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+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+BLA Clinical Review Memorandum*
+Application Type
+Biologics License Application (BLA)
+STN
+125742/0
+CBER Received Date
+May 18, 2021
+PDUFA Goal Date
+January 16, 2022
+Division / Office
+DVRPA / OVRR
+Priority Review (Yes/No)
+Yes
+Reviewer Name(s)
+Susan Wollersheim, MD
+Ann Schwartz, MD
+Review Completion Date /
+August 23, 2021
+Stamped Date
+Supervisory Concurrence
+Lucia Lee, M.D.; Team Leader
+CRB1/DVRPA/OVRR
+Maria Allende, M.D.; Chief,
+CRB1/DVRPA/OVRR
+Applicant
+BioNTech Manufacturing GmbH (in partnership with Pfizer, Inc.)
+Established Name COVID-19 Vaccine. mRNA
+(Proposed) Trade Name
+COMIRNATY
+Pharmacologic Class Vaccine
+Formulation, including Adjuvants Each 0.3 mL dose contains 30ug modified
+mRNA encoding SARS-CoV-2 spike glycoprotein, encapsulated in lipid nanoparticles (LNP)
+Dosage Form and Route of
+Suspension for intramuscular iniection
+Administration
+Dosing Regimen
+Two 0.3 mL doses, 3 weeks apart
+Indication(s) and Intended
+Active immunization to prevent coronavirus
+Population(s)
+disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2
+(SARS-CoV-2) in individuals 16 years of age and older
+Orphan Designated (Yes/No) No
+*Updated version of the previously uploaded memo corrected to add safety information to Sections 6.1.12. 2, 6.1.12.4, and 6.1.12.7 that was inadvertently omitted but does not change overall conclusions.
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+TABLE OF CONTENTS
+GLOSSARY .........
+..4
+1. EXECUTIVE SUMMARY...
+1.1 Demographic Information: Subgroup Demographics and Analysis Summary.................... 7
+1.2 Patient Experience Data .....................
+…....5
+....................... &
+2. CLINICAL AND REGULATORY BACKGROUND.
+........................................................ 9
+2.1 Disease or Health-Related Condition(s) Studied..
+....9
+2.2 Currently Available, Pharmacologically Unrelated Treatments)/Intervention(s) for the Proposed Indication(s).
+2.3 Safety and Efficacy of Pharmacologically Related Products
+2.4 Previous Human Experience with the Product (Including Foreign Experience)
+2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the Submission. 13
+2.6 Other Relevant Background Information
+... 10
+.... 11
+...12
+.... 14
+3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES ................................................... 14
+3.1 Submission Quality and Completeness...
+3.2 Compliance With Good Clinical Practices And Submission Integrity
+3.3 Financial Disclosures
+... 14
+... 15
+... 15
+4. SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES....... 16
+4.1 Chemistry, Manufacturing, and Controls .....
+4.2 Assay Validation....................
+4.3 Nonclinical Pharmacology/Toxicology ........
+4.5 Statistical........
+4.6 Pharmacovigilance............
+4.7 Risk-Benefit Assessment................
+....... 16
+................ 1 6
+.............. 16
+................. 1 6
+........ 16
+........ 17
+5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW ... 18
+5.1 Review Strategy.......
+5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review
+5.3 Overview of Clinical Studies
+5.4 Consultations
+5.4.1 Advisory Committee Meeting
+5.5 Literature Reviewed ....
+18
+... 19
+.... 20
+21
+21
+21
+6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS..
+6.1 Study C4591001
+6.1.1 Objectives and Endpoints....
+6.1.2 Design Overview
+6.1.3 Population......
+6.1.4 Study Treatments or Agents Mandated by the Protocol
+6.1.5 Directions for Use
+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 Analvses ....
+6.1.12 Safety Analyses......
+6.1.13 Study Summary and Conclusions.
+....23
+23
+24
+24
+26
+27
+27
+27
+27
+29
+30
+31
+43
+56
+..... 81
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+6.2 Study BNT162-01.
+7. INTEGRATED OVERVIEW OF EFFICACY
+8. INTEGRATED OVERVIEW OF SAFETY ........
+9. ADDITIONAL CLINICAL ISSUES...............
+9.1 Special Populations.
+9.1.1 Human Reproduction and Pregnancy Data
+9.1.2 Use During Lactation.
+9.1.3 Pediatric Use and PREA Considerations
+9.1.4 Immunocompromised Individuals
+9.1.5 Geriatric Use.
+9.1.6 Patients with Human Immunodeficiency Virus (HIV) Infection
+10. CONCLUSIONS..
+11. RISK-BENEFIT CONSIDERATIONS AND RECOMMENDATIONS
+11.1 Risk-Benefit Considerations.
+11.2 Risk-Benefit Summary and Assessment
+11.3 Discussion of Regulatory Options
+11.4 Recommendations on Regulatory Actions
+11.5 Labeling Review and Recommendations
+11.6 Recommendations on Postmarketing Actions.
+APPENDIX A CHARLSON COMORBIDITY INDEX .......
+STN:125742
+....82
+........... 83
+...........83
+......... 83
+.... 83
+...83
+.... 85
+... 85
+....85
+.... 86
+...... 86
+...92
+...... 94
+...94
+..98
+100
+..101
+..... 101
+..101
+....... 103
+APPENDIX B CARDIAC DISORDERS FROM DOSE 1 TO DATE OF UNBLINDING AMONG PHASE
+2/3 PARTICIPANTS 16 YEARS OF AGE AND OLDER.......
+..................................... 104
+APPENDIX C DEATH NARRATIVES ...........
+......... 106
+
+GLOSSARY
+AE
+AESI
+BLA
+BNT162b2
+CBER
+CDC
+CI
+СМС
+COVID-19
+DVT
+EUA
+FDA
+FDCA
+§필
+ICU
+IRC
+IRR
+LNP
+MedDRA
+MIS-A
+MIS-C
+NAAT
+PD
+PE
+PMC
+PMR
+PREA
+PT
+PVP
+RT-PCR
+SAE
+SARS-CoV-2
+SMQ
+SOC
+Th1
+TTS
+US
+VAERS
+VE
+VOC
+VOI
+VRBPAC
+VSD
+WHO
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+adverse event
+adverse event of special interest
+Biologics License Application
+Pfizer-BioNTech COVID-19 Vaccine
+Center for Biologics Evaluation and Research
+Centers for Disease Control and Prevention
+confidence interval
+chemistry, manufacturing, and controls coronavirus disease 2019 deep vein thrombosis emergency use authorization Food and Drug Administration
+Federal Food, Drug, and Cosmetic Act human immunodeficiency virus interim analysis intensive care unit
+Internal Review Committee incidence rate ratio lipid nanoparticle
+Medical Dictionary for Regulatory Activities multisystem inflammatory syndrome in children multisystem inflammatory syndrome in adults
+nucleic acid amplification-based test
+protocol deviation
+pulmonary embolism
+postmarketing commitment postmarketing requirement
+Pediatric Research Equitv Act
+Preferred Term
+Pharmacovigilance Plan
+reverse transcription-polymerase chain reaction
+serious adverse event
+severe acute respiratory syndrome coronavirus 2
+Standardised MedDRA Query
+System Organ Class
+T helper tvpe 1
+thrombosis with thrombocvtopenia syndrome
+United States
+Vaccine Adverse Event Reporting System
+vaccine efficacy
+variant of concern
+variant of interest
+Vaccines and Related Biological Product Advisory Committee
+Vaccine Safety Datalink
+World Health Organization
+4
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+1. Executive Summary
+BioNTech Manufacturing GmbH, Inc. submitted a Biologics License Application (BLA) for BNT162b2 (30 ug) vaccine (COMIRNATY) and is seeking an indication for active immunization to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older. The primary immunization series consists of 2 intramuscular doses administered 3 weeks apart.
+BNT162b2 contains SARS-CoV-2 spike glycoprotein (S) antigens encoded in RNA formulated in lipid nanoparticles (LNPs). The structural elements of BNT162b2 are modified for translation of the antigen-encoding RNA. Encapsulation of the vaccine mRNA into LPs has been done to (b) (4)
+Study C4591001, the main study to support the safety and efficacy of BNT162b2, is an ongoing multinational, randomized, clinical trial in a total of 44, 165 participants (22,085 BNT162b2, 22,080 saline placebo) 16 years of age and older. A primary objective was to evaluate the efficacy of BNT162b2 to prevent laboratory-confirmed symptomatic
+COVID-19 occurring 27 days after Dose 2 in participants without serological or virological evidence of past SARS-CoV-2 infection before and during the vaccination regimen. The central laboratory nucleic acid amplification-based test (NAAT) result is used for the case definition, with a NAAT test that is authorized under FDA emergency use authorization (EUA). Vaccine efficacy (VE) against severe disease was evaluated as a secondary endpoint. Planned safety analvses included evaluation of: 1) local reactions, systemic events, and antipyretic/pain medication use from Day 1 through Day 7 after each dose in a subset of participants (approximately 4,900 per treatment group);
+2) non-serious unsolicited adverse events from Dose 1 through 1 month after Dose 2 in all participants; 3) serious adverse events from Dose 1 through 6 months after Dose 2 in all participants; and deaths and related serious adverse events from Dose 1 through the end of the study in all participants.
+Efficacy and safety data accumulated in the study through November 14, 2020, which included median follow-up of 2 months after Dose 2, supported FDA's December 11, 2020 issuance of an EUA for use of BNT162b2 in individuals 16 years of age and older.
+Following issuance of the EUA, study participants 16 years of age and older were progressively unblinded to their treatment assignment (when eligible for vaccination per national and local public health prioritization recommendations), and placebo recipients could choose to receive BNT162b2 with continued active unblinded follow-up in the study. This BLA submission included updated efficacy analyses of COVID-19 cases accrued during blinded placebo-controlled follow-up through March 13, 2021, representing up to 6 months of follow up after Dose 2 for participants in the efficacy population. The median follow-up after Dose 2 of all participants in the blinded placebo-controlled period was 4.3 months. Updated safety analyses included in the BLA submission evaluated data accumulated in both blinded and unblinded follow-up through March 13, 2021. The BLA safety database included >12,000 study participants originally randomized to BNT162b2 who completed least 6 months of total safety follow-up after Dose 2.
+As of the March 13, 2021 data cutoff, the efficacy population 16 years of age and older who did not have evidence of SARS-CoV-2 infection through 7 days after the second dose included N=40,111 participants (19,993 BNT162b2, 20,118 placebo). The updated efficacy analyses showed that VE in preventing symptomatic COVID-19 occurring ≥7
+5
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+days after Dose 2 was 91.1% [95% CI 88.8, 93.1]) in participants without evidence of SARS-CoV-2 infection and 90.9% (95%CI 88.5, 92.8) in participants with or without evidence of SARS-CoV-2 infection. These results were consistent with the VE in the protocol-specified event-driven final analyses that supported issuance of the EUA (VE 95% and 94.6%, respectively). The updated analyses of VE against severe COVID-19 in preventing symptomatic COVID-19 occurring ≥7 das after Dose 2 was 95.3% (95% CI: 71.0%, 99.9%) in participants without evidence of SARS-CoV-2 infection and 95.3% (95% CI: 70.9%, 99.9%) in participants with or without evidence of SARS-CoV-2 infection. SARS-CoV-2 variants of concern identified from COVID-19 cases in this study included B.1.1.7 (Alpha) and B. 1.351 (Beta).
+The safety population at the March 13, 2021 data cutoff included 22,026 BNT162b2 recipients and 22,021 placebo recipients 16 years of age and older. During the placebo-controlled phase, the most commonly reported solicited adverse reactions in the BNT162b2 group were pain, redness and swelling at the injection site, fatigue, and headache. Adverse reactions other than solicited reactogenicity events identified from the clinical trial data include lymphadenopathy in regional proximity to the vaccination site and potentially Bell's Palsy (the latter from a small numerical imbalance of temporally associated events). A slight imbalance in hypersensitivity-related events was observed during the trial, and hypersensitivity reactions have been reported during post-authorization use as well. There were otherwise no notable patterns between treatment groups for specific categories of serious or non-serious adverse events (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2. A total of 15 (0.2%) deaths in vaccine recipients and 14 (0.2%) in placebo recipients were reported during blinded, placebo-controlled follow-up, and an additional 6 deaths were reported during unblinded follow-up following vaccination with BNT162b2; none of these deaths were assessed to be related to vaccination. A total of 42 pregnancies were reported by BNT162b2 recipients from Dose 1 through the data cutoff date. The frequencies of spontaneous abortion, miscarriage, and elective abortion were similar between the vaccine and the placebo groups.
+Post-authorization safe surveillance has identified two rare but serious adverse reactions: anaphylaxis and myocarditis/pericarditis. The risk of anaphylaxis associated with BNT162b2 appears to be similar in magnitude to the risk of anaphylaxis following approved preventive vaccines in general and can be managed with standard vaccination practices. The risk of myocarditis/pericarditis appears to be greatest in individuals under the age of 40, in particular in males following Dose 2, and increased with decreasing age. Although some cases required intensive care support, available data from short-term follow-up suggest that most individuals have had resolution of svmptoms with conservative management. Information is not vet available about potential long-term sequelae.
+To address the identified risk of myocarditis/pericarditis, FDA conducted a quantitative, age- and sex-stratified benefit-risk analysis, using healthcare claims and CDC surveillance databases, to evaluate the balance of vaccine benefits (prevention of COVID-19 hospitalizations, intensive care unit admissions and deaths) against excess risk of mvocarditis/pericarditis under various conditions of COVID-19 incidence and vaccine effectiveness informed by real-world data. These analyses supported that based on current understanding of vaccine-associated myocarditis/benefits of vaccination would outweiah risks of mvocarditis/pericarditis for individuals 16 vears of
+6
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+age and older under all conditions examined. Mitigation of the observed risks of myocarditis/pericarditis and associated uncertainties will be accomplished through labeling (including warning statements about the risks of vaccine-associated myocarditis/pericarditis) and through continued safety surveillance and postmarketing studies to be conducted by the Applicant, US government agencies (including FDA and CDC), and other healthcare stakeholders.
+The clinical data submitted exceed FDA's expectations for data to support licensure of vaccines for prevention of COVID-19, including relevant efficacy success criteria and numbers of vaccinated study participants and follow-up time (i.e., at least 3,000 vaccinated participants in each age group with at least 6 months of total safety follow-up) for an acceptable safety database. The clinical data submitted in this application, together with the quantitative benefit-risk assessment summarized in this review, support approval of BNT1622 for the indication of active immunization to prevent symptomatic coronavirus disease 2019 (COVID 19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older.
+Pediatric studies of BNT162b2 in children <16 years of age, as required by the Pediatric Research Equity Act, were deferred for this application and will be completed after approval of BNT162b2 for use in individuals 16 ears of age and older. The Applicant also committed to conduct additional postmarketing safety studies, including the assessment of pregnancy and infant outcomes following immunization with BNT162b2 during pregnancy.
+1.1 Demographic Information: Subgroup Demographics and Analvsis Summary
+The table below summarizes demographic representation of study participants who enrolled in the Phase 2/3 portion of the ongoing study C4591001 and were randomized to a two-dose series of BNT162b2 or placebo.
+Table 1. Randomized Participants by Subgroup, Study C4591001
+Subgroup
+BNT162b2
+Placebo
+Total
+Age (≥16 vears)
+22085
+22080
+44165
+16-55 vears
+13104
+13132
+26236
+>55 vears
+8981
+8948
+17929
+16-17 vears
+378
+377
+755
+Gender
+Male
+11357
+11127
+22484
+Female
+10728
+10953
+21681
+Ethnicity
+Hispanic/Latino
+Non- Hispanic/Non-Latino
+Not reported
+5715
+16259
+111
+5710
+16256
+114
+11425
+32515
+225
+Race
+White
+Black/African American
+All others
+18106
+2106
+1873
+18105
+4232
+1849
+36211
+4232
+3722
+Source: FDA-generated table.
+The demographic characteristics of the valuable efficacy population of 42,244 participants was 83% White, 50.9% male, and 74.7% non-Hispanic/non-Latino ethnicity.
+The younger age group (16-55 years of age) represented 55.8% of the total evaluable efficacy population, while participants >55 years of age represented 39.5% of the total.
+7
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+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.
+The overall safety population was 49.1% female, 50.9% males, 25.6% Hispanic/Latino, 82.0% White, 9.6% African American, 4.3% Asian, <3% other racial groups. The median age was 51 years, and 20.8% were older than 65 years old. The most frequently reported comorbidities were obesity (35.1%), diabetes without chronic complications (7.8%) and chronic pulmonary disease (7.8%). Geographically, enrollment included individuals from the United States (US; 76.5%), Argentina (15.3%), Brazil (6.1%), South Africa (2.0%), Turkey (1.0%), and Germany (1.0%). In safety analyses, reported rates of solicited local and systemic As and antipyretic/pain medication use in the 7 days after BNT162b2 vaccinations were generally lower among older adults (>55 years of age) compared with younger adults and adolescents (16-55 years of age). Other differences between the age groups in overall rates and types of unsolicited As and SAEs largely reflected differences in underlying medical conditions between the respective age groups (as these As were assessed as related to the underlying medical conditions rather than to the vaccine). No clinically meaningful differences in the occurrence of solicited AEs, unsolicited As or SAEs were observed by, ethnicity, race, or sex subgroups.
+1.2 Patient Experience Data
+Data Submitted in the Application
+Check if
+Submitted
+Section Where Discussed, if Applicable
+П
+П
+П
+П
+X
+Type of Data
+Patient-reported outcome
+Observer-reported outcome
+Clinician-reported outcome
+Performance outcome
+Patient-focused drug development meeting summary
+FDA Patient Listening Session
+Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel)
+Observational surve studies
+Natural historv studies
+Patient preference studies
+Other: (please specifv)
+If no patient experience data were submitted
+NIA
+by Applicant, indicate here.
+8
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Section Where Discussed, if Applicable
+Check if
+Considered Type of Data
+Perspectives shared at patient stakeholder meeting
+O
+П
+Patient-focused drug development meeting
+FDA Patient Listening Session
+Other stakeholder meeting summary report
+П
+"
+Observational survey studies
+Other: (please specify)
+2. Clinical and Regulatory Background
+2.1 Disease or Health-Related Condition(s) Studied
+COVID-19 is an infectious disease caused by SARS-CoV-2, a novel, zoonotic coronavirus, which can cause severe respiratory symptoms, pneumonia, respiratory failure, multi-organ failure, and death. 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, leading to multiorgan failure and death. Elderly individuals (in particular men >60 years of age) and those with several underlying medical conditions, including obesity, diabetes, asthma, chronic kidney disease, hypertension, and immunosuppression, have been reported to be at increased risk for severe illness from COVID-19. Multisystem inflammatory syndrome in both children (MIS-C) and adults (MIS-A) is a rare but serious COVID-19-associated condition that can present with persistent fever, laboratory markers of inflammation and heart damage, and, in severe cases, hypotension and shock (CDC 2021a; CDC Advisory Committee on Immunization Practices 2021a).
+The first recorded COVID-19 cases were reported in December 2019 in Wuhan, China.
+During January 2020 cases were reported from several other countries, including the United States. The first case report of novel coronavirus 2019 (2019-nCov) in the United States was published on January 31, 2020 in the New England Journal of Medicine (Holshue et al. 2020). On January 31, 2020, the United States Secretary of Health and Human Services 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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to present a challenge to global health and, at the time of this review, has caused approximately 209 million cases of COVID-19, including 4.4 million deaths worldwide (World Health Organization 2021a). In the United States (US), more than 37 million cases have 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 variants has caused significant challenges and disruptions worldwide to healthcare systems, economies, and many aspects of human activity (travel, employment, education). Socioeconomic effects of the pandemic are exacerbating health and societal disparities that disproportionately affect historically disadvantaged groups, and appear to be leading to widening inequality (CDC 2021b).
+9
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+As such, the COVID-19 pandemic has disproportionately affected individuals of racial and ethnic minority groups, including African American and Hispanic/ Latino groups (CDC 2021c).
+The emergence of SARS-CoV-2 variants with multiple mutations in the SARS-CoV-2 spike (S) protein in India (B1.617 lineage [B1.617.2 delta variant]), the United Kingdom (B.1.1.7 lineage [alpha variant]), Brazil (P.1 lineage [gamma variant]), and South Africa
+(B. 1.351 lineage [beta variant]), has raised concerns regarding increased transmission rates; at the time of this review, these variants of concern account for 82.2%, 9.0%, 3.8% and 0.1%, respectively, of SARS-CoV-2 lineages circulating in the US (CDC
+2021d).
+Since December 2020, COVID-19 vaccines have been available in the United States under EUA. As of August 15, 2021, among more than 168 million fully vaccinated individuals in the U.S., 6,239 hospitalizations and 1,263 deaths due to vaccine breakthrough have been reported by passive surveillance. Of hospitalized or fatal breakthrough cases, 74% occurred among individuals 65 years of age and older.
+Despite the occurrence of breakthrough cases in vaccinated individuals, according to current data, vaccination elicited protection against severe disease, hospitalization, and death remains high. COVID-19 cases, and in particular severe cases, hospitalizations, and deaths, remain overwhelmingly among unvaccinated individuals. Increasing representation of vaccinated individuals among mild to moderate COVID-19 cases is likely due in part to increasing uptake of the vaccine (which is not 100% protective), although waning immunity and/or decreased vaccine effectiveness against the delta variant may be contributing. Surveillance is ongoing to assess the impact of new variants on vaccine effectiveness. Vaccine clinical research and epidemiological surveillance are ongoing to assess durability of protection and parameters to determine whether and when there would be a need for a booster dose.
+2.2 Currently Available, Pharmacologically Unrelated Treatments)/Intervention(s) for the Proposed Indication(s)
+Remdesivir is the only product currently approved by the FDA for use in adults and pediatric patients 12 years of age and older for treatment of COVID-19 requiring hospitalization. Prior to its approval, remdesivir was authorized for emergency use in adults and pediatric patients and remains authorized for emergency use in hospitalized pediatric patients who are not included in the indicated population under licensure.
+Emergency use authorizations of COVID-19 pharmacological products for post-exposure prophylaxis and/or treatment of COVID-19 are as follows:
+10
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 2. Emergency Use Authorized Pharmacological Products for Post-exposure
+Prophylaxis and/or Treatment of COVID-19
+Product
+Date of EUA
+Authorized Use and Population
+SARS-Cov-2-targeting
+Monoclonal Antibodies
+• Bamlanivimab/etesevimab
+Reissued February
+25, 2021
+• Sotrovimab
+May 26, 2021
+• Casirivimab/imdevimab
+Reissued July 30,
+2021
+Antiviral Drugs
+• Remdesivir
+Reissued October 22, 2020 (following
+FDA approval in adults and some pediatric patients)
+Immune Modulators
+• Baricitinib
+All three products are indicated for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients 12 ears and older at high risk for progressing to severe COVID-1ga
+Casirivimab/imdevimab is also authorized for post-exposure prophylaxis (prevention) for COVID-19 in patients at high risk for progressing to severe COVID-19b
+Treatment of COVID-19 in hospitalized pediatric patients weighing at least 3.5 kg to <40 kg, or <12 years of age weighing at least 3.5 kg, or ≥12 years and weighing at least 40 kg
+11/19/2020
+Treatment of COVID-19 in hospitalized patients receiving
+• Actemra
+06/24/2021
+systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO
+COVID-19 Convalescent
+Reissued March 9,
+Treatment of hospitalized patients
+Plasma
+2021
+with COVID-19
+a Indicated for adults and pediatric patients 12 years of age and older weighing at least 40 kg
+b Indicated for adults and pediatric patients 2 years and older
+CMO extracorporal membrane oxygenation, EUA emergency use authorization
+Source: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency use-authorization#coviddrugs Accessed August 2, 2021.
