4591001. This statistical review focuses on the efficacy, immunogenicity, and safety data from adolescents 12 through 15 years of age in the Phase 3 part of Study C4591001 collected up to the September 2, 2021 data cutoff.
+Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blinded Phase 1/2/3 study being conducted in the United States, Argentina, Brazil, Germany, South Africa, and Turkey among participants ≥12 years of age. Adolescents 12 through 15 years of age, included in the Phase 3 portion of the study under a protocol amendment, were enrolled at selected sites in the United States, where 2,264 participants were randomized 1:1 to receive two doses of BNT16262 or placebo 21 days apart.
+Immunogenicity was assessed at 1 month after Dose 2. A random sample of 280 adolescents was selected to support immunobridging to a random sample of 280 young adults 16 to 25 years of age from the same study. Supplementary to immunobridging, adolescents were surveilled for potential cases of COVID-19.
+The prespecified immunobridging success criterion comparing 12 to 15 year-old geometric mean neutralizing titers (GMTs) to 16 to 25 year-old GMTs from Study
+C4591001 was met (GMT ratio [GMR]=1.77; 95% Confidence Interval [CI]: 1.50 to
+2.09). High efficacy against protocol-defined COVID-19 was observed among participants in the Evaluable Efficacy Population without evidence of prior SARS-CoV-2 infection starting at 7 days post Dose 2 (Vaccine Efficacy [VE]=100%; 95% CI: 86.8% to 100%) and among participants in the Dose 1 All-Available Efficacy Population starting after Dose 1 (VE=94.0%; 95% CI: 81.3% to 98.8%). The lack of severe COVID-19 cases observed precludes assessment of efficacy against severe disease in this population.
+The frequency and severity of local and systemic reactions were generally higher among
+BNT162b2 recipients than among placebo recipients after either dose. The most commonly reported adverse reactions were injection site pain, fatigue, and headache.
+There was no notable difference in the frequency of any unsolicited adverse event (AE)
+between arms during blinded follow-up, while a higher percentage of BNT162b2 recipients reported any serious AE (SAE; 0.9%) compared to placebo recipients (0.2%).
+Of note, no SAE reported during blinded follow-up was considered by the investigator to be related to the study intervention. No participants died as of the September 2, 2021 cutoff. One SAE of myocarditis was reported in a 15-year-old male participant 2 days after receiving the second crossover dose of BNT162b2. One SAE of appendicitis in a
+12-year-old female participant was reported 3 days after the second crossover dose and was considered by the investigator to be related to the study vaccination.
+Page 4
+
+Statistical Review
+STN: 125742/45
+Overall, the clinical data support the effectiveness of BNT1622. While there is some reactogenicity associated with BNT162b2, the majority of solicited adverse reactions were mild or moderate in severity and of short duration. I defer to the clinical reviewer, Dr. Susan Wollersheim, on the overall safety conclusion for BNT162b2.
+2. Clinical and Regulatory Background
+The Pfizer-BioNTech COVID-19 Vaccine (BNT16262, COMIRNATY) was authorized under an Emergency Use Authorization (EUA) on December 11, 2020 for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals ≥16 years of age, which was amended to include individuals 12 through 15 years of age on May 10,
+2021. COMIRNATY was licensed for use in individuals ≥16 years of age on August 23,
+2021. Pfizer submitted an BLA (STN 125742/45) on December 16, 2021 to seek licensure of COMIRNATY for use in individuals 12 through 15 years of age.
+3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
+3.1 Submission Quality and Completeness
+The submission was adequately organized for conducting a complete statistical review without unreasonable difficulty.
+3.2 Compliance With Good Clinical Practices And Data Integrity
+Please refer to Kanaeko Ravenell's Bioresearch Monitoring inspections review memo.
+4. SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
+DISCIPLINES
+Please refer to reviews of other review disciplines.
+5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW
+5.1 Review Strategy
+This statistical review focuses on the efficacy, immunogenicity, and safety data from adolescents 12 to 15 years of age in the Phase 3 part of Study C4591001 collected up to the September 2, 2021 data cutoff.
+5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review
+The following documents submitted to the BLA are reviewed:
+STN 125742/45:
+1. Amendment 0 (submitted on 12/16/2021)
+• Module 2. Common Technical Document Summaries
+• Module 5. Clinical Study Reports
+2. Amendment 2 (submitted on 2/2/2022)
+Page 5
+
+Statistical Review
+STN: 125742/45
+• Module 1. Administrative Information and Prescribing Information
+3. Amendment 4 (submitted on 3/11/2021)
+• Module 1. Administrative Information and Prescribing Information
+4. Amendment 7 (submitted on 3/18/2021)
+• Module 1. Administrative Information and Prescribing Information
+5.3 Table of Studies/Clinical Trials
+Data from one ongoing clinical study were submitted to support licensure in adolescents (Table 1). Study C4591001 is a multi-center, Phase 1/2/3, randomized, double-blinded, placebo-controlled study to evaluate safety, immunogenicity, and efficacy of BNT16262.