+2.3 Safety and Efficacy of Pharmacologically Related Products
+At present, no vaccine is approved by the FDA for prevention of COVID-19. The FDA has issued EUAs for three COVID-19 vaccines to mitigate the SARS-CoV-2 pandemic.
+11
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 3. Emergency Use Authorized Vaccines to Prevent COVID-19
+Applicant
+Regimen
+Population
+Pfizer/BioNTech 2 doses 3 weeks
+Individuals ≥16 years of age
+apart
+Individuals ≥12 years of age
+Pfizer/BioNTech
+Certain
+3rd dose
+immunocompromiseda individuals ≥12 years of age
+Moderna
+2 doses 4 weeks
+Adults ≥18 years of age
+apart
+Date of EUA and Amendments
+December 11, 2020
+EUA Amendment: May 10, 2021
+EUA Amendment: August 12,
+2021
+December 18, 2020
+Moderna
+Certain
+3rd dose
+immunocompromiseda
+EUA Amendment: August 12, 2021
+individuals ≥18 ears of age
+Janssen
+Single dose
+Adults 218 years of age
+February 27, 2021
+a Solid organ transplantation, or who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise
+Moderna COVID-19 mRNA vaccine
+In an ongoing Phase 3 study that enrolled participants ≥18 year of age (n=~14,000 vaccine, n=~14,000 placebo), VE was 94.1% to prevent PCR-confirmed COVID-19 occurring at least 14 days after completion of a 2-dose regimen. Common solicited adverse reactions after vaccination were injection site reactions, headache, fatigue, muscle aches, and nausea, which were generally mild to moderate and lasted 1-2 days (FDA 2020a). At the time of this review, more than 142 million doses of the Moderna COVID-19 vaccine have been administered in the US (CDC 2021). Consistent with Phase 3 trials, real-world efficacy of mRNA vaccines has been demonstrated to be about 90% (Pawlowski et al. 2021; Thompson et al. 2021). During post-EUA surveillance myocarditis and pericarditis, and rare cases of anaphylaxis, were reported after vaccination (CDC 2021e).
+Jansen COVID-19 replication-incompetent human adenovirus serotype 26 (Ad26)
+vector vaccine
+In an ongoing Phase 3 study that enrolled participants ≥18 year of age (n=~20,000 vaccine, n=~20,000 placebo), VE was 66.9% to prevent laboratory-confirmed, moderate-severe COVID19 occurring at least 14 days after a single dose. Common solicited adverse reactions were injection site pain, headache, fatigue, and myalgia, which were mostly mild and moderate. In the post-EUA surveillance period, thrombosis with thrombocytopenia syndrome (TTS) and Guillain-Barré svndrome were identified as rare, but serious adverse reactions following vaccination (CDC Advisory Committee on Immunization Practices 2021b).
+2.4 Previous Human Experience with the Product (Including Foreign Experience)
+Clinical trial experience
+EUA of the Pfizer-BioNTech COVID-19 Vaccine (also referred to as BNT1622) was based on the following data: In individuals ≥16 years of age enrolled in a Phase 2/3 portion of an ongoing study (n= ~22,000 vaccine, n=~22,000 placebo), vaccine efficacy (VE) was 95% to prevent PCR-confirmed COVID-19 occurring at least 7 days after completion of a 2-dose regimen. Common solicited adverse reactions after vaccination were injection site reactions, fatigue, headache, muscle pain, chills, and joint pain, which were generally mild to moderate and lasted a few davs. Vaccine effectiveness in participants 12-15 years of age (n=1,131 vaccine, n=1,129 placebo) was inferred by
+12
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+immunobridging, based on a comparison of SARS-CoV-2 50% neutralization antibody titers (SARS-CoV-2 mNG microneutralization assay) at 1 month after Dose 2, to participants 16-25 years of age, and supported by a supplemental efficacy analysis showing VE after 7 days post Dose 2 was 100% (95% CI 75.3; 100.0) without prior evidence of SARS-CoV-2 infection and 100% in participants with or without prior infection (FDA 2020b).
+Post-EUA
+As discussed in more detail above, since the issuance of the EUA, published observational studies have supported the effectiveness of BNT162b2 to prevent COVID-19, including high-level protection against severe disease, hospitalization, and death, although recent evidence suggests some decrease in vaccine effectiveness against mild to moderate disease since emergence of the delta variant in the US (CDC 2021f).
+During the post-EUA surveillance period, cases of myocarditis and pericarditis were reported after vaccination, as well as rare cases of anaphylaxis (CDC Advisory Committee on Immunization Practices 2021c; CDC 2021e).
+Please see CBER pharmacovigilance reviewer's memorandum for details about the Applicant's ongoing post-authorization studies and results of cumulative analvsis of post-authorization A reports received through February 28, 2021.
+2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the Submission
+Prior to BLA submission
+> EUA 27034
+• November 20, 2020: Submission of EU request for individuals ≥16 years of age
+• December 11, 2020: Issuance of EUA for individuals ≥16 years of age
+• April 9, 2021: Submission of EUA request for individuals 12-15 years of age
+• May 10, 2021: Issuance of EUA for individuals 12-15 years of age
+• June 25, 2021: EUA amendment to include warning statement and associated information regarding myocarditis and pericarditis in the Fact Sheet for Vaccination Providers and the Fact Sheet for Recipients and Caregivers
+• Major pre-submission BLA-associated regulatory activity
+• April 22, 2020: IND 19736 submission, first subject enrolled on April 29, 2020
+• June 11, 2020-July 6, 2020 Type C Meeting to discuss clinical development program, including revised Phase 1/2/3 Study C4591001 intended to support
+icensure
+• July 7, 2020: Fast Track Designation granted for individuals ≥18 years of age
+• November 18, 2020-April 2, 2021 Request for Comments and Advice re: Study
+C4591001 Placebo Participants
+• March 31, 2021: Pre-BLA meeting (chemistry, manufacturing, and controls [CMC])
+• March 9, 2021: Pre-BLA meeting (clinical)
+• April 16, 2021: plans for rolling BLA submission agreed upon between CBER and the Applicant
+13
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+• Major post-submission BLA regulatory activity
+• July 15, 2021: Priority review granted
+2.6 Other Relevant Background Information
+Relevant FDA guidance
+In June 2020, FDA published guidance on the Development and Licensure of Vaccines to Prevent COVID-19 (FDA 2020c). In October 2020, FDA published guidance on Emergency Use Authorization for Vaccines to Prevent COVID-19 (revised February
+2021) (FDA 2021a).
+Vaccines and Related Biological Products Advisory Committee (VRBPAC) meetings
+• On October 22, 2020, a VRBPAC meeting was held to discuss considerations for development, EUA and licensure of vaccines to prevent COVID-19. The VRBPAC committee endorsed the principles outlined in the June and October FDA guidance documents regarding safety and effectiveness data to support EUA and licensure and expectations for continued post-authorization and post-approval evaluation of COVID-19 vaccines.
+• On December 10, 2020, a VRBPAC meeting was held to discuss Pfizer-BioNTech's EUA request for their vaccine to prevent COVID-19 in individuals 16 years of age and older. The committee voted in favor of a determination that, based on the totality of scientific evidence available, the benefits of the vaccine outweighed its risks for use in individuals 16 years of age and older.
+Discussion topics included: (a) Pfizer-BioNTech's plan for an unblinded, placebo-controlled follow-up in ongoing trials, in the event that the vaccine were made available under EUA. Study participants 16 years of age and older were then progressively unblinded to their treatment assignment (when eligible per local recommendations), and placebo recipients could choose to receive BNT162b2; (b) scientific knowledge gaps and considerations for evaluation of vaccine safety and effectiveness in populations who would receive the Pfizer-BioNTech COVID-19
+Vaccine under an EUA: the VRBPAC committee 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 individuals with HIV and individuals with prior exposure to SARS-CoV-2.
+• An emerging signal for myocarditis and pericarditis following mRNA COVID-19 vaccines was discussed at FDA VRBPAC and CDC Advisor Committee on
+Immunization Practices meetings held on June 10, 2021. Based on the strength of evidence for a causal association, the Pfizer-BioNTech COVID-19 Vaccine EUA Fact Sheet was revised on June 25, 2021 to add a Warning for myocarditis and pericarditis, and the Pharmacovigilance Plan (PVP was amended to include myocarditis and pericarditis as important identified risks.
+3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES
+3.1 Submission Qualitv and Completeness
+The submission was adequately organized and integrated to accommodate the conduct of a complete clinical review.
+14
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+3.2 Compliance With Good Clinical Practices And Submission Integrity
+Sponsor responsibilities were transferred from BioNTech SE to Pfizer Inc. for the conduct of clinical study C4591001, including compliance with Good Clinical Practice as per 21 CFR 312. Bioresearch Monitoring inspections of nine clinical sites in study
+C4591001 did not identify deficiencies that would affect the integrity of the clinical data submitted in this BLA.
+3.3 Financial Disclosures
+Studies C4591001 and BNT162-01
+Disclosure start date: April 29, 2020. Disclosure Cut off Date: March 25, 2021
+Was a list of clinical investigators provided? W Yes O No Total number of investigators identified: 1834
+Number of investigators who are sponsor employees (including both full-time and part-time employees): 0
+Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 7
+If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b),
+(c) and (f)):
+Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0
+Significant payments of other sorts: 3
+Proprietary interest in the product tested held by investigator: O
+Significant equity interest held by investigator in sponsor of covered study: 4
+Is an attachment provided with details of the disclosable financial interests/arrangements? W Yes O No
+Is a description of the steps taken to minimize potential bias provided?
+[ Yes O No
+Number of investigators with certification of due diligence (Form FDA 3454, box 3): 4
+Is an attachment provided with the reason? W Yes O No
+The investigators with disclosable financial interests represented 0.4% (n=7/1,834) of the total investigators who participated in covered clinical studies.
+Efforts reported to eliminate bias for the covered studies consisted of the following:
+• Randomized, double-blind and multicenter study design as well as pre-specified statistical methods as per the statistical analysis plan
+• Frequent monitoring of investigator trial sites and auditing of study sites
+• Validity of data collected was confirmed by standard monitoring procedures
+• Data processing involved cleaning checks (querying data through electronic edit checks) to ensure that errors were identified and corrected
+• Data were reviewed by clinicians and queries were generated in case of inconsistencies during the course of the trial
+• The study report underwent review by the project team and Quality Control; and
+15
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+• Study sites performing safety evaluations were determined acceptable based on appropriate certification or historical performance and/or qualifications and credentials.
+Reviewer Comment: The Applicant satisfactorily addressed possible study investigator financial interests that could impact clinical data quality.
+4. SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES
+4.1 Chemistry, Manufacturing, and Controls
+The CBER CMC reviewer identified no issues that would impact the conclusions of the clinical review.
+4.2 Assay Validation
+Two clinical diagnostic assays were used to assess clinical endpoints in pre-licensure clinical trials. The information provided in the BLA supported the suitability of Cepheid Xpert Xpress assay and Roche Elecsys Anti-SARS-CoV-2 assay for their intended uses to detect SARS-CoV-2 in clinical specimens and to determine serostatus to SARS-CoV-2, respectively.
+4.3 Nonclinical Pharmacology/Toxicology
+The CBER toxicology reviewer identified no issues in preclinical studies that would affect clinical review of the submitted interim clinical study reports, and based on current hypotheses regarding the etiology of vaccine-associated enhanced disease, the preclinical data provided in the BLA are reassuring due to: (1) the robust induction of functional (i.e., neutralizing) antibodies in mice and rhesus macaques; (2) the T helper type 1 (Th1) bias in T cell responses; and (3) the lack of disease in vaccinated rhesus macaques challenged with SARS-CoV-2. The nonclinical absorption, distribution, metabolism, and excretion studies indicate that the NP mainly localizes to the site of injection and, to a lesser extent, distributes to the liver. Please see CBER toxicology review memorandum for further details.
+4.5 Statistical
+No major statistical issues were identified by CBER statistical reviewers in this application. The key statistical analyses for safety and efficacy were confirmed by CBER statistical reviewers.
+4.6 Pharmacovigilance
+Post-EUA safety surveillance reports received by FDA and CDC identified two rare but clinically important serious adverse reactions: anaphylaxis and myocarditis/pericarditis.
+The crude reporting rate for anaphylaxis in the Vaccine Adverse Event Reporting
+System (VAERS), including unconfirmed and potentially duplicate reports, has been ~6 cases per million doses, which is similar in magnitude to rates of anaphylaxis reported for other preventive vaccines. 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 ears of age (~65 cases per million doses administered as per CDC communication on August 20, 2021). Although some cases of vaccine-associated myocarditis/pericarditis required intensive care support (with several suspected fatal cases under CDC
+16
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+investigation but not confirmed at the time of this review), available data from short-term follow-up suggest that most individuals affected by vaccine-associated myocarditis/pericarditis have had resolution of symptoms with conservative management. Information is not yet available about potential long-term sequelae and outcomes in affected individuals.
+Anaphylaxis will be monitored through routine pharmacovigilance activities, including a data capture aid to identify relevant clinical information, and post licensure safety studies. Mitigation of the observed risks of myocarditis/pericarditis and associated uncertainties will be accomplished through labeling (including warning statements about the risks of vaccine-associated myocarditis/pericarditis) and through continued safety surveillance and postmarketing studies conducted by the Applicant, by public health agencies within the US government (including FDA and CDC), and by other healthcare stakeholders. Please see CBER PVP review memorandum for further details.
+4.7 Risk-Benefit Assessment
+FDA conducted a quantitative benefit-risk assessment to inform the review of Pfizer and BioNTech's Biological Licensure Application (BLA) for use of mRNA COVID-19 vaccines in individuals 16 years of age and older. The assessment evaluated the benefits and risks per million individuals who complete vaccination with two 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 assessed the benefits of vaccine-preventable COVID-19 cases, hospitalizations, ICU visits and deaths, and the risks of vaccine-related excess myocarditis/pericarditis cases, hospitalizations, and deaths. The major sources of data included 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 database, and the vaccine related myocarditis/pericarditis deaths reported through VAERS. The assessment 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 assumed vaccine protection duration of 6 months, 10x COVID-19 case incidence and 4x COVID-19 hospitalization incidence as compared with those of July 10 (recent nadir), 70% vaccine efficacy against COVID-19 case, 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, ICU admissions, and deaths are 136,000, 506, 166 and 4 per million vaccinated individuals, respectively. The excess myocarditis/pericarditis cases, associated hospitalizations, and deaths attributable to vaccine are 196, 196, and 0 per million vaccinated individuals, respectively.
+The worst-case scenario used the most conservative assumptions for all the model inputs and assumed protection against COVID-19 over 6 months post-vaccination, the COVID-19 case and hospitalization incidences 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 predicted that prevented COVID cases, hospitalizations, ICU admissions, and deaths are 14,000, 127, 41, and 1 per million vaccinated individuals in this age group,
+17
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+respectively. The excess myocarditis/pericarditis cases and associated hospitalizations and deaths attributable to the vaccine are 196, 196, and 0 per million vaccinated individuals in this age group, respectively. Even with the conservative assumption on the myocarditis/pericarditis death rate, the model predicted O deaths associated with myocarditis/pericarditis. The model predicts 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, FDA considers the benefits of the vaccine still outweigh the risks for the highest risk group, males 16-17 years old, under this worst-case scenario.
+The benefit-risk estimates are limited by uncertainties associated with the dynamics of pandemics. The major uncertainties in benefits are related to potential changes in COVID-19 incidence over time and 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.
+For further details, please refer to the review memorandum from the Analvtics and Benefit Risk Assessment Team, Office of Biostatistics and Epidemiology, CBER.
+5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN THE REVIEW
+5.1 Review Strategy
+Clinical data that were available as of November 14, 2020 from Phase 1 study BNT162-01 and Phase 1/2/3 study C4591001 participants ≥16 years of age enrolled by October
+9, 2020 were submitted and reviewed by FDA. See the EUA Memorandum for the Pfizer COVID-19 Vaccine.
+This BLA contains new clinical data, as follows:
+Study C4591001
+> Phase 1
+For BNT162b2 (30 mg), for participants ages 18-55 years (inclusive) and 65-85 years (inclusive):
+• Safety to approximately 6 months after Dose 2 (cutoff date: March 13, 2021)
+• Immunogenicity at 6 months after Dose 2 (adults 18-55 ears of age only)
+> Phase 2/3
+For participants 16-55 ears and >55 ears of age:
+• Safety to ≥6 months after Dose 2, comprised of participants in the blinded placebo-controlled and/or open-label follow-up period
+• Efficacy for all participants in the efficacy analysis populations (i.e., ≥12 years of age) with confirmed COVID-19 cases up to March 13, 2021.
+Study BNT162-01
+BNT16262 by dose level (1 to 30 ug) for participants 18-85 vears of age:
+• Safetv to 1 month after Dose 2
+• Immunogenicity: neutralizing antibody titers up to 42 days after Dose 2, T-cell responses up to ~6 months after Dose 2 (18-55 years of age: all dose levels; 56-85 years of age: 20-ug dose level only)
+18
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Only safety and efficacy data in individuals 16 years of age and older, the population for intended use, who received the final vaccine formulation (BNT162b2 30 ug) are presented in this clinical memorandum.
+Because the primary source of pre-licensure study data to support vaccine safety and effectiveness is a single study, C4591001, FDA agreed with the Applicant's proposal not to include integrated summaries of efficacy or safety in the BLA submission.
+Consequently, the sections of the clinical memo usually reserved for review of these integrated summaries (Sections 7 and 8) are not applicable.
+Post-authorization effectiveness data from observational studies referenced in Section 2 and Section 11 are limited to published literature and were not submitted as part of the licensure application. Therefore, FDA has not independently reviewed and confirmed the data or assessed the study designs for potential sources of bias.
+5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review
+The primary source of data considered for review of this investigational vaccine were documents submitted to ST 125742/0. The following sections were reviewed in support of this application:
+Module 1, all sections: Administrative Information and Prescribing Information Section 2.2 Introduction Section 2.5 Clinical Overview
+Section 2.7.3 Summary of Clinical Efficacy
+Section 2.7.4 Summary of Clinical Safety
+Section 2.7.6 Svnopses of Individual Studies
+Section 5.2 Tabular Listing of All Clinical Studies
+Section 5.3.5.1 Clinical Study Reports
+During the BLA review period, the Applicant submitted a total of 35 amendments in response to CBER's requests for clinical information.
+Table 4. Amendments to the Original BLA 125742/0 (submitted May 6, 2021)
+Amendment Date Submitted Description
+Number
+2
+3
+5
+6
+7
+May 18, 2021
+May 19. 2021
+May 19, 2021
+June 7. 2021
+June 16, 2021
+June 17, 2021
+July 2, 2021
+8
+July 2, 2021
+9
+12
+July 16, 2021
+15
+July 23, 2021
+Second roll of the BLA
+Request for proprietary name review
+Response to May 18, 2021 comments re: datasets
+COVID-19 cases: strain sequencing data
+Response to June 8. 2021 comments re: datasets. label
+Response to June 9, 2021 comments re: PREA deferred studies
+Response to June 29, 2021 comments re: latest date of randomization for study C4591001 participants in the reactogenicity subset
+Response to June 25, 2021 comments re: solicited local reactions frequencies, by severity, in study BNT162-01 participants
+Response to July 6, 2021 comments re: HIV cohort: severe
+AEs and AEs leading to study withdrawal
+Response to July 15 and 20, 2021 comments re: study
+C4591007 goal dates and revised pediatric plan
+19
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Amendment Date Submitted Description
+Number
+17,18, 28
+22
+23
+26
+27
+30
+32
+37
+38
+45
+49
+51
+52
+58
+59, 67, 69
+66
+68
+71
+72
+74
+75
+July 26, 2021
+July 28, 2021
+August 2. 2021
+July 30, 2021
+Responses to Q1-2, 3-5 of July 22, 2021 comments re: shell tables and other clinical comments
+Response to July 27, 2021 comments re: vaccine effectiveness
+July 30, 2021
+Response to July 26, 2021 comments re: disposition of pregnant participants
+August 2, 2021
+Response to July 29, 2021 comments re: safety analysis by age
+August 2, 2021
+August 3, 2021
+Response to July 28, 2021 comments for package insert Response to July 28, 2021 comments re: post marketing observational safety studies to assess myocarditis/pericarditis
+August 5, 2021
+Response to August 3, 2021 comment regarding excluding a case from the efficacy analyses
+August 9, 2021
+Response to comment 6 of July 22, 2021 request re: shell tables (efficacy)
+August 9, 2021
+Response to August 5, 2021 comments for package insert
+August 12, 2021
+Response to August 9, 2021 comments re: sequencing data
+August 16, 2021
+Response to August 13, 2021 comments for package insert
+August 16, 2021 Response to August 13, 2021 comments re: safety-related
+PMR/PMC studies
+August 16, 2021
+Response to August 13, 2021 comments re: duration of follow up for the efficacy population
+August 18, 2021 Response to August 17, 2021 comments for package insert
+August 18, 2021 Response to August 17 and 19, 2021 comments re:
+August 19, 2021
+PMC/PMR commitments received in Amendment 51
+August 20, 2021
+August 19, 2021
+Response to August 18, 2021 comments for package insert
+August 20, 2021 Response to August 19, 2021 comments for package insert
+August 20, 2021
+Response to August 20, 2021 comments re: package insert
+August 20, 2021
+Response to August 20, 2021 comments re: shell table for unsolicited AEs
+August 21, 2021
+Response to August 21, 2021 comments for package insert
+August 21, 2021
+Response to August 21, 2021 comments re: PMR/PMC studies and final study protocol date for study C4591007
+Source: FDA-generated table.
+The amendments satisfactorily addressed all clinical requests sent during the review period, and salient responses from the amendments were incorporated into this memorandum.
+Supportive information from EUA 27034/0 and clinical study protocols reviewed under
+IND 19736 were also referenced during the review cycle.
+5.3 Overview of Clinical Studies
+Interim reports from two ongoing clinical studies were submitted to support approval and licensure of Pfizer-BioNTech COVID-19 Vaccine (BNT1622). Study C4591001 is a multicenter, multinational Phase 1/2/3 randomized, blinded, placebo-controlled safety, immunogenicity, and efficacy study. Study BNT162-01 is a Phase 1 study that
+20
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+evaluated various vaccine candidates and dose levels for differing formulations of the vaccine.
+Table 5. Overview of Clinical Studies
+Description
+Study
+Number
+C4591001
+Phase 1.2.3 randomized, placebo-controlled, observer-blind; to evaluate safety, immunogenicity and efficacy of COVID-19 vaccine
+BNT162-01 Phase 1/2 randomized,
+BNT162b2 (30 ug)* Group
+Phase, Number of Participants, Country
+Phase 13: 24 (USA)
+Phase 2/3b: 22085
+Argentina: 2887
+Brazil: 1452
+Germany: 250
+South Africa: 401
+Turkey: 251
+USA: 16844
+Phase 1: 24 (Germany)
+Placebo Group
+Phase, Number of Participants, Country
+Phase 1a: 6 (USA)
+Phase 2/39: 22080
+Argentina: 2889
+Brazil:1448
+Germany: 250
+South Africa: 399
+Turkey: 249
+USA: 16845
+0
+open-label; to evaluate safety and immunogenicity, dose escalation
+Source: ST 125742.037 c4591001-508-safety tables
+N = total number of randomized participants 16 years of age and older, as of March 13, 2021 Placebo: 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 218 years of age (stratified as 18-55 years and 56-85 years); Phase 3: enrolled individuals ≥16 years of age (stratified as 16-55 years and >55 years).
+5.4 Consultations
+For the purpose of informing the design of required postmarketing safety studies and pediatric clinical trials as required by PREA, FDA cardiologists from the Center for Drug Evaluation and Research were asked to provide recommendations for diagnostic evaluations and monitoring for myocarditis/pericarditis (including feasibility of routine screening tests for subclinical myocarditis), interpretation of cardiac testing, and follow-up of identified clinical and subclinical cases. FDA incorporated these recommendations into negotiations with the Applicant on postmarketing studies.
+5.4.1 Advisory Committee Meeting
+The most critical issues involving data to support safety and effectiveness of this vaccine were covered in the October 2020, December 2020, and June 2021 VRBPAC meetings. More complete information concerning the risk of myocarditis/pericarditis became available during the BLA review as post-EUA surveillance and observational studies. FDA's assessment of this information did not impact the overall benefit/risk considerations to an extent that VRBPAC input was needed to guide a licensure decision for use in individuals ages 16 years and older.
+5.5 Literature Reviewed
+CDC, 2021, COVID-19 Vaccinations in the United States. https://covid.cdc.gov/covid-data-tracker/#vaccinations vacc-total-admin-rate-total. Accessed August 20, 2021.
+CDC, 2021a, Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C). February 17, 2021. https://www.cdc.gov/mis-c/hcp/.
+Study
+Status
+Ongoing
+Ongoing
+21
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+CDC, 2021b, Health Equity Considerations and Racial and Ethnic Minority Groups. Updated April 19, 2021. https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/race-ethnicity.html. Accessed August 20, 2021.
+CDC, 2021c, COVID Data Tracker. Demographic trends of COVID-19 cases and deaths in the US reported to the CDC. www.cdc.gov/covid-data-tracker/index.html#demographics. Accessed
+August 2, 2021.
+CDC, 2021d, COVID Data Tracker. Variant Proportions. https://covid.cdc.gov/covid-data-tracker/#variant-proportions . Accessed August 20, 2021.
+CDC, 2021e, COVID-19 Vaccine Safety Update (slide presentation).
+https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-02/28-03-01/05-covid-
+Shimabukuro.pdf Accessed August 20, 2021.
+CDC, 2021f, Update on Emerging SARS-CoV-2 Variants and COVID-19 vaccines (slide presentation). https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-08-13/04-
+COVID-Scobie-508pdf. Accessed August 20, 2021.
+CDC, 2021g, SARS-CoV-2 Variant Classifications and Definitions.
+httos://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html. Accessed August 20, 2021.
+CDC Advisory Committee on Immunization Practices, 2021a, COVID-19 VaST Work Group Report - May 17, 2021. https://www.cdc.gov/vaccines/acip/work-groups-vast/report-2021-05-
+17.html?CDC AA refVal=https%34%2F%2Fwww.cdc.gov%2Fvaccines%2Facip%2Fwork-groups-vast%2Ftechnical-report-2021-05-17.html. Accessed August 20, 2021.
+CDC Advisory Committee on Immunization Practices, 2021b, COVID-19 Vaccine Safety Technical (VaST) Work Group (slide presentation). April 23, 2021.
+https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04-23/05-COVID-Lee-
+508.pdf Accessed August 20, 2021.
+CDC Advisory Committee on Immunization Practices, 2021c, COVID-19 Vaccine Safety Technical (VaST) Work Group (slide presentation). June 23, 2021
+https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-06/04-COVID-Lee-508.odf.
+Accessed August 20, 2021.
+FDA, 2020a, Emergency Use Authorization Review Memorandum for the Moderna COVID-19
+Vaccine/mRNA-1273. December 18, 2020. https://www.fda.gov/media/144673/download
+FDA, 2020b, Emergency Use Authorization Review Memorandum for the Pfizer-BioNTech COVID-19 Vaccine/ BNT1622. December 11, 2020.
+https://www.fda.gov/media/144416/download
+FDA, 2020c, Guidance for Industry: Development and Licensure of Vaccines to Prevent COVID-
+19. June 2020. https://www.fda.gov/media/139638/download.
+FDA, 2021a, Guidance for Industry: Emergency Use Authorization for Vaccines to Prevent COVID-19. February 2021. https://www.fda.gov/media/142749/download
+FDA, 2021b, Emergency Use Authorization Amendment Review Memorandum (for use of the Pfizer COVID-19 Vaccine in adolescents).
+https://fda.report/media/149528/nrEUA+27034. 132+Review+Memo+ Pfizer-BioNTech+COVID-19+Vaccine REVISED24May final.pdf.
+22
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Holshue, ML, C DeBolt, S Lindquist, KH Lofy, J Wiesman, H Bruce, C Spitters, K Ericson, S Wilkerson, A Tural, G Diaz, A Cohn, L Fox, A Patel, SI Gerber, L Kim, S Tong, X Lu, S Lindstrom, MA Pallansch, WC Weldon, HM Biggs, TM Uyeki, and SK Pillai, 2020, First Case of
+2019 Novel Coronavirus in the United States, New England Journal of Medicine, 382(10):929-936.
+Pawlowski, C, P Lenehan, A Puranik, V Agarwal, A Venkatakrishnan, MJM Niesen, JC O'Horo, A Virk, MD Swift, AD Badley, J Halamka, and V Soundararajan, 2021, FDA-authorized COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system, medRxiv:2021.2002.2015.21251623.
+Thompson, MG, JL Burgess, AL Naleway, HL Tyner, SK Yoon, J Meece, LEW Olsho, AJ Caban-Martinez, A Fowlkes, K Lutrick, JL Kuntz, K Dunnigan, MJ Odean, KT Hegmann, E Stefanski, LJ Edwards, N Schaefer-Solle, L Grant, K Ellingson, HC Groom, T Zunie, MS Thiese, L Ivacic, MG Wesley, JM Lamberte, X Sun, ME Smith, AL Phillips, KD Groover, YM Yoo, J Gerald, RT Brown, MK Herring, G Joseph, S Beitel, TC Morrill, J Mak, P Rivers, KM Harris, DR Hunt, ML Arvay, P Kutty, AM Fry, and M Gaglani, 2021, Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers - Eight U.S. Locations, December 2020-March 2021, MMWR Morb Mortal Wkly Rep, 70(13):495-500.
+World Health Organization, 2021a, WHO Coronavirus (COVID-19) Dashboard.
+https://covid19.who.int. Accessed August 20, 2021.
+World Health Organization, 2021b, Weekly epidemiological update on COVID-19 - 1 June 2021.
+https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19--1-june-
+2021. Accessed August 20, 2021.
+6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS
+6.1 Study C4591001
+NCT04368728
+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
+Reviewer Comment: The protocol for this ongoing study has been amended over time to add study populations, interventions, and analyses not included in the original design and not pertinent to this BLA. The study design as described herein reflects objectives, endpoints, and monitoring pertaining to safety, immunogenicity, and efficacy evaluations following a 2-dose BNT1622 primary series, according to protocol amendment 14, which was the active version at the time of the March 13, 2021 data cutoff. Secondary/exploratory obiectives pertaining to immunobridging evaluations in individuals 12-15 years of age, re-vaccination (e.g., 3rd BNT162b2 dose), and evaluation of modified BNT162b2 vaccine formulations were bevond the scope of this BLA, and therefore not presented in this clinical review. Secondary objectives and associated efficacy analyses starting from 14 days after Dose 2, based on CDC definitions, were reviewed but not considered by the clinical reviewers as critically important to the interpretation of the primary endpoint. Lastly, the BLA submission did not include data to address asvmptomatic COVID-19 infection, based on seroconversion or surveillance PC testing or immunogenicity data from Phase 2/3; thus, study
+23
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+objectives pertaining to asymptomatic infection and Phase 2/3 immunogenicity evaluations are not presented.
+6.1.1 Objectives and Endpoints
+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 objectives
+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 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.
+2. To evaluate the efficacy of BNT162b2 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 incidence per 1000 person-years of follow-up based on laboratory-confirmed NAAT
+Primary safety objective: To characterize the safety of BNT162b2.
+Endpoints: 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), AEs, serious adverse events (SAEs)
+Solicited As were assessed for the first 360 participants (Phase 2) and then a subset of at least 6,000 participants in Phase 2/3.
+Pertinent secondar efficac obiectives
+• To evaluate the efficacy of BNT1622 against severe COVID-19 occurring from
+7 days after Dose 2 in
+• participants without evidence of SARS-CoV-2 infection before vaccination
+• participants with and without evidence of SARS-CoV-2 infection before vaccination
+Endpoint for both populations: Severe COVID-19 incidence per 1000 person-years of follow-up
+For all of the study objectives described above, NAAT could be confirmed in a central or local laboratory, unless otherwise specified. Evidence of past SARS-CoV-2 infection (before Dose 1) was documented serologically or virologically.
+6.1.2 Design Overview
+Study C4591001 is an ongoing, randomized Phase 1/2/3 study being conducted in the US, Argentina, Brazil, Germany, South Africa and Turkey. Initially, the study was
+24
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+designed as a placebo-controlled Phase 1 study in healthy US adults to assess the safety and immunogenicity of several vaccine candidates and dose levels. In Phase 1, to facilitate review of phase 1 data in real time, the Applicant was not blinded to the vaccine assignment. The protocol was amended to include observer-blinded, placebo-controlled Phase 2 (US) and Phase 3 (international) portions to evaluate safety and clinical disease efficacy endpoints, initially in adults 18 years of age and older but later amended to include adolescents 16-17 years of age and then adolescents 12-15 years of age. Following FDA issuance of an EUA for BNT162b2, progressive unblinding to the randomized assignment began for all participants. This review focuses on the population of participants 16 years of age and older, the population proposed for initial licensure.
+In Phase 1, two vaccine candidates were evaluated in adults who were not at high risk of SARS-CoV-2 exposure, without medical conditions that represented risk factors for more severe COVID-19, and without serologic/virologic evidence of SARS-CoV-2
+infection. For each vaccine candidate, several dose levels were evaluated in adults 18 through 55 years of age, with progression to the next higher dose level and to adults 65 through 85 years of age based on recommendation from an Internal Review Committee (IRC). 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 selection of the final vaccine candidate and dose level (BNT1622 30 ug) to proceed into Phase 2/3.
+Immune responses in Phase 1 (SARS-CoV-2 neutralizing titer, S1- and receptor binding domain- IgG) were assessed pre-Dose 1, after Dose 1 (at Days 7 and 21) and after Dose 2 (at 7 and 14 days and 1 and 6 months).
+In Phase 2/3, enrolled participants were initially stratified by age (18-55 years and >55 years), with a goal of 40% enrollment in the older adults (>55 years of age). The protocol was later amended to include adolescents 16-17 years of age (and subsequently 12 to 15 years of age), following IRC review of safety data in adults; hence, the age strata for the initial EUA submission and for this BLA submission were revised as follows: 16-55 years of age, and >55 years of age. The study population for Phase 2/3 included 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 BNT162b2 or placebo, 3 weeks apart. The Phase 2 portion of the study evaluated reactogenicity and immunogenicity for 360 participants, and these participants also contribute to the overall efficacy and safety data in the Phase 3 portion.
+Changes in the conduct of the study or planned analyses relevant to the proposed indication and use:
+• Participants 18-55 ears of age and >55 ears of age began enrollment into Phase 2/3 from July 27, 2020 and participants 16-17 years of age began enrollment from
+September 16, 2020.
+25
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Other protocol amendments:
+• Amendment 6, dated September 8, 2020: Added an exploratory objective to describe safety, immunogenicity, and efficacy in participants with stable HIV disease; increased the sample size for Phase 2/3 to ~44,000.
+• Amendment 8, dated October 15, 2020: Clarified that for participants who are not in the reactogenicity subset, local reactions and systemic events following vaccination should be detected and reported as AEs.
+• Amendment 12, dated January 14, 2021: participants ≥16 years of age who originally received placebo would be eligible for receipt of BNT162b2, in a phased manner.
+Per protocol, since December 14, 2020, following issuance of the Emergency Use Authorization for the Pfizer-BioNTech COVID-19 Vaccine, Phase 2/3 participants ≥16 years of age in the vaccine and placebo groups were progressively unblinded to their treatment assignment (when eligible per local recommendations). Participants initially randomized to the placebo group were offered BNT162b2 vaccination at a time no later than the 6-month follow-up visit after the second placebo vaccination. For participants unblinded to his/her vaccine assignment, follow-up evaluations thereafter were conducted in an open-label manner.
+Reviewer Comment: During the blinded placebo-controlled time period in Phases 2 and 3, study staff who prepared and administered the study interventions were unblinded to the treatment assignment, due to differences in appearance of BNT162b2 and saline placebo, and study investigators/personnel collecting and evaluating safety and efficacy information were blinded to the participants' treatment assignment (observer-blinded). In the package insert, double-blind refers only to the study investigators/personnel collecting and evaluating safetv and efficacy information and the participant.
+After BNT162b2 became available for emergency use, participants who elected to receive BNT162b2 were unblinded to their initial study intervention assignment.
+The Applicant and site personnel who are responsible for the ongoing conduct of the study remain blinded to the data from participants whose treatment assignment has not been disclosed.
+6.1.3 Population
+Phase 1: key eligibility criteria described in Section 6.1.2 Design Overview.
+Phase 2/3
+Kev inclusion criteria
+• Healthy or had pre-existing stable chronic medical conditions
+• ≥12 years of age. Individuals <18 years of age were not enrolled in the EU.
+• At higher risk for acquiring COVID-19 (including, but not limited to, use of mass transportation, relevant demographics, frontline essential workers).
+Kev exclusion criteria
+Phase 2 only: Known infection with HIV, hepatitis C virus, or hepatitis B virus
+• Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2
+NAAT result was not available) or microbiological (based on COVID-19
+symptoms/signs and a positive SARS-CoV-2 NAAT result) diagnosis of COVID-19
+26
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+• Known or suspected immunodeficiency, or received/planning treatment with immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, or planned receipt throughout the study
+• Women who are pregnant or breastfeeding
+• Receipt of blood/plasma products or immunoglobulin, from 60 days before study intervention administration or planned receipt throughout the study.
+Criteria for temporarily delaying enrollment/randomization/study intervention administration
+• Current febrile illness (T ≥38°C) or other acute illness within 48 hours before study intervention administration, including symptoms that could represent a potential COVID-19 illness: new or increased cough; new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste/smell, sore throat, diarrhea, vomiting.
+• Receipt or planning to receive a seasonal or pandemic influenza vaccine within 14 days, or any other non-study vaccine within 28 days, before study vaccination.
+6.1.4 Study Treatments or Agents Mandated by the Protocol
+The BNT1622 (30 ug) vaccine candidate was selected for further evaluation in Phase 2/3. BNT162b2 contains a nucleoside-modified messenger RNA that encodes the viral spike (S) glycoprotein of SARS-CoV-2 encapsulated in a lipid nanoparticle. Each dose also includes the following ingredients: lipids ((4-hydroxybutylazanediyl)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 sodiur phosphate dihydrate, and sucrose.
+6.1.5 Directions for Use
+Two doses of BNT162b2 (0.3 mL per dose) were administered 3 weeks apart. Each dose was injected intramuscularly into the deltoid muscle.
+See the full prescribing information for further information regarding preparation of BNT162b2.
+6.1.6 Sites and Centers
+A total of 153 clinical sites enrolled participants for Study C4591001 [US (131), Turkey
+(9), Germany (6), South Africa, (4), Brazil (2) and Argentina (1)]
+6.1.7 Surveillance/Monitoring
+Efficacy
+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 nucleic acid amplification-based test (NAAT), to detect SARS-CoV-2. Case ascertainment is based on central laboratory NAAT results, unless it is not possible to test the sample at the central laboratory. In that case,
+27
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+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 primary and secondary efficacy endpoints were analyzed in the protocol-specified event-driven final efficacy analvsis after at least 164 COVID-19 cases were accrued (see Section 6.1.9)
+Participants are expected to participate for a maximum of approximately 26 months.
+Safety
+Solicited AEs (local and systemic reactions, and antipyretic/pain medication usage from
+Day 1 through Day 7 after each dose) were assessed for the first 360 Phase 2 participants and then a subset of at least 6,000 participants in Phase 2/3.
+Reviewer Comment: The total number of participants enrolled in the reactogenicity subset was 9,839.
+The subset of Phase 2/3 participants ≥16 years of age with stable HIV were analyzed separately per protocol. For all participants, all unsolicited adverse events (AEs) were collected from Dose 1 to 1 month after the last dose and all serious AEs (SAEs) from Dose 1 to 6 months after the last dose. The planned safety follow-up for currently enrolled adolescents and adults is a maximum of 26 months (i.e., through 24 months after vaccination #2) and will include collection of deaths and related SAEs reported after 6 months post-Dose 2. Figure 1 below shows the study safety monitoring plan.
+Figure 1. Safety Monitoring Plan, Study C4591001
+Vaccination period
+X+
+dose
+21 days apart
+Follow-up period
+dose
+2 years
+Active surveillance
+for potential COVID-19 symptoms - telehealth or in-person visit and nasal swab
+Reactogenicity: at least 6000 subjects, at least 500 in each country
+7 days post dose
+7 days post dose
+- Non-serious AE: all subjects
+1 month post dose 2
+- Serious AE: all subjects
+6 months post dose 2
+Deaths and related SAEs: all subjects
+2 years post dose 2
+Reactogenicity assessments included solicited injection site reactions (pain, redness, swelling) and systemic AEs (fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain), and antipyretic/pain medication use were recorded in an e-diary. For Phase 3 participants who were not in the reactogenicity subset, local reactions and systemic events consistent with reactogenicity were detected and reported as unsolicited AEs.
+28
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Clinical laboratory tests were assessed routinely in Phase 1 only, at 1-week post-vaccination.
+Potential COVID-19 illnesses and their sequelae were not to be reported as AEs, with the exception of illnesses that met regulatory criteria for seriousness and were not confirmed to be COVID-19. These illnesses were evaluated and reported as SAEs.
+In Phase 2/3, monitoring for risk of vaccine-enhanced disease was performed by an unblinded team supporting the Data Monitoring Committee that reviewed cases of severe COVID-19 as they were received and reviewed AEs at least weekly for additional potential cases of severe COVID-19. The stopping rule for the theoretical concern of vaccine-enhanced disease was triggered when the 1-sided probability of observing the same or a more extreme case split was 5% or less when the true incidence of severe disease was the same for vaccine and placebo participants, and alert criteria were triggered when this probability was less than 11%. Participants who discontinued study intervention continued the protocol-specified follow-up procedures.
+After BNT1622 was granted emergency use authorization (December 11, 2020), unblinding procedures were initiated to vaccinate the placebo group. Please see Section 6.1.10.1 (Population enrolled/analyzed) for additional details.
+6.1.8 Endpoints and Criteria for Study Success
+Efficacy Evaluation
+The case definition for a confirmed case of COVID-19 for the primary efficacy endpoint, was the presence of at least one of the following symptoms and a positive SARS-CoV-2
+NAAT within 4 davs of the svmptomatic period:
+• 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
+The case definition for severe COVID-19 case included a confirmed COVID-19 case with at least one of the following:
+• Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute, HR ≥125 beats per minute, SpO2593% on room air at sea level, or
+Pa02/Fi02<300 mm Hg)
+• Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporal membrane oxygenation)
+• 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
+29
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+First primarv endpoint: COVID-19 incidence per 1000 person-years of follow-up in participants without serological or virological evidence of past SARS-CoV-2 infection before and during vaccination regimen - cases confirmed ≥7 days after
+Dose 2
+Second primary endpoint: COVID-19 incidence per 1000 person-vears of follow-up in participants with and without evidence of past SARS-CoV-2 infection before and during vaccination regimen - cases confirmed ≥7 days after Dose 2
+Study success criteria: In Phase 2/3, the assessment of VE was based on posterior probability of VEt>30% and VEz>30%, where VE represented VE for prophylactic BNT162b2 against confirmed COVID-19 in participants without evidence of infection before vaccination, and VE2 represented 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 were based on the posterior probability, i.e. Pr(VE >30%|data) at the current number of cases. Efficacy was declared if the posterior probability was 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 was met, the second primary objective was evaluated at the final analysis.
+Pertinent secondar efficac endpoint
+Severe COVID-19: incidence per 1000 person-years of follow-up in participants either
+(1) without or (2) with and without evidence of past SARS-CoV-2 infection before and during vaccination regimen - cases confirmed either ≥7 days after Dose 2
+6.1.9 Statistical Considerations & Statistical Analvsis 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 participants 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 (IAs) 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 e = r(1-VE)/(1+r(1-VE)), where r is the ratio of surveillance time in the
+30
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+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 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 analysis was performed by imputing missing values with the assumption of missing at random. Secondary endpoints were evaluated similarly to the primary endpoints.
+After the protocol-specified event-driven final efficacy analyses at 170 cases, updated efficacy analvses on primary and secondar efficacy endpoints were performed with additional data accrued during the blinded placebo-controlled follow-up time period. The point estimate of VE in the blinded follow-up period and associated 2-sided 95% CI were derived using the Clopper Pearson method adiusting for surveillance time. The posterior probability, r(VE >30%\data), was also provided.
+Reviewer Comment: Although the total planned follow-up for study participants is 2 years, due to complexities introduced by unblinding and placebo cross-over following emergency use authorization of the vaccine longer term vaccine effectiveness (beyond the valuable period from placebo-controlled follow-up in the clinical trial) will be best evaluated in observational studies.
+Solicited safety analyses were based on participants in the reactogenicity subset who received at least one dose of the vaccine and responded ves or no to any reaction within 7 days of each dose. Unsolicited safety analyses were based on the safety population, which consisted of participants randomized in the Phase 2/3 study who received at least one dose of the vaccine, analyzed according to the vaccine received.
+Safety endpoints were summarized descriptively for the number of participants within the analysis set reporting at least one event in each category.