+Table 1. Clinical Study Supporting Licensure in Adolescents 12 Through 15 Years of Age
+Study
+Description
+BNT162b2 (N)
+Placebo (N)
+C4591001 Phase 1/2/3, randomized, 1134 (Phase 3
+1130 (Phase 3
+Status
+Ongoing
+placebo-controlled, observer- adolescents
+adolescents
+blind study to evaluate the only)
+only)
+safety, immunogenicity, and efficacy of BNT16262
+N=number of randomized participants.
+Source: Summarized by the reviewer based on information provided in Clinical Overview.
+6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS
+6.1 Study C4591001 (Phase 3)
+6.1.1 Obiectives
+Primary Safety Objective:
+• To define the safety profile of BNT16262 in participants 12 to 15 years of age.
+Secondary Immunogenicity Objective:
+• To demonstrate the noninferiority of the immune response to BNT1622 in participants 12 to 15 years of age compared to participants 16 to 25 years of age.
+Exploratory Efficacy Obiective:
+• To describe the efficacy of prophylactic BNT16262 against confirmed COVID-19 occurring from 7 days after the second dose through the blinded follow-up period in participants without, and with and without, evidence of infection before vaccination.
+Reviewer comment:
+• Demonstration of efficacy was listed as an exploratory objective as immunobridging was the basis for inferring effectiveness of BNT162b2 among adolescents.
+Page 6
+
+Statistical Review
+STN: 125742/45
+6.1.2 Design Overview
+Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blinded Phase 1/2/3 study being conducted in the United States, Argentina, Brazil, Germany, South Africa, and Turkey among participants ≥12 years of age. Adolescents 12 through 15 years of age, included in the Phase 3 portion of the study under a protocol amendment, were enrolled at selected sites in the United States, where 2,264 participants were randomized 1:1 to receive two doses of BNT16262 or placebo 21 days apart.
+Immunogenicity was assessed at 1 month after Dose 2. A sample of 280 participants was randomly selected from each age group (12 to 15 years and 16 to 25 years) to support immunobridging. Supplementary to immunobridging analyses, adolescents were surveilled for potential cases of COVID-19. Those who developed acute respiratory illness were tested for SARS-CoV-2 infection using reverse transcription-polymerase chain reaction (RT-PCR) in an illness visit. Participants originally randomized to placebo who became eligible to receive BNT1622 were offered the opportunity to receive
+BNT16262 no later than 6 months post Dose 2.
+All adolescents were to record local reactions, systemic events, and antipyretic/pain medication usage from Day 1 through Day 7 after each dose. Unsolicited As and SAEs were collected starting from Dose 1.
+6.1.3 Population
+The study enrolled participants >12 years of age who, in the judgement of the investigator, were at higher risk for acquiring COVID-19, including but not limited to use of mass transportation, relevant demographics, and frontline essential workers. The age groups considered in this review are adolescents 12 to 15 years of age and young adults 16 to 25 years of age randomly sampled to support immunobridging.
+6.1.4 Study Treatments or Agents Mandated by the Protocol
+The study interventions were 30ug of BNT16262 and saline placebo.
+6.1.6 Sites and Centers
+A total of 29 sites in the United States enrolled adolescents in the study.
+6.1.7 Surveillance/Monitoring
+Please refer to Dr. Susan Wollersheim's clinical review memo.
+6.1.8 Endpoints and Criteria for Study Success
+The immunobridging endpoint was the neutralizing antibody titer at 28 days after Dose 2.
+Effectiveness of BNT1622 among adolescents was inferred by bridging their GMT of neutralizing antibodies to the GMT from a random subset of young adults 16 to 25 years of age from the same study. Success would be declared if the lower bound of the two-sided 95% CI for the GMR, where GMR is defined as GMT of adolescents divided by GMT of young adults, was >0.67. Difference in seroresponse rates (SRRs) was evaluated
+Page 7
+
+Statistical Review
+STN: 125742/45
+descriptively. Seroresponse was defined as a change from a baseline (pre-Dose 1) titer below the LLOQ to ≥4*LLOQ 28 days after Dose 2, or a ≥4-fold rise in titer from baseline when the baseline titer is ›LLOQ.
+Efficacy was assessed descriptively based on cases of confirmed COVID-19, defined as having a positive nuclei acid amplification test (NAAT) plus at least one of the following symptoms: fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, sore throat, diarrhea, or vomiting. Severe COVID-19 was defined as a confirmed COVID-19 plus at least one of the following:
+• Clinical signs at rest indicative of severe systemic illness (respiratory rate >30 breaths per minute, heart rate ≥125 beats per minute, SpOz <93% on room air at sea level, or Pa02/FiO2 <300 mm Hg);
+• Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation, or CMO);
+• Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or requiring vasopressors);
+• Significant acute renal, hepatic, or neurologic dysfunction;
+Admission to an ICU;
+• Death.