+6.1.10 Study Population and Disposition
+6.1.10.1 Populations Enrolled/Analyzed
+The study protocol was revised to allow participants ≥16 ears of age who originally received placebo the opportunitv to receive BNT1622 following local or national recommendations or following completion of the active safety surveillance period, following issuance of the EUA (protocol amendment 10). On December 14, 2020, the process of disclosing vaccine assignments for all trial participants ≥16 years of age began (following issuance of the EUA for use of the Pfizer-BioNTech COVID-19 vaccine in individuals 16 years of age and older). Hence, for each trial participant, there are 2 periods in the study: enrollment into the observer-blind phase until the date of vaccine disclosure and the time in the study after disclosure. Participants who originally were randomized to BNT162b2 are continuing to be followed for safety as specified in the protocol. The safety data for participants who originally were randomized to and received placebo prior to disclosure of vaccine assignment include blinded data that contribute to controlled assessment of safety compared to individuals who randomly assigned to BNT162b2. After vaccine treatment disclosure and the administration of BNT162b2, the placebo participants can no longer be used for direct comparison with those who originally were randomized to BNT162b2. Even though individuals were unblinded on different days after December 14, 2020, the difference in the total blinded follow-up duration is minor between the treatment arms. Thus, the analysis of the observer-blinded, placebo-controlled portion of the study as well as the open-label
+31
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+portion is reported in frequencies, such that the number of participants within the analysis set reporting at least one event in each category is displayed.
+Safety data presented for Phase 3 of Study C4591001, based on the data cutoff date of March 13, 2021, include:
+1. Blinded placebo-controlled period: Dose 1 to 1 month after Dose 2 and to unblinding date:
+• Participants with up to ~6 months after Dose 2 (N=43,847; BNT162b2 group
+N=21,926 and placebo group N=21,921).
+• Solicited local As and systemic As were assessed during this time period from a subset of participants.
+2. Open-label observational period: from time of unblinding to data cutoff date:
+• Participants originally randomized to BNT162b2 (N=20,309)
+• Participants originally randomized to placebo who then received BNT162b2
+(N=19,525)
+• Participants originally randomized to placebo who had confirmed COVID-19 then received BNT162b2 (N=852)
+• Only unsolicited As (AEs, SAEs and adverse events of special interest [AESIs]) were assessed during this time period.
+3. Cumulative follow-up from Dose 1 to at least 6 months after Dose 2:
+• Participants originally randomized to BNT1622 inclusive of blinded data and open-label data through the March 13, 2021 data cutoff). (Total N=12,006: 16-55 years of age/younger age group [N =6,666] and >55 years of age/older age group [N =5,340]).
+Reviewer Comment: The BLA safetv database exceeded FDA expectations for at least 3,000 vaccine recipients in each age group with at least 6 months of total safety follow-up.
+A graphic of these three different time periods taken into consideration for the evaluation of the safety data is displayed in Figure 2, below.
+32
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Figure 2. Phase 2/3 Safety Analyses: Time Period and Analysis Groups
+Original BNT162b2 Participants
+Original Placebo Participants
+Unblinding Date
+Blinded
+Open-Label
+I
+Blinded Placebo_Controlled Follow.Up Period:
+Dose 1
+Dose 1
+1 month after Dose 2
+• Unblinding date?
+Dose 1
+6 months after Dose 2
+Open-Label Observational Follow-Up Period:
+Original BNT16262 Particiants
+Unblinding Date
+Data cutoff date
+Unblinding Date
+(Dose 3 Vaccination with BNT162621 I
+Original Placebo Participants
+Data cutoff date
+Source: ST 125742.0 c4591001-interim-mth6-report-body.pdf. Figure 11 (p 140).
+1 Will vary by participant. Adverse event data analyzed from Dose 1 to unblinding date, or from unblinding date to data cutoff date.
+2 Up to ~6 months after Dose 2.
+3 Cumulative BNT162b2 follow-up to at least 6 months after Dose 2.
+Analysis populations
+Population
+Evaluable efficacy
+Description
+All eligible randomized participants who receive all vaccination(s) as randomized within the predefined window and have no other important protocol deviations as determined by the clinician.
+All-available efficacy
+1. All randomized participants who receive at least 1 dose of vaccine.
+2. All randomized participants who complete 2 vaccination doses.
+Safety
+All randomized participants who receive at least 1 dose of the study intervention.
+Reactogenicity subset Subset of participants in the safety population who had e-diary data
+reported after vaccination.
+Data analvsis cutoff dates:
+• August 24, 2020 (Phase 1 safety and immunogenicity data through 1 month after
+Dose 2)
+•
+•
+September 2, 2020 (Phase 2 safety data through 7 days after Dose 2)
+November 4, 2020 (Phase 2/3 first interim analysis for efficacy)
+33
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+• November 14, 2020 (Phase 2/3 final analysis for efficacy, safety data for 37,586 participants with a median follow-up of at least 2 months, and available safety data for all 43,252 participants)
+• March 13, 2021 (Phase 2/3 updated vaccine efficacy analysis and safety follow-up)
+6.1.10.2 Demographics
+A total of 42,436 randomized participants 16 years of age and older (21,136 in the BNT162b2 group and 21,300 in the placebo group) comprise the evaluable efficacy population from the March 13, 2021 data cutoff. Overall, the evaluable efficacy population included 49.2% females; 82.0% White, 9.5% African American, 4.4% Asian, and <4% from other racial groups; 25.5% of participants were Hispanic/Latino; 20.8% of participants were ≥65 years of age. The median age was 51 years. One or more comorbidities that increase the risk of severe COVID-19 disease were present among 45.8% of participants. The most frequently reported comorbidity was obesity (34.5%).
+Only 3.1% of participants had evidence of prior SARS-CoV-2 infection. Geographically, 76.4% of participants lived in the US, 12.7% lived in Argentina, 6.8% lived in Brazil, and <2% of participants lived in each of the following countries: Germany, Turkey and South Africa. The demographics were balanced between the treatment groups. The demographics of the valuable efficacy population used for the updated vaccine efficacy analysis of the second primary endpoint (participants with or without evidence of SARS-CoV-2 infection prior to 7 das post-Dose 2) is displayed in Table 6.
+Table 6. 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
+Characteristic
+Sex: Female
+Sex: Male
+Age at Vaccination: Mean vears (SD)
+Age at Vaccination: Median (years)
+Age at Vaccination: Min, max (years)
+Age Group: 16-18 years
+Age Group: 18-55 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
+Ethnicitv: Hispanic or Latino
+Ethnicity: Not Hispanic or Latino
+Ethnicity: Not reported
+Obesity: Yes°
+Obesity: No
+Comorbidities: Yesd
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+(Na =21136)
+(Na =21300)
+nb (%)
+nb (%)
+10280 (48.6)
+10579 (49.7)
+10856 (51_4)
+10721 (50 3)
+49.8 (15.99)
+49.7 (16.03)
+51.0
+51.0
+(16 89)
+(16 91)
+370 (1.8)
+362 (1.7)
+12120 (57.3)
+12252 (57.5)
+8646 (40.9)
+8686 (40.8)
+4407 (20.9)
+4429 (20.8)
+204 (1.0)
+190 (0.9)
+929 (4.4)
+924 (4.3)
+2009 (9.5)
+2036 (9.6)
+56 (0.3)
+32 (0.2)
+17304 (81.9)
+17487 (82.1)
+545 (2.6)
+519 (2.4)
+89 (0 4)
+112 (0 5)
+5403 (25.6)
+5409 (25.4)
+15628 (73.9)
+15778 (74.1)
+105 (0.5)
+113 (0.5)
+7239 (34.2)
+7386 (34.7)
+13897 (65.8)
+13914 (65.3)
+9712 (46.0)
+9736 (45.7)
+Total
+(Na =42436)
+nb (%)
+20859 (49.2)
+21577 (50.8)
+49.7 (16.01)
+51.0
+(16, 91)
+732 (1.7)
+24372 (57.4)
+17332 (40.8)
+8836 (20.8)
+394 (0.9)
+1853 (4.4)
+4045 (9.5)
+88 (0.2)
+34791 (82.0)
+1064 (2.5)
+201 (0.5)
+10812 (25.5)
+31406 (74.0)
+218 (0.5)
+14625 (34.5)
+27811 (65.5)
+19448 (45.8)
+34
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Characteristic
+Comorbidities: No
+Baseline evidence of prior SARS-CoV-2
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+(Na =21136)
+(Na =21300)
+nb (%)
+nb (%)
+11424 (54.0)
+11564 (54.3)
+20365 (96.4)
+20511 (96.3)
+Total
+(Na =42436)
+n' (%)
+22988 (54.2)
+40876 (96.3)
+infection: Negative
+Baseline evidence of prior SARS-CoV-2 infection: Positive®
+627 (3.0)
+669 (3.1)
+1296 (3.1)
+Baseline evidence of prior SARS-CoV-2
+144 (0.7)
+infection: Missing
+Country: Argentina
+2686 (12.7)
+Country: Brazil
+1437 (6.8)
+Country: Germany
+240 (1.1)
+Country: South Africa
+391 (1.8)
+Country: Turkey
+241 (1.1)
+Country: United States
+16141 (76.4)
+120 (0.6)
+2710 (12.7)
+1432 (6.7)
+243 (1.1)
+392 (1.8)
+238 (1.1)
+16285 (76.5)
+264 (0.6)
+5396 (12.7)
+2869 (6.8)
+483 (1.1)
+783 (1.8)
+479 (1.1)
+32426 (76.4)
+Source: ST 125742.032 c4591001-508-efficacy tables, Table F, Page 9
+Abbreviation: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
+Note: HIV-positive participants are included in this summary but not included in the analyses of the overall study obiectives.
+a. N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage
+calculations.
+b. n = Number of participants with the specified characteristic.
+c. Participants who had BMI 230 kg/m2.
+d. Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as participants who had at least one of the Charlson comorbidity index category or BMI ≥30 kq/m2
+e. Positive N-binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
+*. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
+The population for the updated vaccine efficacy analysis of the first primary endpoint included 40, 111 participants 16 years of age and older (19,993 in the BNT162b2 group and 20,118 in the placebo group) who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose and who were HIV negative.
+Demographics for this analysis population were not meaningfully different from those in the table above, with the exception of being limited to participants without evidence of SARS-CoV-2 infection prior to 7 days post-Dose 2.
+The safety population included 44,047 participants 16 years of age and older (22,026 in the BNT162b2 group and 22,021 in the placebo group). Overall, the safety population included 49.1% females; 82.0% White, 9.6% African American, 4.3% Asian, and <2% from other racial groups; 25.9% of participants were Hispanic/Latino; 20.7% of participants were ≥65 years of age. The median age was 51 years. One or more comorbidities that increase the risk of severe COVID-19 disease were present among 45.8% of participants. Only 3.2% of participants had evidence of prior SARS-CoV-2 infection. Geographically, 76.3% of participants lived in the US, 13.1% lived in Argentina, 6.6% lived in Brazil and, <2% of participants lived in each of the following countries: Germany, Turkey and South Africa. The demographics were balanced between the treatment groups. Table 7 presents the specific demographic characteristics in the studied population.
+35
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 7. Demographics and Other Baseline Characteristics, Participants 16 Years of Age and Older, Safety Population
+Characteristic
+Sex: Female
+Sex: Male
+Age at Vaccination: Mean years (SD)
+Age at Vaccination: Median (vears)
+Age at Vaccination: Min, max (years)
+Age Group: 16-17 years
+Age Group: 18-55 ears
+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
+Obesitv: Yes
+Obesity: No
+Comorbidities: Yes
+Comorbidities: No
+Baseline evidence of prior SARS-CoV-2
+Vaccine Group (as Administered
+BNT162b2
+Placebo
+Total
+(Nª =22026)
+(Na =22021)
+(Na =44047)
+nb (%)
+nb (%)
+nb (%)
+10704 (48.6)
+10923 (49.6)
+21627 (49.1)
+11322 (51.4)
+11098 (50.4)
+22420 (50.9)
+49.7 (15.99)
+49.6 (16.05)
+49.7 (16.02)
+51.0
+51.0
+51.0
+(16, 89)
+(16, 91)
+(16, 91)
+378 (1.7)
+376 (1.7)
+754 (1.7)
+12691 (57.6)
+12719 (57.8)
+25410 (57.7)
+8957 (40.7)
+8926 (40.5)
+17883 (40.6)
+4552 (20.7)
+4545 (20.6)
+9097 (20.7)
+221 (1.0)
+217 (1.0)
+438 (1.0)
+952 (4.3)
+942 (4.3)
+1894 (4.3)
+2098 (9.5)
+2118 (9.6)
+4216 (9.6)
+58 (0.3)
+32 (0.1)
+90 (0.2)
+18056 (82.0)
+18064 (82.0)
+36120 (82.0)
+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)
+7543 (34.2)
+7629 (34.6)
+15172 (34.4)
+14483 (65.8)
+14392 (65.4)
+28875 (65.6)
+10119 (45 9)
+10071 (45.7)
+20190 (45.8)
+11907 (54.1)
+11950 (54.3)
+23857 (54.2)
+21185 (96.2)
+21180 (96.2)
+42365 (96.2)
+infection: Negative
+Baseline evidence of prior SARS-CoV-2
+689 (3.1)
+infection: Positive®
+716 (3.3)
+1405 (3.2)
+Baseline evidence of prior SARS-CoV-2 infection: Missing
+152 (0.7)
+Country: Argentina
+2883 (13.1)
+Country: Brazil
+1452 (6.6)
+Country: Germany
+249 (1.1)
+Country: South Africa
+401 (1.8)
+Country: Turkey
+249 (1 1)
+Countrv: United States
+16792 (76.2)
+125 (0.6)
+2881 (13.1)
+1448 (6.6)
+250 (1.1)
+399 (1.8)
+249 (1 1)
+16794 (76.3)
+277 (0.6)
+5764 (13.1)
+2900 (6.6)
+499 (1.1)
+800 (1.8)
+498 (1.1)
+33586 (76.3)
+Source: ST 125742.037 c4591001-508-safety tables, Table E, Page 9
+Abbreviation: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
+Note: HIV-positive participants are included in this summary but not included in the analvses of the overall study obiectives.
+a. N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage
+calculations.
+b. n = Number of participants with the specified characteristic.
+c. Participants who had BMI ≥30 kg/m2.
+d. Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as participants who had at least one of the Charlson comorbidity index category (see Appendix A) or BMI ≥30 kg/m2
+c. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19
+*. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
+The demographics tables above include participants with chronic, stable HIV infection, but they are excluded from the analysis populations for the efficacy and safety results in
+36
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Sections 6.1.11 and 6.1.12. Efficacy was not evaluated in participants with chronic, stable HIV infection. The safety analyses for this population are discussed in Section 9.1.6.
+6.1.10.3 Subiect Disposition
+The overall study disposition tables are presented below in Table 8 (Blinded Follow-up Time Period) and Table 9 (Open-label Unblinded Follow-up Time Period. Overall, few participants were discontinued or lost to follow-up and these discontinuations were generally balanced between treatment groups.
+A total of 87 (0.4%) Phase 2/3 original BNT162b2 participants received Dose 1 of BNT162b2 during the blinded placebo-controlled follow-up period and then received
+Dose 2 of BNT162b2 during the open-label follow-up period (when they were unblinded.
+During the open-label follow-up period, most participants originaly randomized to the placebo group for Doses 1 and 2 of study vaccine received BNT1622 as Doses 3 and 4 (88.8% and 72.4%, respectively) of study vaccine. Most participants who received
+Dose 3 but not Dose 4 were within the 3-week window between the two doses as of the data cutoff date. There were few participants in this group (0.1%) who were withdrawn from the study, and most were due to withdrawals by the participant. The number of participants originally randomized to the placebo group who were unblinded and received BNT162b2 was 19,525. Additionally, 839 of the initial randomized placebo recipients (610 in the younger age group and 229 in the older age group) either opted not to receive vaccine after unblinding or had not had the opportunity to receive BNT162b2 at the time of the March 13, 2021 data cutoff.
+Table 8. Study Disposition, Phase 2/3 Participants 16 Years of Age and Older, Blinded Follow-up Period
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+Total
+(Na=22085)
+(Na=22080)
+(Na=44165)
+nb (%)
+nb (%)
+nb (%)
+22085 (100.0)
+22080 (100.0)
+44165 (100.0)
+55 (0.2)
+50 (0.2)
+105 (0.2)
+22030 (99.8)
+22030 (99.8)
+21675 (98.1)
+352 (1.6)
+Disposition
+Randomized
+Not vaccinated
+Original blinded placebo-controlled follow-up period
+Vaccinated
+Dose 1
+Dose 2
+Discontinued from original blinded placebo-controlled vaccination periods
+Reason for discontinuation
+Lost to follow-up
+Withdrawal by subiect
+No longer meets eligibility criteria
+Adverse event
+Physician decision
+Pregnancy
+Protocol deviation
+Death
+Medication error without associated AE
+Withdrawal by parent/guardian
+151 (0.7)
+109 (0.5)
+26 (0.1)
+27 (0.1)
+5 (0.0)
+6 (0.0)
+3 (0.0)
+3 (0.0)
+3 (0.0)
+1 (0.0)
+22030 (99.8)
+22030 (99.8)
+21650 (98.1)
+528 (2.4)
+153 (0.7)
+181 (0.8)
+120 (0.5)
+26 (0.1)
+8 (0.0)
+6 (0.0)
+8 (0.0)
+4 (0.0)
+2 (0.0)
+44060 (99.8)
+44060 (99 .8)
+43325 (98.1)
+880 (2.0)
+304 (0.7)
+290 (0.7)
+146 (0.3)
+53 (0.1)
+13 (0.0)
+12 (0.0)
+11 (0.0)
+7 (0.0)
+5 (0.0)
+1 (0.0)
+37
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Disposition
+Other
+Unblinded before 1-month post-Dose 2 visit
+Completed 1-month post-Dose 2 visit
+Withdrawn from the study
+Withdrawn after Dose 1 and before Dose 2
+Withdrawn after Dose 2 and before 1-month
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+(Na=22085)
+(Na=22080)
+nb (%)
+nb (%)
+18 /0 1)
+20 (0 1)
+253 (1.1)
+240 (1.1)
+21382 (96.8)
+21293 (96.4)
+343 (1.6)
+484 (2.2)
+176 (0.8)
+211 (1.0)
+100 (0.5)
+139 (0.6)
+post-Dose 2 visit
+Withdrawn after 1-month post-Dose 2 visit
+67 (0.3)
+134 (0.6)
+Reason for withdrawal from the stud
+Lost to follow-up
+Withdrawal by subiect
+Protocol deviation
+Death
+Adverse event
+Physician decision
+No longer meets eligibility criteria
+Pregnancy
+Medication error without associated AE
+Withdrawal by parent/guardian
+Other
+174 (0.8)
+122 (0.6)
+11 (0.0)
+16 (0.1)
+9 (0.0)
+3 (0.0)
+1 (0.0)
+O
+1 (0.0)
+1 (0.0)
+5 (0.0)
+191 (0.9)
+226 (1.0)
+24 (0.1)
+15 (0.1)
+8 (0.0)
+6 (0.0)
+4 (0.0)
+1 (0.0)
+O
+0
+9 (0.0)
+Source: ST 125742.037 c4591001-508-safety tables, Table B, Page 1
+Note: Human immunodeficiency virus (HIV)-positive participants are included in this summary but analyzed and reported separately
+Note: Participants randomized but did not sign informed consent or had a significant quality event due to lack of Pl oversight are not included in any analysis population.
+Note: Because of a dosing error, 4 participants received an additional dose of BNT162b2 at an unscheduled visit after receiving 1 dose of BNT1622 and 1 dose of placebo.
+a. N = number of randomized participants in the specified group, or the total sample. This value is the
+denominator for the percentage calculations
+b. n = Number of participants with the specified characteristic
+c. Original blinded placebo-controlled vaccination period is defined as the time period from Dose 1 to 1 month post-Dose 2.
+Total
+(Na=44165)
+nb (%)
+38 (0.1)
+493 (1.1)
+42675 (96.6)
+827 (1.9)
+387 (0.9)
+239 (0.5)
+201 (0.5)
+365 (0.8)
+348 (0.8)
+35 (0.1)
+31 (0.1)
+17 (0.0)
+9 (0.0)
+5 (0.0)
+1 (0.0)
+1 (0.0)
+1 (0.0)
+14 (0.0)
+Table 9. Study Disposition, Phase 2/3 Participants 16 Years of Age and Older, Open-label (Unblinded) Follow-up Period
+Disposition
+Randomized
+Not vaccinated
+Originally randomized to BNT16262
+Received Dose 2/unplanned dose
+Completed 6-month post-Dose 2 visit
+Withdrawn from the study
+Withdrawn before 6-month post-Dose 2 visit
+Withdrawn after 6-month post-Dose 2 visit
+Reason for withdrawal from the study
+Withdrawal by subiect
+Protocol deviation
+Lost to follow-up
+Death
+Phvsician decision
+Adverse event
+Vaccine Group (as Randomized)
+BNT162b2
+(Na =22085)
+nb (%)
+22085 (100.0)
+55 (0.2)
+Placebo
+(Na =22080)
+nb (%)
+22080 (100.0)
+50 (0.2)
+20404 (92.4)
+87 (0.4)
+6414 (29.0)
+105 (0.5)
+103 (0.5)
+2 (0.0)
+56 (0.3)
+35 (0.2)
+4 (0.0)
+3 (0.0)
+2 (0.0)
+1 (0.0)
+38
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Vaccine Group (as Randomized)
+BNT162b2
+(Na =22085)
+nb (%)
+Placebo
+(Na =22080)
+nb (%)
+1 (0.0)
+3 (0.0)
+Disposition
+No longer meets eligibility criteria
+Other
+Originally randomized to placebo
+Completed 6-month post-Dose 2 visit
+Withdrawn from the study after unblinding and before
+Dose 3
+Received Dose 3 (first dose of BNT162b2)
+Received Dose 4 (second dose of BNT162b2)
+Discontinued from open-label vaccination period
+Reason for discontinuation from open-label vaccination period
+Protocol deviation
+Adverse event
+Withdrawal by subject
+Pregnancy
+Death
+Lost to follow-up
+Completed 1-month post-Dose 4 visit
+Withdrawn from the study
+Withdrawn after Dose 3 and before Dose 4
+Withdrawn after Dose 4 and before 1-month post-
+Dose 4 visit
+Withdrawn after 1-month post-Dose 4 visit
+Reason for withdrawal from the study
+Withdrawal by subject
+Protocol deviation
+Death
+Adverse event
+Lost to follow-up
+Source: ST 125742.037 c4591001-508-safety tables Table B, Page 1
+Note: Open-label (unblinded) vaccination period is defined as the time period from Dose 3 (first dose of BNT162b2) to 1 month post-Dose 4 (second dose of BNT162b2).
+Note: Human immunodeficiency virus (HIV)-positive participants are included in this summary but analyzed and reported separately.