+Solicited safety endpoints included the occurrence of local (redness, swelling, injection site pain) and systemic (fever, fatigue, headache, chills, vomiting, diarrhea, muscle pain, joint pain) reactions within 7 days of each dose. Unsolicited safety endpoints included the occurrence of AEs and SAEs within three different risk windows: 1) Dose 1 to 1 month post Dose 2, 2) Dose 1 to 6 months post Dose 2, unblinding, or the September 2, 2021 data cutoff, whichever was earlier, and 3) unblinding to the cutoff.
+6.1.9 Statistical Considerations & Statistical Analysis Plan
+GMR and 95% CIs were obtained by exponentiating the difference and associated 95% CIs of the mean log-titers based on the t-distribution. The confidence interval for the SRR difference was estimated via the Miettinen-Nurminen method. The primary immunobridging analysis was based on the Evaluable Immunogenicity Population, defined as participants who: 1) received both doses of the randomized vaccine, with Dose 2 within 19 to 42 days after Dose 1, 2) had at least 1 valid and determinate immunogenicity result collected within 28 to 42 days after Dose 2, and 3) had no other important protocol deviations. In addition, for the primary analysis, participants must not have any evidence of SARS-CoV-2 infection up to 1 month after Dose 2.
+VE was estimated as 1 minus the incidence rate ratio of COVID-19 relative to placebo, with associated 95% CI calculated by the Clopper-Pearson method adiusted for surveillance time. Analysis was based on the Evaluable Efficacy Population, defined as participants who received the randomized intervention within the predefined window and had no major protocol deviations up to 7 days post Dose 2, and the Dose 1 All-Available Efficacy Population, defined as all randomized participants who received at least 1 dose of the intervention. Participants were analyzed according to the intervention randomized.
+Page 8
+
+Statistical Review
+STN: 125742/45
+VE in the Evaluable Efficacy Population was descriptively presented among participants:
+1) without evidence of SARS-CoV-2 infection up to 7 days post Dose 2, and 2) with or without evidence of prior infection.
+Solicited safety analyses were based on participants who received at least one dose of the study intervention and responded yes or no to any reaction within 7 days of each dose.
+Unsolicited safety analyses were based the Safety Population, defined as all participants who received at least 1 dose of study intervention, analyzed according to the intervention received. Safety endpoints were summarized descriptively.
+6.1.10 Study Population and Disposition
+6.1.10.1 Populations Enrolled/Analyzed
+Table 2 shows the disposition of randomized adolescents 12 to 15 years of age. A total of 2,264 adolescents were randomized. The percentages of participants who received each dose were similar between the vaccine and placebo groups. In addition, 280 participants 12 to 15 years old and 280 participants 16 to 25 years old were selected for immunobridging, of which 208 (74%) and 190 (68%), respectively, had a determinate immunogenicity result available after Dose 2. The lower number of participants with an available immunogenicity result, noted by the Applicant on March 15, 2021, was due to an insufficient supply of a critical assay reagent leading to a halt to laboratory testing. A total of 190 (68%) and 170 (61%) participants, respectively, were included in the Evaluable Immunogenicity Population without evidence of infection.
+Table 2. Subject Disposition
+BNT162b2 n (%)
+Randomized
+1134 (100)
+Not vaccinated
+3 (0.3)
+Vaccinated
+1131 (99.7)
+Dose 1
+1131 (99.7)
+Dose 2
+1124 (99.1)
+Withdrawn from the stud
+5 (0.4)
+Lost to follow-up
+3 (0.3)
+Withdrawal by subject
+1 (0.1)
+Withdrawal by parent/guardian
+1 (0.1)
+Dose 1 All-Available Efficacy Population
+1131 (99.7)
+Evaluable Efficacy Population
+1119 (98.7)
+Without evidence of infection
+1057 (93.2)
+Source: Adapted from Tables 4 and 10 of Interim Clinical Study Report.
+Placebo
+Total
+n (%)
+n (%)
+1130 (100)
+2264 (100)
+1 (0.1)
+4 (0.2)
+1129 (99 9)
+2260 (99.8)
+1129 (99 9)
+2260 (99 8)
+1117 (98.8)
+2241 (99.0)
+14 (1.2)
+19 (0.8)
+2 (0.2)
+5 (0.2)
+7 (0.6)
+8 (0.4)
+5 (0.4)
+6 (0.3)
+1129 (99 9)
+2260 (99.8)
+1109 (98.1)
+2228 (98 4)
+1030 (91.2)
+2087 (92.2)
+6.1.10.1.1 Demographics
+Table 3 presents the demographic characteristics of the adolescent Safety Population.
+Demographic characteristics were generally similar with regard to age, sex, race, ethnicity, and baseline SARS-CoV-2 serostatus between participants who received BNT16262 and those who received placebo. Among all participants who received either
+Page 9
+
+Statistical Review
+STN: 125742/45
+intervention, 51.0% were male, 85.5% were White, 4.8% were Black or African American, 6.3% were Asian, and 0.3% were American Indian or Alaska Native.
+Demographic characteristics in the Evaluable Efficacy Population were generally similar to those in the Safety Population.
+Table 3. Demographics Characteristics of the Safety Population
+BNT162b2
+N=1131 n (%)
+Sex
+-
+Male
+567 (50.1)
+Female
+564 (49.9)
+Race
+-
+White
+970 (85.8)
+Black/African-American
+52 (4.6)
+American Indian/Alaskan Native
+4 (0.4)
+Asian
+72 (6.4)
+Native Hawaiian/Other Pacific Islander
+3 (0.3)
+Multiracial
+24 (2.1)
+Not Reported
+6 (0.5)
+Ethnicity
+Hispanic/Latino
+132 (11.7)
+Non-Hispanic/Non-Latino
+997 (88.2)
+Not Reported
+2 (0.2)
+Age (years)
+Mean (Standard Deviation)
+13.6 (1.1)
+Median (Minimum, Maximum)
+14.0 (12. 15)
+Baseline SARS-CoV-2 status
+Positive
+46 (4 1)
+Negative
+1083 (95.8)
+Missing
+2 (0.2)
+Source: Table 11 of Interim Clinical Stud Report.
+Placebo
+N=1129 n (%)
+-
+585 (51.8)
+544 (48.2)
+-
+962 (85.2)
+57 (5.0)
+3 (0.3)
+71 (6.3)
+0
+29 (2.6)
+7 (0.6)
+-
+130 (11.5)
+996 (88.2)
+3 (0.3)
+Total
+N=2260 n (%)
+-
+1152 (51.0)
+1108 (49.0)
+-
+1932 (85.5)
+109 (4.8)
+7 (0.3)
+143 (6.3)
+3 (0.1)
+53 (2.3)
+13 (0.6)
+13.6 (1.1)
+14.0 (12, 15)
+262 (11.6)
+1993 (88.2)
+5 (0.2)
+-
+13.6 (1.1)
+14.0 (12, 15)
+50 (4.4)
+1078 (95.5)
+1 (0.1)
+96 (4.2)
+2161 (95.6)
+3 (0.1)
+6.1.11 Efficacy Analyses
+6.1.11.1 Analyses of Immunogenicity Endpoints
+Table 4 presents the immunobridging analysis of GMR at 28 days after Dose 2 in the Evaluable Immunogenicity Population without evidence of SARS-CoV-2 infection up to 1 month post Dose 2. The GMR comparing 12 to 15 year-old GMTs to 16 to 25 year-old
+GMTs was 1.77 (95% CI: 1.50 to 2.09), meeting the prespecified success criterion.
+Table 4. Geometric Mean Titer Ratio - Evaluable Immunogenicity Population
+Group
+GMT (95% CI)
+GMT (95% CI)
+12-15 Years of Age
+16-25 Years of Age
+N=190
+N=170
+BNT16262
+1253.6 (1117.7, 1406.1)
+708.1 (625.9, 801.1)
+GMR (95% CI)
+12-15 Years/16-
+25 Years
+1.77 (1.50, 2.09)
+N=number of participants with available titer at I month after Dose 2.
+Source: Summarized by the reviewer based on response to March 7, 2022 information request.
+Page 10
+
+Statistical Review
+STN: 125742/45
+Table 5 presents descriptive analysis results for the SR difference. Overall, 97.2% and 96.8% of adolescents and young adults, respectively, in the Evaluable Immunogenicity Population without evidence of SARS-CoV-2 infection achieved seroresponse, resulting in an SRR difference of 0.4% (95% CI: -4.2% to 5.5%).
+Table 5. Seroresponse Rate Difference - Evaluable Immunogenicity Population
+Group
+Seroresponse
+Seroresponse
+n (%, 95% CI)
+n (%,95% CI)
+12-15 Years of Age
+16-25 Years of Age
+N=143
+N=124
+BNT16262
+139 (97.2)
+120 (96.8)
+Seroresponse %
+Difference (95% CI)
+12-15 Years Minus 16-25
+Years
+0.4(-4.2,5.5)
+(93.0, 99.2)
+(91.9, 99.1)
+N=number of participants with available titer before vaccination and at I month after Dose 2. n=number of participants achieving seroresponse at I month after Dose 2.
+Source: Summarized by the reviewer based on response to March 7, 2022 information request.
+Reviewer comment:
+Analyses of GMR and SRR difference based on the same population were used to support the May 10, 2021 EUA. Of note, the applicant discovered that the assay LLO9 should have been 41 instead of in the submitted datasets. The results presented in Tables 4 and 5 reflect the updated LLOQ.
+6.1.11.2 Analyses of Efficacy Endpoints
+In the Evaluable Efficacy Population without evidence of SARS-CoV-2 infection, 28
+COVID-19 cases among placebo recipients and none among BNT16262 recipients were observed during blinded follow-up from 7 days post Dose 2 to the September 2, 2021
+cutoff (Table 6), resulting in a VE point estimate of 100% (95% CI: 86.8% to 100%). A similar VE was observed among participants with or without evidence of infection (VE=100%; 95% CI: 87.5% to 100%). These analyses were based on a median follow-up of 4.4 months post Dose 2.