+Note: Participants randomized but did not sign informed consent or had a significant quality event due to lack of PI oversight are not included in any analysis population.
+a. N = number of randomized participants in the specified group, or the total sample. This value is the denominator for the
+percentage calculations.
+b. n = Number of participants with the specified characteristic.
+The duration of blinded follow-up after completion of the 2-dose vaccine series in the safetv and evaluable efficacy populations are displayed in Table 10 and Table 11, respectively. Because this study is ongoing, and participants were unblinded to their study intervention following issuance of the EUA in December 2020 or at their 6-month follow-up visit, the number of participants with blinded follow-up decreases beyond 6 months, as expected.
+20948 (94.9)
+153 (0.7)
+497 (2.3)
+19612 (88.8)
+15986 (72.4)
+24 (0.1)
+6 (0.0)
+540.0
+4 (0.0)
+2 (0.0)
+2 (0.0)
+7209 (32.6)
+14 (0.1)
+11 (0.0)
+2 (0.0)
+1 (0.0)
+7 (0.0)
+3 (0.0)
+2 (0.0)
+1 (0.0)
+1 (0.0)
+39
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 10. Blinded Follow-up Duration After Dose 2, Participants 16 Years of Age and Older, Safety Population
+Vaccine Group (as Administered)
+BNT162b2
+Placebo
+Na =22026
+Na =22021
+Length of Follow-up°
+nb (%)
+nb (%)
+<2 Months
+1251 (5.7)
+1331 (6.0)
+≥2 Month to <4 months
+7744 (35.2)
+8070 (36.6)
+≥4 Months to <6 months
+11253 (51.1)
+11316 (51.4)
+≥6 Months
+1778 (8.1)
+1304 (5.9)
+Total
+Na =44047 n° (%)
+2582 (5.9)
+15814 (35.9)
+22569 (51.2)
+3082 (7.0)
+Source: ST 125742.0 c4591001-interim-mth6-report-body.pdf, Table 9, page 84
+a N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage
+calculations.
+b n = number of participants with the specified characteristic.
+Length of follow-up is the total exposure from Dose 2 to cutoff date or the date of unblinding, whichever date was earlier.
+Table 11. Blinded Follow-up Duration after Dose 2, Phase 2/3 Participants 16 Years of Age and Older, Evaluable Efficacy Population
+Duration of Follow-up
+<2 Months
+≥2 Months to <4 Months
+≥4 Months to <6 Months
+≥6 Months
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+Na =21047
+Na =21210
+nb (%)
+nb (%)
+840 (4.0)
+910 (4.3)
+7411 (35.2)
+7851 (37.0)
+11031 (52.4)
+11158 (52.6)
+1765 (8.4)
+1291 (6.1)
+Total
+Na =42257 nb (%)
+1750 (4.1)
+15262 (36.1)
+22189 (52.5)
+3056 (7.2)
+Source: Source: ST 125742.0.52 Table 1, page 4
+Note: HIV-positive participants are not included in this summary because they are not included in the efficacy analyses.
+a. N = number of participants in the analysis population for the primary efficacy endpoints (evaluable participants with and
+without evidence of prior infection). This value is the denominator for the percentage calculations
+b. n = Number of participants with the specified characteristic.
+The number of participants originally randomized to the BNT162b2 group who received both doses, were included in the evaluable efficacy population and had at least 6 months of blinded follow-up after Dose 2 is 1765 (8.4%).
+Disposition tables are presented below in Table 12 (efficacy analysis populations) and Table 13 (Phase 2/3 safety population). Overall, few participants were discontinued or lost to follow-up, and these and other analysis population exclusions were generally balanced between treatment groups.
+For the evaluable efficacy population, most participants who were excluded from the analysis had not received all vaccinations as randomized or did not receive Dose 2
+within the predefined window (i.e., 19 to 42 days after Dose 1). A total of 240 participants in the BNT162b2 group and 60 participants in the placebo group were excluded for having important protocol deviations (PDs) on or prior to 7 davs after Dose
+2. In the BNT162b2 group, most of these deviations were related to improper administration of the investigational product (203 participants, as compared with 23 participants in the placebo group). Specifically, in the BNT162b2 group most PDs were due to dosing/administration errors (errors in dilution of the vaccine, 76 participants) or administration of investigational product that was deemed not suitable for use (temperature excursions in shipment or storage at the distributor, 110 participants) that would have not applied to placebo.
+40
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 12. Disposition, Participants 16 Years of Age and Older, Efficacy Population
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+Total
+Disposition
+na (%)
+na (%)
+na (%)
+Randomized
+22085 (100.0) 22080 (100.0) 44165 (100.0)
+Dose 1 all-available efficacy population
+22009 (99.7) 22008 (99.7)
+44017 (99.7)
+Participants without evidence of infection
+21172 (95.9) 21168 (95.9)
+42340 (95.9)
+before Dose 1
+Participants excluded from Dose 1 all-available
+76 (0.3)
+72 (0.3)
+148 (0.3)
+efficacy population
+Reason for exclusion°
+Did not receive at least 1 vaccination
+55 (0.2)
+50 (0.2)
+105 (0.2)
+Data considered potentially unreliable due to
+21 (0.1)
+22 (0.1)
+43 (0.1)
+lack of PI oversight identified as significant quality event
+Dose 2 all-available efficacy population
+21648 (98.0) 21624 (97.9)
+43272 (98.0)
+Participants without evidence of infection
+20536 (93.0) 20487 (92.8)
+41023 (92.9)
+prior to 7 davs after Dose 2
+Participants excluded from Dose 2 all-available
+437 (2.0)
+456 (2.1)
+893 (2.0)
+efficacy population
+Reason for exclusion~
+Did not receive 2 vaccinations
+374 (1.7)
+430 (1 9)
+804 (1.8)
+Data considered potentially unreliable due to
+21 (0.1)
+22 (0.1)
+43 (0.1)
+lack of PI oversight 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)
+21300 (96.5)
+42436 (96.1)
+Participants without evidence of infection
+20064 (90.8) 20197 (91.5) 40261 (91.2)
+prior to 7 days after Dose 2
+Participants excluded from valuable efficacy
+949 (4.3)
+780 (3.5)
+1729 (3.9)
+(7 days) population
+Reason for exclusion©
+Randomized but did not meet all eligibility
+32 (0.1)
+30 (0.1)
+62 (0.1)
+criteria
+Data considered potentially unreliable due to
+21 (0.1)
+22 (0.1)
+43 (0.1)
+lack of PI oversight identified as significant quality event
+Did not receive all vaccinations as
+718 (3.3)
+729 (3.3)
+1447 (3.3)
+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
+44(0.2)
+11 (0. 0)
+55 (0.1)
+Had other important protocol deviations on or
+240 (1.1)
+58 (0.3)
+298 (0.7)
+prior to 7 davs after Dose 2
+Source: ST 125742.032 c4591001-508-efficacy tables, Table D, Page 7
+Note: HIV-positive participants are included in this summary but not included in the analyses of the overall study obiectives.
+a. n = Number of participants with the specified characteristic.
+b. These values are the denominators for the percentage calculations.
+c. Participants may have been excluded for more than 1 reason.
+The safety population included a total of 44,050 participants: 22,026 participants in the BNT162b2 group and 22,021 participants in the placebo group. Most of the 115 participants excluded from the safety population were excluded because they did not receive study vaccine.
+41
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 13. Disposition, Participants 16 Years of Age and Older, Safety Population
+Vaccine Group (as Administered)
+BNT162b2
+Placebo
+(Na =22026)
+(Na =22021)
+nb (%)
+nb (%)
+Disposition
+Randomized
+Not vaccinated
+Vaccinated
+Completed 1 dose
+Completed 2 doses
+Safety population
+Reactogenicity subset
+HIV-positive
+Indeterminate vaccine
+Participants excluded from safety population
+Reason for exclusion
+Participant did not receive study vaccine
+Unreliable data due to lack of PI oversight
+Completed at least 6 months follow-up after Dose 2 in blinded placebo-controlled follow-up period
+Completed at least 6 months follow-up after Dose 2 in blinded and open-label follow-up period
+Completed 1-month post-Dose 2 visit (vaccination period)
+Discontinued from vaccination period but continued in the study up to 1-month post-
+Dose 2 visit
+Discontinued after Dose 1 and before Dose
+2
+Discontinued after Dose 2 and before 1-month post-Dose 2 visit
+Reason for discontinuation from vaccination period
+Lost to follow-up
+Withdrawal by subject
+No longer meets eligibility criteria
+Adverse event
+Physician decision
+Pregnancy
+Protocol deviation
+Death
+Medication error without associated adverse event
+Withdrawal by parent/guardian
+Other
+Withdrawn from study before 1-month post-
+Dose 2 visit
+Withdrawn after Dose 1 and before Dose 2
+Withdrawn after Dose 2 and before 1-month post-Dose 2 visit
+Reason for withdrawal
+Total
+(Na =44050)
+nb (%)
+44165
+105
+22026 (100.0) 22021 (100.0) 44050 (100.0)
+22026 (100.0)
+22021 (100.0)
+44050 (100.0)
+21674 (98.4)
+21645 (98.3)
+43319 (98.3)
+22026 (100.0) 22021 (100.0)
+44050 (100.0)
+5033 (22.9)
+5032 (22.9)
+10068 (22.9)
+100 (0.5)
+100 (0.5)
+200 (0.5)
+3 (0.0)
+115 (0.3)
+1778 (8.1)
+1304 (5.9)
+12006 (54.5)
+21378 (97.1) 21291 (96.7)
+350 (1.6)
+520 (2.4)
+233 (1.1)
+359 (1.6)
+117 (0.5)
+161 (0.7)
+151 (0.7)
+108 (0.5)
+25 (0.1)
+27 (0.1)
+5 (0.0)
+6 (0.0)
+3 (0.0)
+3 (0.0)
+2 (0.0)
+149 (0.7)
+181 (0.8)
+120 (0.5)
+26 (0.1)
+7 (0.0)
+6 (0.0)
+8 (0.0)
+4 (0.0)
+1 (0.0)
+19 (0.1)
+273 (1.2)
+19 (0 1)
+344 (1.6)
+173 (0.8)
+100 (0.5)
+205 (0.9)
+139 (0.6)
+105 (0.2)
+10 (0.0)
+3082 (7.0)
+42669 (96.9)
+873 (2.0)
+595 (1.4)
+278 (0.6)
+300 (0.7)
+289 (0.7)
+145 (0.3)
+53 (0. 1)
+12 (0.0)
+12 (0.0)
+11 (0.0)
+7 (0.0)
+5 (0.0)
+1 (0.0)
+38 (0.1)
+617 (1.4)
+378 (0.9)
+239 (0.5)
+42
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Disposition
+Lost to follow-up
+Withdrawal bv subiect
+Adverse event
+Physician decision
+Death
+Protocol deviation
+Medication error without associated
+Vaccine Group (as Administered)
+BNT162b2
+Placebo
+(Na =22026)
+(Na =22021)
+no (%)
+n' (%)
+151 (0.7)
+153 (0.7)
+101 (0.5)
+168 (0.8)
+9 (0.0)
+7 (0.0)
+3 (0.0)
+5 (0.0)
+3 (0.0)
+4 (0.0)
+O
+1 (0.0)
+1 (0.0)
+Total
+(Na =44050)
+n° (%)
+304 (0.7)
+269 (0.6)
+16 (0.0)
+8 (0.0)
+7 (0.0)
+1 (0.0)
+1 (0.0)
+adverse event
+No longer meets eligibility criteria
+1 (0.0)
+Withdrawal by parent/guardian
+1 (0.0)
+Other
+4 (0.0)
+5 (0.0)
+1 (0.0)
+1 (0.0)
+9 (0.0)
+Source: ST 125742.037 c4591001-508-safety tables, Table C, Page 6
+Note: Human immunodeficiency virus (HIV)-positive participants are included in this summary but not included in the analyses of the overall study objectives
+Note: Participants randomized but did not sign informed consent or had a significant quality event due to lack of PI oversight are not included in any analysis population.
+Note: Because of a dosing error, Participants C4591001 (b) (6)
+, C4591001 (b) (6)
+C4591001 (b) (6)
+and C4591001 (b) (6)
+received an additional dose of BNT162b2 (30 ug) at an unscheduled visit after
+receiving 1 dose of BNT162b2 (30 g) and 1 dose of placebo.
+Note: "Indeterminate vaccine refers to participants whose vaccine group (as administered) could not be determined.
+These participants were included in the number of participants for "Total" column. These participants were not included in the safety analysis but their safety data are listed separately.
+a. N = number of randomized participants in the specified group, or the total sample. This value is the denominator for the
+percentage calculations
+b. n = Number of participants with the specified characteristic
+The disposition tables above include participants with chronic, stable HIV infection, but they are excluded from the analysis populations for the efficacy and safety results in Sections 6.1.11 and 6.1.12. Efficacy was not evaluated in participants with chronic, stable HIV infection. The safety analyses for this population are discussed in Section 9.1.6.
+6.1.11 Efficacy Analyses
+6.1.11.1 Analyses of Primary Endpoints)
+Vaccine Efficacy (Evaluable Efficacy Population)
+Protocol-specified, event-driven final primary efficacy analysis
+For the primary efficacy endpoint, vaccine efficacy (VE) for BNT162b2 against confirmed COVID-19 was evaluated in participants without evidence of prior SARS-Cov-2 infection prior to 7 davs after Dose 2. Cases were counted from 7 davs after Dose 2. 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 BNT1622 group compared to 162 COVID-19 cases in the placebo group. This protocol-specified, event-driven final primary efficacy
+43
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+analysis was the basis for issuance of the emergency use authorization for the Pfizer-BioNTech COVID-19 Vaccine on December 11, 2020. Please refer to the EUA Review Memo for the Pfizer COVID-19 Vaccine for additional details from that analysis time point.
+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, representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population. All of the following updated primary and secondar VE analvses are from this blinded placebo-controlled follow-up period through the March 13, 2021 data cutoff.
+For the first updated efficacy endpoint, vaccine efficacy (VE) for BNT162b2 against confirmed COVID-19 was evaluated in participants without evidence of prior SARS-CoV-2 infection prior to 7 days after Dose 2. For the second updated efficacy endpoint, VE for BNT162b2 against confirmed COVID-19 was evaluated in participants with and without evidence of prior SARS-CoV-2 infection prior to 7 days after Dose 2. Cases were counted from 7 days after Dose 2 for both endpoints.
+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 BNT162b2 group compared to
+833 COVID-19 cases in the placebo group (Table 14).
+Table 14. Updated Vaccine Efficacy Against Confirmed COVID-19 in Participants Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy Population (Data Cutoff
+March 13, 2021)
+BNT16262
+(Na =19993)
+Cases nib
+Surveillance Time
+Pre-specified Age Group
+All participants
+(n2d)
+77
+6.092 (19711)
+16-55 ears of age
+52
+3.593 (11517)
+>55 years of age
+25
+2.499 (8194)
+Placebo
+(Na =20118)
+Cases n1b
+Surveillance Time Vaccine Efficacy %
+(n2d)
+(95% CI)e
+833
+91.1
+5.857 (19741)
+(88.8, 93.1)
+568
+91.2
+3.439 (11533)
+(88.3, 93.5)
+265
+90.9
+2.417 (8208)
+(86.2, 94.2)
+Source: ST 125742.032 c4591001-508-efficacy tables, Table H, Page 13
+Abbreviations: -binding = SARS-CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test;
+SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy
+Note: Participants 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 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 davs after Dose 2 to the end of the surveillance period.
+d. n2 = Number of participants at risk for the endpoint.
+e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adiusted for surveillance time.
+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
+44
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+days after Dose 2 was 90.9%, with 81 and 854 cases in the BNT162b2 and placebo groups, respectively (Table 15).
+Table 15. Updated Vaccine Efficacy Against Confirmed COVID-19 in Participants With or Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy Population BNT162b2
+Placebo
+(Na =21047)
+(Na =21210)
+Cases
+Cases
+n1b
+n1b
+Pre-specified Age
+Group
+All participants
+Surveillance Time
+Surveillance Time
+(n2d)
+(n2d)
+81
+854
+6.340 (20533)
+6.110 (20595)
+16-55 years of age
+56
+584
+3.766 (12088)
+3.619 (12142)
+>55 years of age
+25
+270
+2.573 (8445)
+2.492 (8453)
+Vaccine Efficacy %
+(95% CI)e
+90.9
+(88.5, 92.8)
+90.8
+(87.9, 93.1)
+91.0
+(86.5, 94.3)
+Source: ST 125742.032 c4591001-508-efficacy tables, Table I, Page 14
+Abbreviations: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
+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. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+Multiole Cases of COVID-19
+Five placebo recipients developed 2 separate and clinically symptomatic instances of
+COVID-19 which were confirmed by NAAT at the central laboratory. Only the first occurrence of the confirmed COVID-19 illness was counted towards the updated VE analyses. All of the second confirmed COVID-19 cases occurred during the period before their first dose of BNT162b2 except for 1 participant developed their second COVID-19 diagnosis 4 days after his second dose of BNT162b2. All participants were N-binding antibody negative prior to their first instance of COVID-19. The time interval between the COVID-19 episodes varied from 1 to 5 months. Multiple cases of COVID-19 did not occur in vaccine recipients during the blinded portion of the study follow-up.
+Subgroup Analyses
+Subgroup analyses of the updated second vaccine efficacy endpoint provide additional information about the VE for participants with and without evidence of infection prior to vaccination in specific populations enrolled, which is the endpoint considered to represent the general population who may receive the vaccine, as prior infection status may not be known by vaccine recipients. The results are displayed below in Table 16.
+The VE point estimates for the subgroup analyses were comparable to results for the first primary efficacy endpoint.
+VE point estimates were consistent across the subaroups examined with the exception of participants identifying as multiracial and participants with evidence of prior SARS-Cov-2 infection at enrollment, for which too few COVID-19 cases occurred to interpret efficacy data for these subgroups. Additionally, the numbers of participants and cases in some other specific subgroups, such as the adolescent age group and racial subgroups, limits the interpretability of the VE results because of the wide credible intervals, but are displayed for completeness.
+45
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 16. Subgroup Analyses of Second Primary Endpoint, by Demographic and Baseline Characteristics: Updated Vaccine Efficacy Against Confirmed COVID-19 in Participants With or Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy Population
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+(Na =21047)
+(Na =21210)
+Cases n1b
+Cases n1b
+Vaccine
+Surveillance
+Surveillance
+Efficacy (%)
+Subgroup
+Times (n2d)
+Times (n2d)
+(95% CIe)
+Overall
+81
+854
+90.9
+6.340 (20533)
+6.110 (20595)
+(88.5. 92.8)
+Age group: 16-17 years
+0
+11
+100.0
+0.065 (365)
+0.061 (355)
+(62.4, 100.0)
+Age group: 18-64 years
+74
+715
+90.0
+5.008 (15853)
+4 817 (15914)
+(87.3, 92.3)
+Age group: ≥65 years
+7
+128
+94.7
+1.267 (4315)
+1.232 (4326)
+Age group: 65-74 years
+6
+102
+(88.7, 97.9)
+94.3
+1.021 (3450)
+0.992 (3468)
+(87.1, 98.0)
+Age group: ≥75 years
+1
+26
+96.2
+0.246 (865)
+0.240 (858)
+(77.2, 99.9)
+Sex: Female
+37
+455
+92.0
+3.051 (9985)
+3.013 (10241)
+(88.8, 94.4)
+Sex: Male
+44
+399
+89.6
+3.289 (10548)
+3.097 (10354)
+(85.8, 92.6)
+Ethnicity: Hispanic or Latino
+32
+240
+87.1
+1.841 (5280)
+1.777 (5266)
+(81.3, 91.4)
+Ethnicity: Not Hispanic or Latino
+48
+614
+92.5
+4.466 (15149)
+4.300 (15220)
+(89.9, 94.5)
+Ethnicity: Not reported
+1
+- O
+0.032 (104)
+0.034 (109)
+(NA, NA)
+Race: American Indian or Alaska
+O
+3
+100.0
+native
+0.043 (196)
+0.038 (180) (-116.0, 100.0)
+Race: Asian
+3
+24
+88.0
+0.258 (907)
+0.247 (896)
+(60.6, 97.7)
+Race: Black or African American
+4
+49
+92.0
+0.602 (1909)
+0.591 (1928)
+(78.1, 97.9)
+Race: Native Hawaiian or other
+O
+100.0
+Pacific Islander
+0.016 (54)
+0.008 (31) (-1947.9, 100.0)
+Race: White
+69
+749
+91.1
+5.234 (16846)
+5.054 (16952)
+(88.6, 93.2)
+Race: Multiracial
+5
+22
+80.1
+0.160 (538)
+0.140 (503)
+(46.1, 94.1)
+Race: Not reported
+6
+100.0
+0.027 (83)
+0.031 (105)
+(1.4, 100.0)
+Baseline SARS-CoV-2
+3
+6
+46 7
+Status:Positiveh
+0.183 (593)
+0.195 (643)
+(-149.5, 91.4)
+Baseline SARS-CoV-2
+77
+846
+91.2
+Status:Negative'
+6.119 (19805)
+5.883 (19838)
+(88.9. 93.2)
+Baseline SARS-CoV-2
+1
+2
+56.9
+Status:Unknown
+0 038 (135)
+0.033 (114)
+(-728.5. 99.3)
+Country: Argentina
+16
+110
+85.7
+1.033 (2655)
+1.017 (2670)
+(75.7, 92.1)
+Country: Brazil
+14
+82
+84.2
+0.441 (1419)
+0.408 (1401)
+(71.9, 91.7)
+46
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+(Na =21047)
+(Na =21210)
+Cases nib
+Cases n1b
+Vaccine
+Surveillance
+Surveillance
+Efficacy (%)
+Subgroup
+Country: Germany
+Time (n24)
+Time~ (n29)
+(95% CI°)
+1
+100.0
+0.047 (237)
+0.048 (243) (-3868.6, 100.0)
+Country: South Africa
+10
+100.0
+0.099 (358)
+0.096 (358)
+(56.6, 100.0)
+Country: Turkey
+O
+6
+100.0
+0.029 (238)
+0.026 (232)
+(22.2, 100.0)
+Country: United States
+51
+645
+92.4
+4.692 (15626)
+4.515 (15691)
+(89.9, 94.4)
+Source: ST 125742.032 c4591001-508-efficacy tables, Table J, Page 15
+Abbreviations: -binding = SARS-CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test;
+SARS-Cov-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
+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. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+* Includes participants who had at least one of the Charison Comorbidity Index category (see Appendix A) or obesity
+(BMI ≥30 kg/m2).
+9. Participants (≥16 years of age) who had BMI ≥30 kg/m2
+h. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19
+i. Negative N-binding ant body result and negative NAAT result at Visit 1 and no medical history of COVID-19.