+Figure 1 shows the cumulative incidence of COVID-19 in the Dose 1 All-Available
+Efficacy Population, where 48 cases in the placebo group and 3 cases in the BNT162b2 group were observed during blinded follow-up starting after Dose 1 (VE=94.0%; 95% CI: 81.3% to 98.8%). All 3 cases from BNT16262 recipients occurred prior to Dose 2.
+No protocol-defined severe COVID-19 was observed in either group as of the cutoff.
+Page 11
+
+Statistical Review
+STN: 125742/45
+Table 6. Efficacy by Population and Time Period
+Population/Surveillance Period
+BNT162b2 n (1000-py)
+N=1057
+Placebo n (1000-py)
+N=1030
+VE (95% CI)
+Evaluable Efficacy Population without evidence of infection
+>7 davs after Dose 2
+>7 davs to <2 months after Dose 2
+>2 months to <4 months after Dose 2
+>4 months after Dose 2
+Evaluable Efficacy Population with or
+0 (0 343)
+0 (0.138)
+0 (0.148)
+0 (0.057)
+N=1119
+28 (0.322)
+15 (0.133)
+10 (0.139)
+3 (0.050)
+N=1109
+100.0 (86.8, 100.0)
+100.0 (73.2, 100.0)
+100.0 (58.0, 100.0)
+100.0 (-112.1, 100.0)
+-
+without evidence of infection
+>7 davs after Dose 2
+>7 days to <2 months after Dose 2
+>2 months to <4 months after Dose 2
+>4 months after Dose 2
+Dose 1 All-Available Efficacy
+0 (0.362)
+0 (0.146)
+0 (0.155)
+0 (0.061)
+N=1131
+30 (0.345)
+17 (0.142)
+10 (0.148)
+3 (0.055)
+N=1129
+100.0 (87.5, 100.0)
+100.0 (76.4, 100.0)
+100.0 (57.4, 100.0)
+100.0 (-117.8, 100.0)
+Population
+After Dose 1
+3 (0.450)
+48 (0.434)
+Dose 1 to before Dose 2
+3 (0.065)
+12 (0.065)
+Dose 2 to <7 davs after Dose 2
+0 (0.021)
+5 (0.021)
+≥7 days after Dose 2
+0 (0.364)
+31 (0.348)
+94.0 (81.3, 98.8)
+75.1 (7.6, 95.5)
+100.0 (-8.7, 100.0)
+100.0 (87.9, 100.0)
+N=number of participants in the population; n=number of participants meeting the primary endpoint definition: py=person-vears of surveillance.
+Source: Tables 12, 13, and 15 of Interim Clinical Study Report.
+Fioure 1 Cumulative Incidence of COVTD-19 - Dose 1 All-Availahle Efficacy Penulation
+060
+0.055
+0.050
+0.045
+Cumulative Incidence of COVID-19 Occ
+0.030
+0.020
+0.010
+0.005
+0.000
+thieere at rick
+Dave After Dose 1
+Cumulative Number of Events
+A: BNT16262 (30 mg)
+R. Parenc
+Source: Figure I of Interim Clinical Study Report.
+Page 12
+
+Statistical Review
+STN: 125742/45
+6.1.11.3 Subpopulation Analyses
+Table 7 presents the subgroup efficacy analysis results for the Dose 1 All-Available Efficacy Population. Overall, high efficacy was observed regardless of sex or ethnicity and among White participants. The limited number of cases observed among non- White participants precludes meaningful interpretation of efficacy within this subgroup.
+Table 7. Efficacy Starting at Dose 1 by Subgroup - Dose 1 All-Available Efficacy Population
+Population/Surveillance Period
+BNT162b2
+-
+Male
+3 (0.227)
+Female
+0 (0.223)
+Race
+-
+White
+2 (0.384)
+Black or African American
+0 (0.024)
+Other
+1 (0.042)
+Ethnicity
+-
+Hispanic/Latino
+1 (0.055)
+Non-Hispanic/Non-Latino
+2 (0 394)
+Placebo
+I (1000-py)
+48 (0.434)
+-
+26 (0.223)
+22 (0.211)
+-
+45 (0.367)
+2 (0.026)
+1 (0.042)
+-
+11 (0.051)
+37 (0.382)
+VE (95% CI)
+n (1000-py)
+Overall
+3 (0.450)
+Sex
+94.0 (81.3, 98.8)
+-
+88.7 (63.0, 97.8)
+100.0 (82.7. 100.0'
+-
+95.8 (83.8, 99.5)
+100.0 (-479.7, 100.0)
+1.4 (-7638.0, 98.7)
+-
+91.6 (42.3, 99.8)
+94.8 (79.7, 99.4)
+n=number of participants meeting the primary endpoint definition. py=person-vears of surveillance.
+Source: Table 14.13 of Interim Clinical Study Report.