+The subgroup analyses of updated vaccine efficacy by risk status in participants are presented in Table 17
+Table 17. Subgroup Analyses of Second Primary Endpoint, by Risk Status: Updated Vaccine Efficacy Against Confirmed COVID-19 in Participants With or Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy Population
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+(Na =21047)
+(Na =21210)
+Cases n1b
+Cases nib
+Surveillance
+Surveillance
+Time
+Time
+Subgroup
+Overall
+(n2d)
+(n2d)
+81
+854
+6.340 (20533)
+6.110 (20595)
+At risk: Yes
+36
+402
+2.887 (9359)
+2.772 (9340)
+At risk: No
+45
+452
+3 453 (11174)
+3.338 (11255)
+Age group and Risk: 16-64 and not
+44
+397
+at risk
+risk
+risk
+2.887 (9254)
+2.779 (9289)
+Age group and Risk: 16-64 and at
+30
+329
+2.186 (6964)
+2.100 (6980)
+Age group and Risk: ≥65 and not at
+1
+55
+0.566 (1920)
+0.559 (1966)
+Age group and Risk: ≥65 and at risk
+§
+73
+0.701 (2395)
+0.672 (2360)
+Obese: Yes'
+28
+314
+2.185 (6999)
+2.139 (7111)
+Vaccine
+Efficacy (%)
+(95% CI°)
+90.9
+(88.5. 92.8)
+91.4
+(87.9, 94.1)
+90.4
+(86.9, 93.1)
+89.3
+(85.4, 92.4)
+91.2
+(87.3, 94.2)
+98.2
+(89.6, 100.0)
+92.1
+(82.0, 97.2)
+91.3
+(87.1, 94.3)
+47
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+(Na =21047)
+(Na =21210)
+Cases n1b
+Cases n1b
+Surveillance
+Surveillance
+Time
+Time
+Subgroup
+Obese: No
+(n2d)
+(n2d)
+53
+540
+4 153 (13528)
+3 970 (13478)
+Age group and obese: 16-64 and
+49
+458
+not obese
+3.303 (10629)
+3.158 (10614)
+Age group and obese: 16-64 and
+25
+268
+obese
+1.768 (5584)
+1.719 (5649)
+Age group and obese: ≥65 and not
+4
+82
+obese
+0.850 (2899)
+0.811 (2864)
+Age group and obese: 265 and
+3
+46
+obese
+0.417 (1415)
+0.420 (1462)
+Vaccine
+Efficacy (%)
+(95% CIe)
+90.6
+(87.5, 93.1)
+89.8
+(86.2, 92.5)
+90.9
+(86.3, 94.2)
+95.3
+(87.6, 98.8)
+93.4
+(79.5, 98.7)
+Source: STN 125742.032 c4591001-508-efficacy tables, Table J, Page 15
+Abbreviations: -binding = SARS-CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test;
+SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
+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.
+°. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+* Includes participants who had at least one of the Charlson Comorbidity Index category (see Appendix A) or obesity
+(BMI ≥30 kg/m2).
+9. Participants (≥16 years of age) who had BMI ≥30 kg/m2.
+h. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
+i. Negative N-binding ant body result and negative NAAT result at Visit 1 and no medical history of COVID-19.
+Participants with positive prior SARS-CoV-2 status at baseline were defined as those with positive N-binding antibod or NAAT results at Visit 1 or a medical history of
+COVID-19. In the evaluable efficacy analysis for this subgroup, the estimated VE against cases occurring 27 days after Dose 2 was 46.9% (3 cases BNT162b2; 6 cases placebo), and in the all-available efficacy analysis the estimated VE against cases occurring at any time after Dose 1 was 19.2% (13 cases BNT162b2, 17 cases placebo).
+The low baseline seropositivity rate and small number of cases that occurred in these participants limits the interpretation of these data but indicate that symptomatic re-infections did occur among participants who were previously infected.
+Additional analvses of the updated vaccine efficacy endpoint were conducted to evaluate the vaccine efficacy, by demographic characteristics, geographic area, and comorbidity status, as displayed above in Section 6.1.11.1. VE point estimates were uniformly high across the comorbidities examined, though interpretation of some of the results is limited by small numbers of participants and/or cases.
+The demographics of the participants with confirmed COVID-19 cases contributing to the updated vaccine efficacy analysis are displayed below in Table 18.
+48
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 18. Demographic Characteristics of Participants With Protocol-Defined COVID-19, Participants Without Evidence of Prior SARS-CoV-2 Infection
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+Total
+(Na =77)
+(Na =833)
+(Na =910)
+Characteristic
+nb (%)
+n" (%)
+n' (%)
+Age at Vaccination: Mean years (SD)
+46.9 (14.79)
+47.1 (15.58)
+47.1 (15.51)
+Age at Vaccination: Median (years)
+50.0
+47.0
+48.0
+Age at Vaccination: Min, max (years)
+(19, 77)
+(16. 88)
+(16, 88)
+Age Group: 16-17 years
+10 (1.2)
+10 (1.1)
+Age Group: 18-64 years
+70 (90.9)
+699 (83.9)
+769 (84.5)
+Age Group: ≥65 years
+7 (9.1)
+124 (14.9)
+131 (14.4)
+Age Group: 65-74 years
+6 (7.8)
+98 (11.8)
+104 (11.4)
+Age Group: ≥75 years
+1 (1.3)
+26 (3.1)
+27 (3.0))
+Race: American Indian or Alaska Native
+3 (0.4)
+3 (0.3)
+Race: Asian
+3 (3.9)
+23 (2.8)
+26 (2.9)
+Race: Black or African American
+4 (5.2)
+48 (5.8)
+52 (5.7)
+Race: Native Hawaiian or Other Pacific
+1 (0.1)
+1 (0.1)
+slander
+Race: White
+67 (87.0)
+730 (87.6)
+797 (87.6)
+Race: Multiracial
+3 (3.9)
+22 (2.6)
+25 (2.7)
+Race: Not reported
+6 (0 7)
+6 (0.7)
+Sex: Female
+35 (45.5)
+444 (53.3)
+479 (52.6)
+Sex: Male
+42 (54 5)
+389 (46.7)
+431 (47.4)
+Ethnicity: Hispanic or Latino
+29 (37.7)
+236 (28.3)
+265 (29.1)
+Ethnicity: Not Hispanic or Latino
+47 (61.0)
+597 (71.7)
+644 (70.8)
+Ethnicitv: Not reported
+1 (1.3)
+1 (0.1)
+Comorbidities: Yes°
+35 (45.5)
+395 (47.4)
+430 (47.3)
+Comorbidities: No
+42 (54 5)
+438 (52 6)
+480 (52.7)
+Obesity: Yesd
+27 (35.1)
+310 (37.2)
+337 (37.0)
+Obesity: No
+50 (64.9)
+523 (62.8)
+573 (63.0)
+Country: Argentina
+15 (19 5)
+108 (13.0)
+123 (13.5)
+Country: Brazil
+12 (15.6)
+80 (9.6)
+92 (10.1)
+Country: Germany
+1 (0 1)
+1 (0.1)
+Countrv: South Africa
+9 (1.1)
+9 (1.0)
+Country: Turkey
+5 (0.6)
+5 (0.5)
+Countrv: United States
+50 (64.9)
+630 (75.6)
+680 (74.7)
+Source: ST 125742.032 c4591001-508-efficacy tables, Table K, Page 22
+a. N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage
+calculations.
+b. n = Number of participants with the specified characteristic.
+c. Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as participants who had at least one of the Charison comorbidity index category (see Appendix A) or BMI ≥30 kg/m?.
+d. Participants who had BMI ≥30 kg/m?.
+Additional analyses of the updated vaccine efficacy endpoint were conducted to evaluate the vaccine efficacy by comorbidity status. VE point estimates were uniformly high across the comorbidities examined, though interpretation of some of the results is limited by small numbers of participants and/or cases Table 19.
+49
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 19. Updated Vaccine Efficacy by Comorbidity Status, Participants Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy Population
+Vaccine Group (as Randomized)
+BNT162b2
+Placebo
+(Na =19993)
+(Na =20118)
+Cases n1b
+Cases n1b
+Surveillance Time Surveillance Time
+Subgroup
+Overall
+(n2d)
+(n2d)
+77
+833
+6.092 (19711)
+5.857 (19741)
+Vaccine
+Efficacy (%)
+(95% CI°)
+91.1
+(88.8, 93.1)
+Comorbidity
+42
+No comorbidity
+3.329 (10757)
+35
+Any comorbidity
+2.763 (8954)
+3
+Cardiovascular
+0.172 (584)
+8
+Chronic pulmonary disease
+0.474 (1582)
+9
+Diabetes
+0.465 (1528)
+27
+Obese (230.0 kg/m2)
+2.083 (6673)
+15
+Hypertension
+1.481 (4900)
+Diabetes (including gestational
+9
+diabetes)
+0.468 (1537)
+438
+3.207 (10808)
+395
+2.65 (8933)
+22
+0.159 (555)
+66
+0.443 (1562)
+60
+0.444 (1513)
+310
+2.034 (6770)
+190
+1.427 (4895)
+62
+0.447 (1527)
+90.8
+(87.3, 93.4)
+91.5
+(88.0, 94.2)
+87.4
+(58.1, 97.6)
+88.7
+(76.3, 95.3)
+85.7
+(70.9, 93.7)
+91.5
+(87.4, 94.5)
+92.4
+(87.1, 95.8)
+86.1
+(71.9, 93.9)
+Source: ST 125742.032 c4591001-508-efficacy tables, Table L, Page 25
+Abbreviations: -binding = SARS-CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test; SARS-CoV-2 =
+severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy
+Note: Participants 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 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.
+din2 = Number of participants at risk for the endpoint.
+.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time. tSubiect who had 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as participants who had at least one of the Charison comorbidity index category (see Appendix A) or BMI 230 kg/m?
+Cumulative incidence curves
+Based on the cumulative incidence curve for the all-available efficac population after Dose 1, (Figure 3), COVID-19 disease onset appears to occur similarly for both BNT162b2 and placebo groups until approximately 14 days after Dose 1, at which time point, the curves diverge.
+50
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Figure 3. Updated Cumulative Incidence Curves for the First COVID-19 Occurrence After Dose 1, All-Available Efficacy Population (data cutoff March 13, 2021)
+Cumulative Incidence of COVID-19 Occwc
+0.07
+0.05
+0.05
+0.01
+0.03
+0.01
+0.00
+Subjects at Risk
+22505
+10
+84
+140
+154
+182
+196
+210
+138
+Davs After Dose
+29181
+21325
+20550
+15191
+14582
+79901
+2463
+19629
+TEARIE
+116
+509
+344
+1015
+1034
+§ E
+1034
+A: BNT16262 (30 lg)
+B: Placebo
+Note IS indicates cubiects with severe ('OUTD-19
+Source: Adapted from ST 125742.0 c4591001-interim-mth6-report-body.pdf. Figure 2. page 104.
+An updated analysis of the number of confirmed COVID-19 cases following Dose 1 was conducted with the all-available efficacy population, for all participants regardless of evidence of prior infection through 7 days after Dose 2, and at time intervals following completion of the vaccine series (Table 20).
+Table 20. Updated Vaccine Efficacy after Dose 1, Dose 1 All-Available Efficacy Population
+BNT16262
+Placebo
+(Na =21909)
+(Na =21908)
+Cases
+Cases
+n16
+n16
+Surveillance
+Surveillance
+Time
+Time
+Efficacy Endpoint Subgroup
+First COVID-19 occurrence after Dose 1
+(n2d)
+(n2d)
+128
+998
+8.155 (21385)
+7.874 (21315)
+43
+98
+After Dose 1 to before Dose 2
+1.273 (21385)
+1.266 (21315)
+3
+30
+Dose 2 to 7 days after Dose 2
+0.403 (21049)
+0.401 (20952)
+82
+870
+≥7 Days after Dose 2
+≥7 Days after Dose 2 to <2 Months after
+Dose 2
+6.479 (21019)
+6.207 (20901)
+12
+296
+2.786 (21019)
+2.750 (20901)
+Vaccine
+Efficacy %
+(95% CI)e
+87.6
+(85.1, 89.8)
+56.4
+(37.0, 70.3)
+90
+(68.0, 98.1)
+91
+(88.7, 92.9)
+96.0
+(92.9, 98)
+51
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+BNT162b2
+(Na =21909)
+Cases
+n1b
+Surveillance
+Time
+Efficacy Endpoint Subgroup
+≥2 Months after Dose 2 to 4 Months after
+Dose 2
+(n2d)
+46
+2.665 (20160)
+24
+≥4 Months after Dose 2
+1.028 (12624)
+Placebo
+(Na =21908)
+Cases
+n1b
+Surveillance
+Time (n2d)
+446
+2.564 (19720)
+128
+0.893 (11760)
+Vaccine
+Efficacy %
+(95% CI)e
+90.1
+(86.5, 92.8)
+83.7
+(74.7, 89.9)
+Source: ST 125742.032 c4591001-508-efficacy tables, Table O, Page 30
+Abbreviation: VE = vaccine efficacv.
+a N = number of participants in the specified group.
+b 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 Dose 1 to the end of the surveillance period.
+d n2 = Number of participants at risk for the endpoint.
+Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+The VE estimate for the prevention of COVID-19 disease after Dose 1 in the all-available efficacy population is 87.6%. Additionally, VE at 24 Months after Dose 2 is 83.7% in the all-available efficacy population, suggesting some modest attenuation in efficacy over time. However, this attenuation was limited to efficacy against non-severe
+COVID-19, as the only protocol-confirmed severe case reported during blinded, placebo-controlled follow-up among BNT162b2 recipients in the all-available efficacy population occurred with onset at 35 davs after Dose 2 and did not result in hospitalization (see Section 6.1.11.2 for further details). Based on the number of cases accumulated after Dose 1 and before Dose 2, there does seem to be some protection against COVID-19 disease following one dose; however, these data do not provide information about longer term protection beyond 3 weeks after a single dose. VE estimates over these time intervals in the all-available efficac population were similar to estimates in the valuable efficacy population.
+Additional analvses assessed vaccine efficacy in two successive periods of follow-up, from days 35-90 and 91-224, to explore whether changes in COVID-19 epidemiology or potential waning of immunity during the blinded follow-up period may have impacted vaccine efficacy over time. Vaccine efficacy for days 35-90 and days 91-224 were 93.7% [90.6;96.0] and 88.3% [84.6;91.2], respectively. The risk ratio of the incidence rates between vaccine and placebo in the period from Dose 1 to Day 57 and from Dose 1 to Day 224 were 0.173 [95% CI 0. 128;0.232] and 0.122 [95% CI 0.101;0.147], suggesting a small, non- significant change in vaccine efficacy over time.
+Reviewer Comment: Updated efficacy analyses were conducted in March 2021, prior to the emergence of the B. 1.617.2 (Delta) variant in the US.
+6.1.11.2 Analyses of Secondary Endpoints
+In the protocol-specified event-driven final analysis of the evaluable efficacy population, vaccine efficacv against severe COVID-19 for participants without prior SARS-CoV-2 infection occurring at least 7 days after Dose 2 was 66.4% (95% Credible Interval: - 124.8%, 96.3%). In this analysis, only four participants had severe COVID-19 disease at least 7 days after Dose 2 (1 BNT162b2 group; 3 placebo group). Please refer to the EUA Review Memo for additional details from that analvsis time point.
+52
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Updated efficacy analyses of the secondary efficacy endpoint for prevention of severe
+COVID-19 were also evaluated with additional confirmed COVID-19 cases accrued during blinded placebo-controlled follow-up through March 13, 2021. Vaccine efficacy against severe COVID-19 is presented in Table 21 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 severe COVID-19 cases in one participant who received BNT162b2 and 21 participants who received placebo. 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 based on a larger number of severe cases now show more compelling protection against severe COVID-19 disease offered by BNT162b2. The vaccine recipient who had severe COVID-19 disease met the severe case definition because oxygen saturation at the COVID-19 illness visit was 93% on room air. COVID-19 symptoms began 35 days after Dose 2. The participant was <55 years of age, not hospitalized, did not seek further medical care, and did not have risk factors for severe disease. Additional details about the severe cases in placebo recipients are discussed below, with the all-available efficacy population.
+Table 21. Updated Vaccine Efficacy Against Severe COVID-19, Participants Without Evidence of Prior SARS-CoV-2 Infection, Evaluable Efficacy Population
+BNT16262
+Placebo
+(Na =19993)
+(Na =20118)
+Cases
+Cases
+n16
+nib
+Surveillance
+Surveillance
+Time©
+Times
+Vaccine Efficacy %
+Secondary Efficacy Endpoint
+(n2d)
+(n2d)
+(95% CI)e
+First severe COVID-19 occurrence
+1
+21
+95.3
+from 7 days after Dose 2 in
+6 103
+5.971
+(71.0, 99.9)
+participants without evidence of
+(19711)
+(19741)
+prior SARS-CoV-2 infection
+Source: STN 125742.032 c4591001-508-efficacy tables, Table M, Page 28
+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: Participants 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 participants in the specified group.
+b 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.
+• n2 = Number of participants at risk for the endpoint.
+Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+In the all-available efficacy population, 31 participants had severe COVID-19 disease after Dose 1 (one subiect who received BNT1622 and 30 participants who received placebo) (Table 22).
+53
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 22. Updated Vaccine Efficacy Against First Occurrence of Severe COVID-19 After Dose 1, Dose 1 All-Available Efficacy Population
+BNT162b2
+Placebo
+(Na =21909)
+(Na =21908)
+Cases
+Cases
+n1b
+п16
+Surveillance
+Surveillance
+Time
+Time
+Vaccine Efficacy %
+Secondary Efficacy Endpoint
+(n2d)
+(n24)
+(95% CI)°
+First severe case occurrence after
+1
+30
+96.7
+Dose 1
+8.181 (21385)
+8.032 (21316)
+(80.3, 99.9)
+0
+6
+100
+After Dose 1 to before Dose 2
+1.285 (21385)
+1 293 (21316)
+(14.6, 100.0)
+1
+100
+Dose 2 to 7 davs after Dose 2
+0.403 (21056)
+0.402 (20962)
+(-3783.8, 100.0)
+1
+23
+95.8
+≥7 davs after Dose 2
+6.493 (21029)
+6.337 (20940)
+(73.9, 99.9)
+Source: STN 125742.032 c4591001-508-efficacy tables, Table N, Page 29
+Abbreviation: VE = vaccine efficacy.
+a N = number of participants in the specified group.
+b 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 Dose 1 to the end of the surveillance period.
+n2 = Number of participants at risk for the endpoint.
+• Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
+The 30 placebo recipients who had severe COVID-19 had a mean age of 51 years, with a range of 19 to 71 years of age. The demographics of these 30 participants are as follows: 17 (56.7%) participants were in the younger age group, 20 (66.7%) were male, 11 (36.7%) identified as Hispanic or Latinx, 15 (50%) were obese, and 9 (30%) had other comorbidities that increased the risk for severe disease. Ten (33.3%) participants were on high flow oxygen, 8 (26.7%) were admitted to the ICU, 2 (6.7%) were on a ventilator, and 1 participant died with septic shock while hospitalized for severe
+COVID 19.
+6.1.11.4 Dropouts and/or Discontinuations
+The number of participants who dropped out and/or discontinued from the study did not affect the interpretation of the vaccine efficacy outcomes. Refer to Section 6.1.12.7 for details regarding dropouts and/or discontinuations.
+6.1.11.5 Exploratory and Post Hoc Analyses
+Sequencing Data from Centrally Confirmed COVID-19 Cases
+During the Phase 2/3 portion of Study C4591001 (July 27, 2020, through the data cutoff date of March 13, 2021), new SARS-CoV-2 variants emerged in geographical regions where the study was conducted. In a post hoc analysis, whole genome sequencing was performed for confirmed cases of COVID-19 evaluated for efficacy during the blinded placebo-controlled follow-up period up to the data cutoff date of March 13, 2021. SARS-Cov-2 variants of concern identified from COVID-19 cases in this study 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.
+54
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 23 below displays the sequence analysis summary for all SARS-CoV-2 lineages associated with confirmed COVID-19 cases in the BNT162b2 and placebo groups, including any designated as variants of concern (VOCs) or variants of interest (VOls), based on WHO and CDC SARS CoV-2 variant classifications and definitions (World Health Organization 2021b; CDC 2021g). The designation as "Other" indicates that the sequenced SARS CoV-2 lineages were not considered VOCs or VOls.
+Table 23. SARS-Cov-2 Variants of Concern or Variants of Interest for the First COVID-19
+Occurrence From 7 Days After Dose 2, Blinded Placebo-Controlled Follow-up Period, Subjects With or Without Evidence of Infection Prior to 7 Days After Dose 2, Evaluable Efficacy (7 Days) Population
+Vaccine Group (as Randomized)
+BNT162b2 (30 pg)
+Placebo
+Total
+SARS-CoV-2 Lineage
+(Na =81)
+(Na =873)
+(Na =954)
+(Location First Identified)
+n°(%)
+n°(%)
+n°(%)
+B.1.1.7 (United Kingdom)
+3 (0.3)
+3 (0.3)
+B.1.351 (South Africa)
+O
+9 (1.0)
+9 (0.9)
+B. 1.427/B. 1.429 (USA)
+1 (1.2)
+23 (2.6)
+24 (2.5)
+B.1.525 (UK and Nigeria)
+1 (0.1)
+1 (0.1)
+B. 1.526 (USA)
+1 (0.1)
+1 (0.1)
+B.1.616 (France)
+B.1.617 (India)
+B.1.618 (India)
+0
+P.1 (Brazil/Japan)
+1 (1.2)
+1 (0.1)
+2 (0.2)
+P.2 (Brazil)
+6 (7.4)
+40 (4.6)
+46 (4.8)
+P.3 (Philippines)
+Other
+66 (81.5)
+755 (86.5)
+821 (86.1)
+Unknownd
+7 (8.6)
+33 (3.8)
+40 (4.2)
+Not seguenced
+0
+8 (0.9)
+8 (0.8)
+Source: ST 125742.6 c4591001-sequencing-report.pdf, Table 1, page 11.
+Abbreviation: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
+a. N = number of subjects with first COVID-19 occurrence. This value is the denominator for the percentage calculations.
+b. Based on PANGO lineages (cov-lineages.org).
+c. n = Number of subiects with the specified characteristic.
+. Include indeterminate result and not quantifiable samples.
+Reviewer Comment: The updated efficacy analyses were done prior to the emergence of the B. 1.617.2 (Delta) variant in the US.
+Updated Vaccine Efficacy Against Severe COVID-19, CDC definition
+The Applicant conducted an additional updated analysis of vaccine efficacy against severe cases of COVID-19 using the CDC definition of severe COVID-19 (hospitalization, admission to the ICU, intubation or mechanical ventilation, or death), based on confirmed COVID-19 cases accrued during blinded placebo-controlled follow-up through March 13, 2021. Among participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, the estimated VE against CDC-defined severe
+COVID-19 occurring at least 7 days after Dose 2 was 100.0% (2-sided 95% Cl: 88.1%, 100.0%), with 0 and 31 cases in the BNT162b2 and placebo groups, respectively. This additional analysis further supports the conclusion that BNT1622 offers protection against severe COVID-19 disease.
+55
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+6.1.12 Safety Analyses
+The Phase 2/3 safety data presented in this section are categorized in following time periods:
+1. Blinded placebo-controlled period: Dose 1 to 1 month after Dose 2 and to unblinding date:
+• Participants with up to ~6 months after Dose 2 (N=43,847; BNT162b2 group
+N=21,926 and placebo group N=21,921).
+• Solicited local ARs and systemic As were assessed during this time period from a subset of participants.
+2. Open-label observational period: from time of unblinding to data cutoff date:
+• Participants originally randomized to BNT162b2 (N=20,309)
+• Participants originally randomized to placebo who then received BNT162b2
+(N=19,525)
+• Participants originally randomized to placebo who had confirmed COVID-19 then received BNT162b2 (N=852)
+• Only unsolicited AEs (AEs, SAEs and adverse events of special interest [AESIs]) were assessed during this time period.
+3. Cumulative follow-up from Dose 1 to at least 6 months after Dose 2:
+• Participants originally randomized to BNT1622 (inclusive of blinded data and open-label data through the March 13, 2021 data cutoff). (Total N=12,006: 16-55 years of age/younger age group IN =6,6661 and >55 years of age/older age group [N =5,3401).
+Reviewer Comment: Interpretation of safet data from the open-label observational period are limited because there was no longer a study group for safety comparisons in the unblinded portion of the study. Additionally, 839 of the initial randomized placebo recipients (610 in the younger age group and 229 in the older age group) either opted not to receive vaccine after unblinding or had not had the opportunity to receive BNT162b2 at the time of the March 13, 2021 data cutoff.
+Participants with chronic, stable HIV infection were excluded from the general safety population analyses and are summarized in a separate analysis (see Section 9.1.6 of this memo).
+6.1.12.1 Methods
+Please see Section 6.1.7.
+6.1.12.2 Overview of Adverse Events
+Overview of adverse events
+Table 24 below presents an overview of immediate unsolicited adverse events and solicited local reactions and systemic adverse events in the safety population. Table 25 below presents an overview of participants reporting at least 1 unsolicited adverse event during the blinded placebo-controlled time period.
+In the blinded placebo-controlled time period, the most frequently reported solicited adverse reactions in all age groups included injection site pain, fatigue, headache, muscle pain, and chills. Additionally, unsolicited ARs reported at higher frequency by
+56
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+the BNT162b2 group than the placebo group among participants not included in the reactogenicity subset were consistent with local and systemic adverse reactions adverse reactions solicited among participants in the reactogenicity subset.
+Table 24. Immediate and Solicited Local Reactions and Systemic Adverse Events, Participants 16 Years of Age and Older, Safety Population BNT162b2
+Placebo
+Event
+na/Nb (%)
+naNb (%)
+Immediate unsolicited AE within 30 minutes after vaccination
+Dose 1
+105/21926 (0.5)
+81/2191 (0.4)
+Dose 2
+71/21571 (0.3)
+54/21549 (0.3)
+Solicited local reaction within 7 days
+Dose 1
+3877/4907 (79.0)
+639/4897 (13.0)
+Dose 2
+3351/4542 (73.8)
+483/4517 (10.7)
+Solicited systemic AE within 7 days
+Dose 1
+2963/4907 (60.4)
+2308/4897 (47.1)
+Dose 2
+323714542 (71.3)
+1542/4517 (34.1)
+Source: ST 125742.0.37 c4591001-508-safety-tables.pdf, Table P, page 12.
+Note: MedDRA (v23.1) coding dictionary applied.
+Note: Immediate A refers to an A reported in the 30-minute observation period after vaccination.
+an = Number of subjects reporting at least 1 occurrence of the specified event category.
+b N: number of participants in the specified age group in the reactogenicity subset of the safety population with data available for the adverse event..
+Table 25. Unsolicited Adverse Events, Blinded Placebo-controlled Follow-up Period, Participants 16 Years of Age and Older, Safety Population
+BNT162b2 BNT162b2 BNT162b2
+Placebo Placebo
+16-55 Years >55 Years
+Total 16-55 Years >55 Years
+(Na =12995) (Na=8931) (Na =21926) (Na =13026) (Na =8895) (Na =21921)
+nb (%)
+nb (%)
+nb (%)
+nb (%)
+nb (%)
+Placebo
+Total
+nb (%)
+Adverse Event
+Dose 1 through 1 Month after Dose 2
+Any unsolicited AE
+Unsolicited non-serious AE
+SAEs
+Withdrawal due to unsolicited AF
+Death
+4233
+(32.6)
+4207
+(32.4)
+52
+(0.4)
+19
+(0.1)
+(0.0)
+2384
+(26.7)
+2350
+(26.3)
+75
+(0.8)
+13
+(0.1)
+3
+(0.0)
+6617
+(30.2)
+6557
+(29.9)
+127
+(0.6)
+32
+(0.1)
+3
+(0.0)
+1871
+(14.4)
+1855
+(14.2)
+49
+(0.4)
+20
+(0.2)
+ク
+(0.0)
+1177
+(13.2)
+1141
+(12.8)
+67
+(0.8)
+16
+(0.2)
+3
+(0.0)
+3048
+(13.9)
+2996
+(13.7)
+116
+(0.5)
+36
+(0.2)
+5
+(0.0)
+Dose 1 to cutoff date or participant unblinding (whichever is earlier)
+Any unsolicited AE
+Unsolicited non-serious AE
+SAE
+4396
+(33.8)
+4347
+(33.5)
+103 (0.8)
+Withdrawal due to unsolicited AE
+Death
+22 (0.2)
+3
+(0.0)
+2551
+(28.6)
+2471
+(27.7)
+165
+(1.8)
+23
+(0.3)
+12
+(0.1)
+6947
+(31.7)
+6818
+(31.1)
+268
+(1.2)
+45
+(0.21)
+15
+(0.1)
+2136
+(16.4)
+2086
+(16.0)
+117
+(0.9)
+28
+(0.2)
+4
+(0.0)
+1432
+(16.1)
+1347
+(15.1)
+151
+(1.7)
+23
+(0.3)
+10
+(0.1)
+3568
+(16.3)
+3433
+(15.7)
+268
+(1.2)
+51
+(0.2)
+14
+(0.1)
+57
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Source: ST 125742.0, amendment 66. Response to IR.
+N = number of subjects in the specified group. This value is the denominator for the percentage calculations.
+n = Number of subjects reporting at least 1 occurrence of the specified event category. For "any event," n = number of
+subjects reporting at least 1 occurrence of any event.
+Cutoff date: March 13, 2021; unblinding date varied depending on subject contact date for unblinding.
+Immediate AEs
+The frequency of immediate As (defined as events occurring within the first 30 minutes following any dose) reported in the vaccine group was 0.5% after Dose 1 and 0.3% after Dose 2 and were mainly consistent with solicited reactogenicity events. In both study groups, the most frequently reported immediate A was injection site pain (BNT162b2 vaccine 0.3%, placebo 0.2%). For both study groups, no participant reported an immediate allergic reaction that was considered by the study investigator to be related to vaccination or to the saline placebo.
+Reviewer Comment: FDA agrees with the study investigators' assessment.
+Anaphylaxis
+No anaphylactic reactions to BNT1622 were reported through the cutoff date of March 13, 2021. During the open-label observational follow-up period for study C4591001, among participants ≥16 years of age, 1 participant who received BNT162b2 as Dose 3 (crossover vaccination as subject was originally randomized to placebo) experienced an SAE of anaphylactoid reaction, which was assessed as related to study vaccine. The subject, a female adolescent with a medical history significant for multiple allergies since infancy reported that 2 days after receiving BNT162b2, the appearance of hives on her left arm deltoid. Approximately 24 minutes after the appearance of the hives she self-administered an epinephrine pen (personal medication given the history of anaphylaxis to multiple allergens). Six minutes after injection, the subject experienced shortness of breath. Hives and shortness of breath resolved within 10 and 30 minutes, respectively, of epinephrine treatment. The subject did not seek additional medical attention. As a result of the anaphylactoid reaction, the subject was permanently withdrawn from the study (FDA 2021b).
+During the blinded placebo-controlled follow-up period, three SAEs involving allergic reactions were reported among three participants ≥16 years of age (previously reported at November 14, 2020 cutoff date). A review of the temporal relationship to vaccination and alternate inciting etiology does not support the administration of BNT162b as the causative agent:
+• Anaphylactic reaction following a bee sting in a BNT1622 recipient (8 davs after
+Dose 2)
+• Drug hypersensitivity to an antibiotic in a BNT162b2 recipient (9 days after Dose 2)
+• Anaphylactic shock due to an ant bite in a placebo recipient (18 days after Dose 2).
+Solicited local reactions and systemic adverse events
+Solicited Local Reactions
+For each age group in the reactogenicity subset (younger: 16-55 years, older: >55 years) and overall (16 years and older), the median onset of solicited local reactions in the vaccine group was 0 (day of vaccination) to 2 days after either dose and solicited reactions lasted a median duration between 1 and 2 days.
+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
+58
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+the older age group (78.3% vs 66.1%) and also pain characterized as moderate (29.4% vs. 18.7%); a similar pattern was observed after Dose 1. Injection site redness and swelling after each dose were generally similar for both age groups.
+Table 26 and Table 27 present the frequency and severity of reported solicited local reactions within 7 days following each dose of BNT162b2 and placebo in the subset of participants 16 55 years of age, and older than 55 years of age, respectively, included in the safety population who were monitored for reactogenicity with an electronic diary.
+Subgroup analvses by age
+Table 26. Frequency of 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*
+BNT162b2
+Dose 1
+Na =2899 n° (%)
+Placebo
+Dose 1
+Na =2908 nb (%)
+BNT162b2
+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)
+Severe
+39 (1.3)
+3 (0.1)
+39 (1.5)
+312 (11.6)
+284 (10.6)
+28 (1.0)
+O
+Source: ST 125742.0 c4591001-interim-mth6-report-body.pdf, Table 14.68, pages 531-532
+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.
+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.
+Table 27. Frequency of Local Reactions, by Maximum Severity, Within 7 Days After Each Dose, Participants Older Than 55 Years of Age, Reactogenicity Subset of the Safety Population*
+Redness~
+Any (>2.0 cm)
+Mild
+Moderate
+Severe
+BNT162b2
+Dose 1
+Na =2008 nb (%)
+Placebo
+Dose 1
+Na =1989 nb (%)
+BNT162b2
+Dose 2
+Na =1860 nb (%)
+Placebo
+Dose 2
+Na =1833 nb (%)
+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)
+59
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+BNT162b2
+Dose 1
+Na =2008 nb (%)
+Placebo
+Dose 1
+Na =1989 n° (%)
+BNT162b2
+Dose 2
+Na =1860 n' (%)
+Placebo
+Dose 2
+Na =1833 n' (%)
+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 (0.0)
+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 (0.0)
+10 (0.5)
+143 (7.8)
+138 (7.5)
+5 (0.3)
+0 (0.0)
+Source: STN 125742.0 c4591001-interim-mth6-report-body.pdf, Table 14.68, pages 532-534.
+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.
+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 510.0 cm; Severe: >10.0 cm.
+d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
+Solicited Systemic Reactions
+For each age group in the reactogenicity subset (younger: 16-55 years, older: >55 years) and overall (16 years and older), the median onset of solicited systemic AEs in the vaccine group in general was 1 to 2 days after either dose, and solicited systemic AEs lasted a median duration of 1 day.
+The frequencies of any and severe solicited systemic As were higher in the younger than the older age groups. Within each age group, the frequencies of any and severe systemic AEs were higher after Dose 2 than Dose 1, except for diarrhea, which was generally similar regardless of dose. For both age groups, fatigue, headache and new/worsened muscle pain were most common.
+Subgroup analyses by age
+Table 28 and Table 29 present the frequencies and severities of reported solicited systemic reactions within 7 days following each dose of BNT1622 and placebo in the subset of participants 16-55 years of age, and >55 years of age, respectively, included in the safety population who were monitored for reactogenicity with an electronic diary.
+Table 28. Frequency of Solicited Systemic Reactions, by Maximum Severity, Within
+7 Days After Each Dose, Participants 16 Through 55 Years of Age, Reactogenicity Subset of the Safetv Population*
+Fever
+>38 0°C
+≥38 0°C to 38 4°C
+>38 4°~ to 38 0°c
+>38 9°C to 40 0°C
+>40.0°C
+BNT16262
+Dose 1
+Na =2899 nb (%)
+119 (4.1)
+86 (3.0)
+25 (0.9)
+8 (0.3)
+0 (0.0)
+Placebo
+Dose 1
+Na =2908 nb (%)
+25 (0 9)
+16 (0.6)
+5 (0.2)
+4 (0.1)
+0 (0.0)
+BNT16262
+Dose 2
+Na =2682 nb (%)
+440 (16 4)
+254 (9.5)
+146 (5.4)
+39 (1 5)
+1 (0.0)
+Placebo
+Dose 2
+Na =2684 nb (%)
+11 (0.4)
+5 (0.2)
+4 (0.1)
+2 (0.1)
+0 (0.0)
+60
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+BNT16262
+Dose 1
+Na =2899 n° (%)
+Placebo
+Dose 1
+Na =2908 nb (%)
+BNT162b2
+Dose 2
+Na =2682 nb (%)
+STN:125742
+Placebo
+Dose 2
+Na =2684 nb (%)
+Fatigue
+Any
+Mild
+Moderate
+Severe
+1431 (49.4)
+760 (26.2)
+630 (21.7)
+41 (1.4)
+960 (33.0)
+570 (19.6)
+372 (12.8)
+18 (0.6)
+1649 (61.5)
+558 (20.8)
+949 (35.4)
+142 (5.3)
+614 (22.9)
+317 (11.8)
+283 (10.5)
+14 (0.5)
+Headache
+Any
+Mild
+Moderate
+Severe
+1262 (43.5)
+785 (27.1)
+444 (15.3)
+33 (1.1)
+975 (33.5)
+633 (21.8)
+318 (10.9)
+24 (0.8)
+1448 (54.0)
+699 (26.1)
+658 (24.5)
+91 (3.4)
+652 (24.3)
+404 (15.1)
+230 (8.6)
+18 (0.7)
+Chills
+Any
+Mild
+Moderate
+Severe
+479 (16.5)
+338 (11.7)
+126 (4.3)
+15 (0.5)
+199 (6.8)
+148 (5.1)
+49 (1.7)
+2 (0.1)
+1015 (37.8)
+477 (17.8)
+469 (17.5)
+69 (2.6)
+114(4.2)
+89 (3.3)
+23 (0.9)
+2 (0.1)
+Vomitingd
+Any
+Mild
+Moderate
+Severe
+34 (1.2)
+29 (1.0)
+5 (0.2)
+0 (0.0)
+36 (1.2)
+30 (1.0)
+5 (0.2)
+1 (0.0)
+58 (2.2)
+42 (1_6)
+12 (0.4)
+4 (0.1)
+30 (1.1)
+20 (0.7)
+10 (0.4)
+0 (0.0)
+Diarrhea
+Any
+Mild
+Moderate
+Severe
+309 (10.7)
+251 (8.7)
+55 (1.9)
+3 (0.1)
+323 (11.1)
+264 (9 1)
+58 (2.0)
+1 (0.0)
+269 (10.0)
+219 (8 2)
+44 (1.6)
+6 (0.2)
+205 (7.6)
+169 (6.3)
+35 (1.3)
+1 (0.0)
+New or worsened muscle pain
+Any
+Mild
+Moderate
+Severe
+664 (22.9)
+353 (12.2)
+296 (10.2)
+15 (0.5)
+329 (11.3)
+231 (7 9)
+96 (3.3)
+2 (0.1)
+1055 (39.3)
+441 (16 4)
+552 (20.6)
+62 (2.3)
+237 (8.8)
+150 (5.6)
+84 (3.1)
+3 (0.1)
+New or worsened ioint pain©
+Any
+342 (11.8)
+168 (5.8)
+638 (23.8)
+Mild
+200 (6.9)
+112 (3.9)
+291 (10 9)
+Moderate
+137 (4.7)
+55 (1.9)
+320 (11.9)
+Severe
+5 (0.2)
+1 (0.0)
+27 (1.0)
+Use of antipyretic or pain medication/
+805 (27.8)
+398 (13.7)
+1213 (45.2)
+147 (5.5)
+82 (3.1)
+61 (2.3)
+4 (0.1)
+320 (11.9)
+Source: ST 125742.0 c4591001-interim-mth6-report-body.pdf, Table 14.75, pages 553-557.
+Reactions and use of antipyretic or pain medication were collected in the electronic diary (-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.
+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: 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.
+61
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 29. Frequency of Solicited Systemic Reactions, by Maximum Severity, Within 7 Days After Each Dose, Participants Older than 55 Years of Age, Reactogenicity Subset of the Safety Population*
+BNT162b2
+Dose 1
+Na =2008 nb (%)
+Placebo
+Dose 1
+Na =1989 n° (%)
+BNT16262
+Dose 2
+Na =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
+26 (1.3)
+23 (1.1)
+2 (0.1)
+1 (0 0)
+0 (0.0)
+8 (0 4)
+3 (0.2)
+3 (0.2)
+2 (0 1)
+0 (0.0)
+219 (11_8)
+158 (8.5)
+54 (2.9)
+7 (0 4)
+0 (0.0)
+4 (0.2)
+2 (0.1)
+1 (0.1)
+1 (0.1)
+0 (0.0)
+Fatique
+Any
+Mild
+Moderate
+Severe
+Grade 4
+677 (33.7)
+415 (20.7)
+259 (12.9)
+3 (0.1)
+0
+447 (22.5)
+281 (14.1)
+163 (8.2)
+3 (0.2)
+949 (51.0)
+391 (21.0)
+497 (26.7)
+60 (3.2)
+1 (0.1)
+306 (16.7)
+183 (10.0)
+121 (6.6)
+2 (0.1)
+O
+Headache
+Any
+Mild
+Moderate
+Severe
+503 (25.0)
+381 (19.0)
+120 (6.0)
+2 (0.1)
+363 (18.3)
+267 (13.4)
+93 (4.7)
+3 (0.2)
+733 (39.4)
+464 (24.9)
+256 (13.8)
+13 (0.7)
+259 (14.1)
+189 (10.3)
+65 (3.5)
+5 (0.3)
+Chills
+Any
+Mild
+Moderate
+Severe
+130 (6.5)
+102 (5.1)
+28 (1.4)
+0
+69 (3.5)
+49 (2.5)
+19 (1.0)
+1 (0.1)
+435 (23.4)
+229 (12.3)
+185 (9.9)
+21 (1.1)
+57 (3.1)
+45 (2.5)
+12 (0.7)
+Vomitingd
+Any
+Mild
+Moderate
+Severe
+10 (0.5)
+9 (0.4)
+1 (0.0)
+0
+9 (0.5)
+9 (0.5)
+13 (0.7)
+10 (0 5)
+1 (0.1)
+2 (0.1)
+5 (0.3)
+5 (0.3)
+O
+Diarrhea®
+Any
+Mild
+Moderate
+Severe
+168 (8.4)
+137 (6.8)
+27 (1.3)
+4 (0.2)
+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
+274 (13.6)
+183 (9.1)
+90 (4.5)
+1 (0.0)
+165 (8.3)
+111 (5.6)
+51 (2.6)
+3 (0.2)
+537 (28.9)
+229 (12.3)
+288 (15.5)
+20 (1.1)
+99 (5.4)
+65 (3.5)
+33 (1.8)
+1 (0.1)
+New or worsened ioint pain
+Any
+175 (8.7)
+Mild
+119 (5 9)
+Moderate
+53 (2.6)
+Severe
+3 (0.1)
+124 (6.2)
+78 (3 9)
+45 (2.3)
+1 (0.1)
+353 (19.0)
+183 /9 8)
+161 (8.7)
+9 (0.5)
+Use of antipyretic or
+382 (19.0)
+224 (11.3)
+pain medication
+688 (37.0)
+72 (3.9)
+44 (2.4)
+27 (1.5)
+1 (0.1)
+170 (9.3)
+Source: ST 125742.0 c4591001-interim-mth6-report-body.pdf, Table 14.75, pages 557-562
+Reactions and use of antiovretic or pain medication were collected in the electronic diarv (e-diarv) from Day 1 to Dav 7 after each dose.
+The only Grade 4 solicited systemic reaction reported in participants >55 years of age was fatigue
+62
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+* 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: 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
+nours
+f. Severity was not collected for use of antipyretic or pain medication.
+Unsolicited (non-serious and serious) AEs
+Non-serious unsolicited AEs
+Dose 1 through 1 month after Dose 2
+A higher frequency of unsolicited, non-serious adverse events was reported in the vaccine group (29.9% compared to placebo group (13.7%). These excess AEs in the vaccine group were primarily attributed to local reactions and systemic adverse events reported during the first 7 days following vaccination in participants not enrolled in the reactogenicity subset and are consistent with solicited reactions/events reported by reactogenicity subset participants. Table 30 below presents unsolicited adverse events reported by at least 1% of participants in any treatment group for the safety population, with the total number of events reported, in addition to the number of events that were graded as severe.
+Table 30. Frequency of Any and Severe Unsolicited Adverse Events Occurring in ≥1% of Participants in Any Treatment Group From Dose 1 to 1 Month After Dose 2, Safety Population
+System Organ Class
+Preferred Term
+Gastrointestinal disorders
+BNT162b2
+(N=21926)
+Any n (%)
+Severe n (%)
+Placebo
+(N=21921)
+Any n (%)
+Severe n (%)
+Diarrhea
+Nausea
+248 (1.1)
+4 (<0.1)
+274 (1.2)
+1 (<0 1)
+188 (0.9)
+5 (<0.1)
+87 (0.4)
+2 (<0.1)
+General disorders and administration site conditions
+Chills
+Fatigue
+Injection site pain
+Pain
+Pyrexia
+Musculoskeletal and connective tissue disorders
+1365 (6.2)
+18 (0.1)
+1463 (6.7)
+24 (0.1)
+2915 (13.3)
+19 (0.1)
+628 (2.9)
+9 (<0.1)
+1517 (6.9)
+38 (0.2)
+120 (0.5)
+O
+379 (1.7)
+2 (<0.1)
+397 (1.8)
+0 (<0.1)
+61 (0.3)
+O
+77 (0.4)
+1 (<0.1)
+Arthralgia
+Myalgia
+268 (1.2)
+4 (<0.1)
+1239 (5.7)
+21 (0.1)
+102 (0.5)
+6 (<0.1)
+168 (0.8)
+3 (<0.1)
+63
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+BNT162b2
+Placebo
+(N=21926)
+(N=21921)
+System Organ Class
+Any n (%)
+Any n (%)
+Preferred Term
+Severe n (%)
+Severe n (%)
+Nervous system disorders
+1339 (6.1)
+424 (1.9)
+Headache
+25 (0.1)
+10 (<0.1)
+Source: ST 125742.037 c4591001-508-safety tables, Table R, Page 18
+MedDRA v23.1 coding dictionary applied.
+Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
+%: n/N. n = number of participants reporting at least 1 occurrence of the specified event.
+of any event. N = number of participants in the specified group. This value is the denominator for the percentage
+calculations.