+Reviewer Comment:
+• The immunogenicity and efficacy data reported by the applicant were consistent with the Study Data Tabulation Model (SDTM) data.
+6.1.12 Safety Analyses
+Solicited Local and Systemic Reactions
+Table 8 shows the frequency by severity of each solicited local and systemic reaction within 7 days of each dose among adolescents. In general, incidence of any redness, swelling, injection site pain, fever, fatigue, headache, chills, vomiting, new or worsened muscle pain, and new or worsened joint pain was higher among BNT1622 recipients than among placebo recipients after either dose.
+Injection site pain, fatigue, and headache were the most frequently reported solicited adverse reactions. The incidences of solicited local reactions were slightly higher after Dose 1 than after Dose 2, while the incidences of solicited systemic reactions were generally higher after Dose 2 with the exception of vomiting and diarrhea.
+Among BNT162b2 recipients, the median onset day of solicited local reactions was Day 1 (i.e. day of vaccination) to Day 2 after either dose, with a median duration of 2 days.
+The median onset day of solicited systemic reactions was Day 2 to Day 3 after either dose, with a median duration of 1 to 2 days.
+Page 13
+
+Table 8. Frequency of Solicited Reactions Within 7 Days of each Dose
+BNT162b2
+Placebo
+Dose 1
+Dose 1
+N=1127
+N=1127
+n (%)
+n (%)
+Redness
+-
+-
+Any (>2.0 cm)
+65 (5.8)
+12 (1.1)
+Mild
+44 (3.9)
+11 (1.0)
+Moderate
+20 (1.8)
+1 (0.1)
+Severe
+1 (0.1)
+0 (0.0)
+Swelling
+Any (>2.0 cm)
+78 (6.9)
+11 (1.0)
+Mild
+55 (4.9)
+9 (0.8)
+Moderate
+23 (2.0)
+2 (0.2)
+Severe
+0 (0.0)
+0 (0.0)
+Pain at the injection site
+-
+-
+Any
+971 (86.2)
+263 (23.3)
+Mild
+467 (41.4)
+227 (20.1)
+Moderate
+493 (43.7)
+36 (3.2)
+Severe
+11 (1.0)
+0 (0.0)
+Fever
+-
+>38.0°C
+114 (10.1)
+12 (1.1)
+>38.0°C to 38.4°C
+74 (6.6)
+8 (0.7)
+>38 4°C to 38 9°C
+29 (2.6)
+2 (0.2)
+>38.9°C to 40.0°C
+10 (0.9)
+2 (0.2)
+>40.0°C
+1 (0.1)
+0 (0.0)
+Fatigue
+Any
+Mild
+Moderate
+Severe
+Headache
+Anv
+Mild
+Moderate
+Severe
+677(60.1)
+278 (24.7)
+384 (34.1)
+15 (1.3)
+-
+623 (55.3)
+361 (32.0)
+251 (22.3)
+11 (1.0)
+457 (40.6)
+250 (22.2)
+199 (17.7)
+8 (0.7)
+396 (35.1)
+256 (22.7)
+131 (11.6)
+9 (0.8)
+Chills
+Any
+Mild
+Moderate
+Severe
+Vomiting
+Any
+Mild
+Moderate
+Severe
+Diarrhea
+Anv
+Mild
+311 (27.6)
+195 (17.3)
+111 (9.8)
+5 (0.4)
+-
+31 (2.8)
+30 (2.7)
+0 (0.0)
+1 (0.1)
+-
+90 (8.0)
+77 (6.8)
+109 (9.7)
+82 (7.3)
+25 (2.2)
+2 (0.2)
+-
+10 (0.9)
+8 (0.7)
+2 (0.2)
+0 (0.0)
+-
+82 (7.3)
+72 (6.4)
+BNT162b2
+Dose 2
+N=1097 n (%)
+-
+55 (5.0)
+29 (2.6)
+26 (2.4)
+0 (0.0)
+54 (4.9)
+36 (3.3)
+18 (1.6)
+0 (0.0)
+-
+866 (78.9)
+466 (42.5)
+393 (35.8)
+7 (0.6)
+-
+215 (19.6)
+107 (9 8)
+83 (7.6)
+25 (2.3)
+0 (0.0)
+-
+726 (66.2)
+232 (21.1)
+468 (42.7)
+26 (2.4)
+-
+708 (64.5)
+302 (27.5)
+384 (35.0)
+22 (2.0)
+455 (41.5)
+221 (20 1)
+214 (19.5)
+20 (1.8)
+-
+29 (2.6)
+25 (2.3)
+4 (0.4)
+0 (0 0)
+-
+65 (5.9)
+59 (5.4)
+Statistical Review
+STN: 125742/45
+Placebo
+Dose 2
+N=1078 n (%)
+-
+10 (0.9)
+8 (0.7)
+2 (0.2)
+0 (0.0)
+-
+6 (0.6)
+4 (0.4)
+2 (0.2)
+0 (0.0)
+-
+193 (17.9)
+164 (15.2)
+29 (2.7)
+0 (0.0)
+7 (0.6)
+5 (0.5)
+1 (0.1)
+1 (0.1)
+0 (0.0)
+-
+264 (24.5)
+133 (12.3)
+127 (11.8)
+4 (0.4)
+-
+264 (24.5)
+170 (15.8)
+93 (8.6)
+1 (0.1)
+74 (6.9)
+53 (4.9)
+21 (1.9)
+0 (0.0)
+-
+12 (1.1)
+11 (1.0)
+1 (0.1)
+0 (0.0)
+44(4.1)
+39 (3.6)
+Page 14
+
+Statistical Review
+STN: 125742/45
+BNT162b2
+Dose 1
+N=1127 n (%)
+Moderate
+13 (1.2)
+Severe
+0 (0.0)
+Placebo
+Dose 1
+N=1127 n (%)
+10 (0.9)
+0 (0.0)
+BNT162b2
+Dose 2
+N=1097 n (%)
+6 (0.5)
+0 (0 0)
+New or worsened muscle pain
+-
+-
+Any
+272 (24.1)
+148 (13.1)
+355 (32.4)
+Mild
+125 (11.1)
+88 (7.8)
+152 (13.9)
+Moderate
+145 (12.9)
+60 (5.3)
+197 (18.0)
+Severe
+2 (0.2)
+0 (0.0)
+6 (0.5)
+New or worsened joint pain
+-
+-
+-
+Any
+109 (9.7)
+77 (6.8)
+173 (15.8)
+Mild
+66 (5.9)
+50 (4.4)
+91 (8.3)
+Moderate
+42 (3.7)
+27 (2.4)
+78 (7.1)
+Severe
+1 (0.1)
+0 (0.0)
+4 (0.4)
+Antipyretic use
+413 (36.6)
+111 (9.8)
+557 (50 .8)
+Placebo
+Dose 2
+N=1078 n (%)
+5 (0.5)
+0 (0.0)
+-
+90 (8.3)
+51 (4.7)
+37 (3.4)
+2 (0.2)
+-
+51(4.7)
+30 (2.8)
+21 (1.9)
+0 (0.0)
+95 (8.8)
+N=number of subjects responding yes or no for any reaction within 7 days of dosing. n=number of subiects with the specified reaction.
+Source: Summarized by the reviewer based on response to March 14, 2022 information request.
+Unsolicited Adverse Events
+Tables 9 and 10 present the numbers and percentages of adolescent participants who reported any unsolicited AE, SAE, nonserious AE, or AE leading to withdrawal after Dose 1. These numbers are reported for three separate risk windows: 1) Dose 1 to 1 month post Dose 2, 2) Dose 1 to 6 months post Dose 2, unblinding, or the September 2, 2021 data cutoff, whichever was earlier, and 3) unblinding to the cutoff.
+The percentages of subjects who reported any AE were similar between BNT1622 and placebo recipients from Dose 1 to 1 month after Dose 2, while a slightly higher percentage of placebo recipients reported any AE from Dose 1 to 6 months after Dose 2.
+A higher percentage of BNT162b2 recipients reported any A considered by the investigator to be related to the study intervention in both risk windows. A total of 10
+(0.9%) BNT16262 recipients and 2 (0.2%) placebo recipients reported any SAE up to 6 months post Dose 2, none of which was considered by the investigator to be related to the study intervention. No participants died as of the cutoff. The median duration of blinded follow-up after Dose 2 was approximately 4.4 months among all participants.
+A total of 1,010 subjects who originally received placebo received at least 1 dose of BNT162b2 after unblinding prior to the September 2, 2021 cutoff. Among these subjects, 6 (0.6%) reported any SAE, of whom a 12 year-old female participant reported an SAE of appendicitis 3 days after the second crossover dose that was considered by the investigator to be related to vaccination. The median duration of follow-up after unblinding was approximately 4 months among all unblinded participants.
+Page 15
+
+Statistical Review
+STN: 125742/45
+Table 9. Number of Subjects Reporting at Least 1 A by Time Period - Safety Population
+BNT162b2
+Placebo
+BNT162b2
+1 Month Post
+1 Month Post
+6 Months Post
+Dose 2 or
+Dose 2 or
+Dose 2 or
+Unblinding
+Unblinding
+Unblinding
+N=1131
+N=1129
+N=1131
+n (%)
+n (%)
+n (%)
+Any AE
+74 (6.5)
+77 (6.8)
+95 (8.4)
+Related
+36 (3.2)
+24 (2.1)
+36 (3.2)
+Severe
+7 (0.6)
+2 (0.2)
+13 (1.1)
+Life-Threatening
+1 (0.1)
+1 (0.1)
+2 (0.2)
+Anv SAE
+4 (0.4)
+1 (0.1)
+10 (0.9)
+Related
+O
+O
+0
+Severe
+2 (0.2)
+O
+7 (0.6)
+Life-Threatening
+0
+1 (0.1)
+1 (0.1)
+Any nonserious AE
+72 (6.4)
+76 (6.7)
+89 (7.9)
+Related
+36 (3.2)
+24 (2.1)
+36 (3.2)
+Severe
+5 (0.4)
+2 (0.2)
+6 (0.5)
+Life-Threatening
+1 (0.1)
+O
+1 (0.1)
+Any AE leading to withdrawal
+1 (0.1)
+0
+1 (0.1)
+N=number of subjects who received at least I dose of the study intervention. n=number of subjects reporting at least I event.
+Source: Adapted from Table P of 508 Tables and Table 18 of Interim Clinical Study Report.
+Placebo
+6 Months Post
+Dose 2 or
+Unblinding
+N=1129 n (%)
+113 (10.0)
+24 (2.1)
+5 (0.4)
+1 (0.1)
+2 (0.2)
+O
+1 (0.1)
+1 (0.1)
+111 (9.8)
+24 (2.1)
+4 (0.4)
+0
+O
+Table 10. Number of Subjects Reporting at Least 1 A After Unblinding - Safety Population
+BNT16262
+Placebo - BNT162b2
+Unblinding to Cutoff
+Crossover to Cutoff
+N=1107
+N=1010
+n (%)
+n (%)
+Any AE
+18 (1.6)
+265 (26.2)
+Related
+4 (0.4)
+242 (24.0)
+Severe
+3 (0.3)
+12 (1.2)
+Life-Threatening
+0
+Any SAE
+4 (0.4)
+Related
+O
+Severe
+1 (0.1)
+6 (0.6)
+1 (0.1)
+3 (0.3)
+Life-Threatening
+0
+An nonserious AE
+14 (1.3)
+Related
+4 (0.4)
+Severe
+2 (0.2)
+Life-Threatening
+0
+Any AE leading to withdrawal
+0
+262 (25 9)
+241 (23.9)
+9 (0.9)
+0
+0
+N=number of subjects who received at least I dose of the study intervention. n=number of subjects reporting at least I event.
+Source: Tables 25 and 35 of Interim Clinical Study Report.
+Reviewer Comments:
+• The solicited and unsolicited AEs reported in the interim clinical study report were consistent with the SDTM data.
+Page 16
+
+Statistical Review
+STN: 125742/45
+Myocarditis and Pericarditis
+No myocarditis or pericarditis was reported during blinded follow-up. One SAE of myocarditis was identified in a 15-year-old male participant 2 days after receiving the second crossover vaccination dose of BNT16262.
+7. INTEGRATED OVERVIEW OF EFFICACY
+No integrated analysis of efficacy was performed.
+8. INTEGRATED OVERVIEW OF SAFETY
+No integrated analysis of safety was performed.
+9. ADDITIONAL STATISTICAL ISSUEs
+There are no additional statistical issues.
+10. CONCLUSIONS
+10.1 Statistical Issues and Collective Evidence
+No major statistical issues affecting study conclusions were identified for the immunogenicity, efficacy and safety data. The prespecified immunobridging success criterion comparing 12 to 15 year-old neutralizing GMTs to 16 to 25 year-old GMTs from Study C4591001 was met (GMR=1.77; 95% CI: 1.50 to 2.09). High efficacy against protocol-defined COVID-19 was observed among participants in the Evaluable Efficacy Population without evidence of prior SARS-CoV-2 infection starting at 7 days post Dose 2 (VE=100%; 95% CI: 86.8% to 100%) and among participants in the Dose 1 All-Available Efficacy Population starting after Dose 1 (VE=94.0%; 95% CI: 81.3% to 98.8%). The lack of observed severe COVID-19 precludes assessment of efficacy against severe disease in this population.
+The frequency and severity of local and systemic reactions were generally higher among
+BNT16262 recipients than among placebo recipients after either dose. The most commonly reported adverse reactions were injection site pain, fatigue, and headache.
+There was no notable difference in the frequencies of any unsolicited A between arms during blinded follow-up, while a higher percentage of BNT162b2 recipients reported any SAE (0.9%) compared to placebo recipients (0.2%). Of note, no SAE reported during blinded follow-up was considered by the investigator to be related to the study intervention. No participants died as of the cutoff. One SAE of myocarditis was reported in a 15-year-old male participant 2 days after receiving the second crossover vaccination dose of BNT16262. One SAE of appendicitis in a 12-year-old female participant was reported 3 days after the second crossover dose and was considered by the investigator to be related to the study vaccination.
+Page 17
+
+Statistical Review
+STN: 125742/45
+10.2 Conclusions and Recommendations
+Overall, the clinical data support the effectiveness of BNT162b2. While there is some reactogenicity associated with BNT16262, the majority of solicited adverse reactions were mild or moderate in severity and of short duration. I defer to the clinical reviewer, Dr. Susan Wollersheim, on the overall safety conclusion for BNT162b2.
+Page 18
+

requirements.txt

@@ -0,0 +1,5 @@
+openai
+gradio
+langchain
+chromadb
+tiktoken