+Data analysis cutoff date: March 13, 2021
+Unsolicited AEs of clinical interest (serious and non-serious)
+FDA independently conducted Standardised MedDRA Queries (SMQs) using FDA-developed software to evaluate for constellations of unsolicited adverse event Preferred Terms that could represent various diseases and conditions, including but not limited to allergic, neurologic, inflammatory, and autoimmune conditions were queried to evaluate the occurrence of unsolicited events in the vaccine and placebo groups during the various follow-up periods (blinded, placebo-controlled and open label).
+Dose 1 to 1 month after Dose 2
+The SMQs conducted on the Phase 2/3 safetv population from Dose 1 to 1 month after Dose 2 revealed a slight numerical imbalance of adverse events potentially representing allergic reactions, with more participants reporting hypersensitivity-related adverse events in the vaccine group (272 participants [1.1%] reporting 234 events) compared with the placebo group (225 participants [0.9%] reporting 190 events).
+Review of the hypersensitivit-related events indicates that most events were classified as skin or subcutaneous disorders with a slightly increased incidence in the vaccine group when compared to the placebo group of 152 and 123 events, respectively. Rash was the most commonly noted skin finding with 60 events in the vaccine group and 46 events in the placebo group. No imbalances between treatment groups were evident for any of the other SMQs evaluated.
+Reports of lymphadenopathy were imbalanced with notably more cases in the vaccine group (83, one of which was serious) vs. the placebo group (7). The majority of events were mild or moderate, with 3 severe events reported, all in the BNT1622 group. The median onset of lymphadenopathy following BNT1622 was 5.5 days for Dose 1, with a shorter median onset of 2 days following Dose 2 of BNT162b2. Median duration of lymphadenopathy was 5.5 days in the BNT162b2 group.
+Dose 1 to data cutoff date or participant's unblinding date (whichever was earlier)
+The previously noted imbalances between the vaccine and the placebo group for hypersensitivity-related adverse events and lymphadenopathy remained evident, as described above. Notable findings regarding other As of clinical interest reported during blinded, placebo-controlled follow-up are summarized below. Very small numerical imbalances between the vaccine and placebo groups for Optic neuritis (2 vaccine vs. 0 placebo) and Encephalopathy (2 vaccine vs. 0 placebo) involved adverse events that were not assessed as related to BNT162b2 by the investigator, and FDA review of the details of these adverse events did not identif a basis to conclude a
+64
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+causal relationship. Otherwise, no imbalances in non-serious unsolicited As between treatment groups were evident for any of the other SMQs evaluated.
+AEs of clinical interest
+• Cardiac Disorders
+The overall occurrence of cardiac disorders was numerically greater in the BNT162b2 vaccine group when compared to the placebo group (87 to 78, respectively), but for both groups the numbers represented an occurrence rate of 0.4%, with more participants in the older age groups (>55 years of age) reporting cardiac disorders compared with the younger age groups. Within each age group, rates of cardiac disorders were similar between the BNT162b2 vaccine group and placebo group, with the exception of tachycardia, which occurred more frequently in the younger age group subjects who received BNT162b2. See Appendix B for a list of cardiac disorders that occurred from Dose 1 to date of unblinding among Phase 2/3 participants 16 years of age and older.
+• Bell's Palsy
+Bell's palsy (facial paralysis) was reported by 4 participants in the BNT162b2 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.
+• Deafness
+A total of 11 cases (6 in the BNT162b2 group and 5 in the placebo group) were reported that included the following preferred terms associated with deafness: deafness, deafness unilateral, deafness neurosensory, hypoacusis and sudden hearing loss. The toxicity grades were mostly mild (4 in the BNT1622 group and 2 in placebo) or moderate (1 in the BNT162b2 group and 3 in placebo), with one being severe (BNT162b2 group). For BNT162b2 recipients, the age range was 43-65 years of age, with one event occurring 19 days after Dose 1 and onset ranging from 1-55 days after Dose 2. Two of the reported events were considered by investigators as possibly related to BNT162b2:
+• One female participant >55 ears of age reported unilateral deafness which occurred 19 days after Dose 1 and resolved 9 days later. The participant was discontinued from study intervention and remained in the study for safetv evaluation.
+• One female participant 16-55 ears of age reported unilateral deafness and dizziness which occurred 1 day after Dose 2, which was ongoing at the time of the data cutoff.
+One report of sudden unilateral neurosensory deafness was still ongoing at the time of the data cutoff and occurred in a BNT1622 recipient 55 days after Dose 2. The event was considered unlikely to be related to the study intervention by the investigator, and FDA agrees with this assessment.
+• Deep Vein Thrombosis (DVT) and Other Venous Thromboembolic Events
+One BNT1622 recipient and one placebo recipient reported DVT characterized as non-serious AEs. The BNT1622 recipient developed a DVT in the leg 14 days after Dose 2, which resolved after 6 days and was assessed by the study investigator as unrelated to vaccination; no hematologic results or medical intervention details were provided. The placebo recipient developed a DVT in the leg 85 days after placebo
+65
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Dose 2 that resolved after 1 day and was attributed by the study investigator to metabolic causes. No further information was provided.
+During the blinded placebo-controlled follow-up period, two subjects who received
+BNT162b2 experienced venous thromboembolic events following Dose 2 (coagulopathy at 150 days and ophthalmic vein thrombosis at 70 days after the last vaccination). No similar events were observed in the placebo cohort. Neither event was temporally related to vaccination; both events were considered not related to vaccination by FDA.
+None of the above events were associated with thrombocytopenia per the Applicant.
+• Guillain-Barre syndrome
+One male placebo recipient (baseline SARS-CoV-2 negative) <55 years of age reported the occurrence of Guillain-Barre syndrome, which was considered a SAE and ongoing at the data cutoff. No vaccine recipients reported As consistent with Guillain-Barre syndrome.
+Open-label observational follow-up: from participant unblinding to the March 13, 2021
+data cutoff
+In independent FDA analyses of SMQs of non-serious As occurring in the unblinded follow-up period, there were no notable patterns of specific categories of AEs that would suggest a causal relationship to BNT162b2.
+Original BNT162b2 recipients
+Overall, 20,309 original BNT162b2 recipients were followed after unblinding. Of these, 243 (1.2%) participants reported any adverse event; 20 (0.1%) participants had at least
+1 occurrence of an event that was considered related to the vaccine, and 43 (0.2%) participants had at least 1 occurrence of an event that was graded as severe.
+Overall, the rates of As in all System Organ Classes (SOCs) after the unblinding date decreased or remained similar to those in the blinded placebo-controlled period. The most commonly reported events occurred in the SOC of Injury, poisoning and procedural complications with 40 (0.2%) participants reporting at least 1 event, and the Preferred Term (PT) Fall had the highest number of participants (n=10). The SOC of Vascular disorders was reported by 23 (0.1%) participants, with the PT Hypertension having the highest number of participants (n=17).
+Of the 20 participants who reported at least 1 event considered related to the vaccine, the events were similar to reactogenicity events, reflecting AEs within 7 days of vaccination (n=3 participants) or events reported more than 7 days from vaccination indicating either recurrent or prolonged reactogenicity symptoms. Note that one participant can report multiple events.
+The most common SOCs and PTs are listed below:
+• 13 participants reported at least 1 event in the SOC General disorders and administration site conditions: Injection site pain (7), Fatigue (6), Chills (3), Pain, and Pyrexia (2 each) and 1 reported Injection site swelling.
+• 6 participants reported at least 1 event in the SOC Nervous system disorders:
+Headache (5), Dizziness (2) and 1 reported Dysgeusia (altered/impaired taste).
+66
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+• 4 participants reported at least 1 event in the SOC Musculoskeletal and connective tissue disorders: Myalgia (2) and 1 participant each reported Back pain and Pain in extremity.
+Placebo recipients who were unblinded and received BNT162b2
+Overall, 19,525 original placebo participants were unblinded and received BNT162b2.
+The number of participants reporting any AE and at least 1 related AE were 4,885/19,525 (2.5%) and 4,508/19,525 (2.3%), respectively. The number of participants reporting severe AEs was 142/19,525 (0.1%).
+The comparison to participants randomized to BNT162b2 from Dose 1 to the unblinding date shows that the number of participants who reported any AE, at least 1 related AE and severe AE for participants who originally received placebo and then received
+BNT162b2 are slightly greater (4,885/19,525 [2.5%], 4,508/19,525 [2.3%], 142/19,525
+[0.1%]) than the frequencies (6,947/21,926 [3.2%], 5,246/21,926 [2.4%], 356/21,926 [0.2%]) for participants who originally were randomized to BNT162b2, respectively.
+Immediate adverse events after either BNT162b2 dose (Dose 3 or 4, for original placebo recipients), were low in frequency (0.6%) Most immediate As after BNT162b2 were primarily injection site reactions, with injection site pain (0.4%) most frequently reported. Additionally, the following other immediate Als were assessed as related to the stud intervention:
+• 1 participant in the younger age group reported 2 immediate As of edema mouth and tongue edema (both mild in severity) after Dose 4. The AE of tongue edema resolved the same day and the AE of edema mouth resolved the following day.
+• 1 participant in the younger age group reported an immediate A of hypoesthesia oral (mild in severity) after Dose 3 and resolved the same day.
+• 1 participant in the younger age group reported 3 immediate AEs of swelling face, allergy to vaccine, and flushing after Dose 3, which were all were moderate in severity. All 3 As resolved the following day. The participant also reported nausea and urticaria (hives abdomen) (both mild in severity) on the same dav but were not immediate. The A of nausea resolved the same day and the AE of urticaria resolved the following day.
+• 1 participant in the older age group reported an immediate AE of urticaria (hive on back of neck; moderate in severity) after Dose 4 and was ongoing at the time of the data cutoff date.
+FDA agrees with the investigator assessments of relatedness to the study interventions listed for the four participants above.
+Bell's Palsv
+Three female participants, all ≤55 years of age, who originally received placebo, reported facial paralysis within 3 to 8 days of receiving either Dose 1 or 2 of BNT162b2.
+One case had a duration of 12 days, and the other 2 were ongoing as of the data cutoff date.
+Reviewer Comment: While these reports are from uncontrolled, open-label follow-up, the temporal relationship suggests a potential causal association between the vaccine and rare occurrence of Bell's Palsy, though the lack of a control group limits the interpretation. Considering all of the available evidence, Bell's Palsy will remain
+67
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+described in the US package insert as a potential, but unconfirmed, infrequent adverse reaction.
+Placebo recipients who had COVID-19 occurrence after Dose 1 and then received
+BNT162b2 after unblinding
+There were 852 participants who originally received placebo, had protocol-confirmed
+COVID-19 during the blinded follow-up period, and then received BNT1622 after unblinding. Of these, 225 (26.4%) participants reported any adverse event; 211 (24.7%) participants had at least 1 occurrence of an event that was considered related to the vaccine, and 4 (0.5%) participants had at least 1 occurrence of an event that was graded as severe. Of note, per protocol, these participants did not receive an e-diary for solicited local and systemic reactogenicity following vaccine administration.
+Most AEs reported from Dose 3 (the first dose of BNT162b2) to the data cutoff date were in SOCs with reactogenicity events and were consistent with the As reported in the BNT162b2 group in the blinded portion of the study:
+• General disorders and administration site conditions (207 [24.3%1)
+• Musculoskeletal and connective tissue disorders (42 [4.9%1)
+• Nervous system disorders (58 ™6.8%1 including 52 listed with the PT Headache)
+• Gastrointestinal disorders (15 [1.8%])
+Reviewer Comment: Although collected with different methodology (solicited versus unsolicited and blinded versus unblinded), the events corresponding to solicited reactogenicity were not reported at higher frequencies or with greater severity following Dose 3 or Dose 4 in these participants with prior COVID-19 compared to solicited reactions following Dose 1 or Dose 2 in participants without prior COVID-
+19. Thus, these data do not suggest that reactogenicity is increased in individuals with prior symptomatic COVID-19.
+Placebo-controlled and Open-label follow up from Dose 1 to 6 Months after Dose 2:
+Original BNT162b2 Participants
+A total of 12,006 participants who originally received BNT1622 had at least 6 months of follow-up post-Dose 2. Of these, 3,454 (28.8%) participants reported at least 1 AE, and 2,245 (18.7%) participants reported at least 1 related AE. The most frequently reported As were reactogenicity events: General disorders and administration site conditions reported in 2,016 (16.8%) (primarily injection site pain reported in 1,191
+[9.9%], Pyrexia reported in 633 (5.3%), and Chills and Fatigue reported in 606 and 598 (both 5%), respectively, Musculoskeletal and connective tissue disorders reported in 905 (7.5%) (primarily Myalgia reported in 549 [4.6%] and Arthralgia reported in 153 [1.3%]), Nervous system disorders reported in 726 (6.0%) (primarily Headache reported in 572 [4.8%]), and Gastrointestinal disorders reported in 407 (3.4%). Additionally, the AE of lymphadenopathy in 29 (0.2%) was assessed by the investigator as related to the study intervention.
+When frequencies of As for participants with at least 6 months of follow-up time are examined by time since the second dose, the frequency of As and related AEs is 25.8% and 18.6% through 1 month after Dose 2 compared with 4.8% and 0.1% from 1 month after Dose 2 to 6 months after Dose 2.
+68
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+In the younger age group, the numbers of participants who reported at least 1 AE and 1
+related AE from Dose 1 to 6 months after Dose 2 were 2013 (30.2%) and 1.386 (20.8%), respectively. In the older age group, the numbers of participants who reported at least 1 AE and 1 related AE from Dose 1 to 6 months after Dose 2 were 1,441 (27.0%) and 859 (16.1%), respectively. The most frequently reported As were reactogenicity events, as outlined in Table 31, below.
+Table 31. Frequency of Unsolicited As with Occurrence in ≥1% From Dose 1 to 6 Months After Dose 2, Participants Who Originally Received BNT162b2 With at Least 6 Months of Follow-up Time, Safety Population
+System Organ Class
+Preferred Term
+Anv Event
+General disorders and administration site
+16-55 Years
+N=6666 n (%)
+2013 (30.2)
+1246 (18.7)
+>55 Years
+NE=5340 n (%)
+1441 (27)
+770 (14.4)
+Total
+N=12006 n (%)
+3454 (28.8)
+2016 (16.8%)
+conditions
+Injection site pain
+Pyrexia
+Fatigue
+Chills
+Pain
+Musculoskeletal and connective tissue
+715 (10.7)
+442 (6.6)
+372 (5.6)
+412 (6.2)
+190 (2.9)
+539 (8.1)
+476 (8.9)
+191 (3.6)
+226 (4.2)
+194 (3.6)
+87 (1.6)
+366 (6.9)
+1191 (9.9)
+633 (5.3)
+598 (5.0)
+606 (5.0)
+277 (2.3)
+905 (7.5)
+disorders
+Myalgia
+Arthralgia
+Nervous system disorders
+Headache
+Gastrointestinal disorders
+Diarrhea
+Nausea
+Infections and Infestations
+Injury, Poisoning and Procedural Complications Skin and Subcutaneous Tissue Disorders Respiratory, Thoracic and Mediastinal
+355 (5.3)
+84 (1.3)
+449 (6.7)
+359 (5.4)
+231 (3.5)
+69 (1.0)
+88 (1.3)
+161 (2.4)
+100 (1.5)
+80 (1.2)
+79 (1.2)
+194 (3.6)
+69 (1.3)
+277 (5.2)
+213 (4.0)
+176 (3.3)
+54 (1.0)
+52 (1.0)
+134 (2.5)
+107 (2.0)
+73 (1.4)
+66 (1.2)
+549 (4.6)
+153 (1.3)
+726 (6.0)
+572 (4.8)
+407 (3.4)
+123 (1.0)
+140 (1.2)
+295 (2.5)
+207 (1.7)
+153 (1.3)
+145 (1.2)
+Disorders
+Source: FDA-generated.
+MedDRA v23.1 coding dictionary applied.
+Adverse events in any PT = at least one adverse event experienced (regardless of the MedDRA Preferred Term)
+%: n/N. n = number of participants reporting at least 1 occurrence of the specified event.
+of any event. N = number of participants in the specified group. This value is the denominator for the percentage
+calculations.
+From unblinding date to the data cutoff date, the number of participants who reported at least 1 AE was 243/20,309 (1.2%) in participants originally randomized to BNT162b2.
+Overall, the rates in all SOCs after the unblinding date decreased or remained similar to those in the blinded placebo-controlled period.
+Subgroup Analyses
+There were no specific safety concerns identified in subgroup analyses by age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection, and occurrence of solicited or unsolicited in these subgroups were generally consistent with the overall study population.
+69
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Suspected COVID-19 Cases
+As specified in the protocol, suspected cases of symptomatic COVID-19 that were not PCR-confirmed were not recorded as adverse events unless they met regulatory criteria for seriousness.
+A total of 4,931 participants (2,285 in the BNT162b2 group and 2,636 in the placebo group) in the evaluable efficacy population for the second primary efficacy endpoint developed protocol-defined symptoms after 7 days post Dose 2 during the blinded follow-up period but were not counted as a confirmed case. Of these, 4,331 (87.8%) had negative PCR results (2,026 [88.7%] and 2,305 [87.1 %] in the BNT162b2 and placebo groups, respectively). The remaining 699 (14.2% total; 303 [13.3%] and 396 [15%] in the BNT162b2 group and placebo groups, respectively) were not counted as a confirmed case because the PCR results were unknown or unavailable for the following reasons: the swab was not taken (477 [9.7%] total; 210 [9.2%] and 267 [10.1%] in the BNT162b2 group and placebo groups, respectively), the swab was taken outside of the symptom window (168 [3.4%] total; 80 [3.5%] and 88 [3.3%] in the BNT1622 group and placebo groups, respectively or the swab was taken, but results were not available (54 [1.1%%] total; 13 [0.6%] and 41 [1.5%] in the BNT1622 group and place groups, respectively).
+Reviewer Comment: The number of participants who had COVID-19 symptoms but were not counted as a confirmed case because the PCR results were unknown or unavailable was small (n=699) and slightly higher in the placebo group (396 versus 303 in the BNT162b2 group). Excluding them from the efficacy analyses likely had minimal impact on VE results. Upon request, the Applicant provided a sensitivity analysis, and the average VE after imputation was over 70%, which was reassuring that these missing PC results would not have a significant effect on the VE results.
+Please refer to the statistical review memo of vaccine efficacy for additional details of this analysis.
+6.1.12.3 Deaths
+From Dose 1 to the data cutoff (March 13, 2021), there were a total of 38 deaths among participants >16 years of age (19 BNT1622 recipients, 2 Placebo/BNT1622 recipients and 17 placebo recipients). A total of 29 deaths (15 BNT162b2, 14 placebo) occurred during the blinded, placebo-controlled period. There were more deaths in the population
+>55 years of age as expected due to increased age and comorbidities. The demographics for those that died in the study were representative of the study population as a whole.
+A total of 21 participants (14 males/7 females; mean age 68 years) received at least one dose of BNT162b2 prior to their deaths. Deaths occurred 62 to 142 days following the last dose of vaccine. For the seventeen participants (9 male/8 female: mean age 60 vears) who received at least one dose of placebo there were six cases of documented COVID-19 with deaths occurring ~93 days following vaccination. Table 32 below shows the subject age, cause of death and investigational product received for participants in the safetv population. Seven deaths were due to COVID-19 (1 BNT1622 recipient and 6 placebo recipients). Each case had a positive COVID test (PCR or NAAT), but not all tests (including the positive PC in the case of fatal COVID-19 pneumonia reported 109 davs after Dose 2 of BNT162b2) were within the specifications of the study protocol for tests with acceptable sensitivity and specificity and were therefore not included in
+70
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+protocol-specified efficacy analyses of severe COVID-19 cases. Abbreviated narratives are provided for those participants who died from COVID-19 in Appendix C.
+Cardiac conditions were reported as the cause of death for 9 participants (cardiac arrest
+[7], congestive heart failure [1] and cardiovascular disease [1] who had received at least one dose of BNT162b2. The time from the last dose of BNT-162b2 to a cardiac- related death was 25-128 days. The event occurring 25 days from Dose 1 BNT162b2 occurred in a subiect who had previously received two doses of placebo and was classified as cardiopulmonary arrest secondary to aortic stenosis. In the placebo group there were 5 cardiac related deaths (2 myocardial infarction, 1 aortic rupture, 2 cardiac arrest) occurring 15-81 days following study intervention (placebo). This excludes deaths due to COVID-19 which may have included cardiac-related presentations as part of the clinical course.
+Reviewer Comment: Based on clinical review of the individual cases, the lack of a clear temporal association to vaccination, the presence of confounding factors (e.g., pre-existing comorbidities) and the small number of cases, FDA assessed these deaths as unlikely to be related to vaccination.
+Table 32. Deaths from Dose 1 to Data Cutoff of March 13, 2021, Phase 2/3 Participants 16
+Years of Age and Older, Safety Population
+Vaccines
+Received
+BNT162b2
+BNT162b2
+BNT162b2
+BNT16262
+Age/Sex
+56/F
+54/M
+64/M
+84/M
+Number of
+Doses
+2
+5
+2
+2
+Time Since
+Last Dose (davs)
+62
+87
+90
+70
+Cause of Death
+Cardiac arrest
+Congestive heart failure
+MVA
+Cardiovascular disease
+Emphysematous cholecystitis
+BNT16262
+BNT16262
+BNT16262
+BNT162b2
+BNT16262
+BNT162b2
+BNT162b2
+BNT162b2
+BNT162b2
+BNT16262
+77/M
+82/
+63/F
+86/F
+63/F
+58/F
+51/M
+53/M
+78/F
+76/M
+2
+2
+2
+2
+120
+142
+69
+97
+and sepsis
+Metastatic pancreatic cancer
+COPD
+Septic shock due to bowel obstruction
+NNNN
+2
+2
+41
+72
+112
+85
+128
+30
+Sudden cardiac death
+Cardiac arrest
+Metastatic lung cancer
+Cardiopulmonary arrest
+Cardiac arrest
+Cardiac arrest
+Cardiac arrest
+BNT162b2
+BNT16262
+BNT16262
+BNT16262
+58/M
+2
+116
+following seizure &
+72/M
+1
+62/F
+2
+60/M
+1
+35
+73
+3
+Shigella sepsis
+MVA^
+"Atherosclerosis"
+(Found dead at home)
+BNT16262
+80/M
+2
+109
+COVID pneumonia*
+Placebo/
+21
+Cardiopulmonary arrest
+84/M
+25
+BNT162b2
+1
+secondary aortic stenosis
+Placebo/
+21
+67/M
+4
+Suicide
+BNT16262
+1
+Placebo
+67/M
+2
+86
+Metastatic biliary cancer
+71
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Vaccines
+Received
+Number of
+Doses
+Placebo
+Placebo
+Placebo
+Age/Sex
+68/F
+58/M
+51/F
+2
+1
+2
+Time Since
+Last Dose (days)
+102
+15
+36
+Cause of Death
+COVID-19* (respiratory failure
+Myocardial infarction
+Mvocardia infarction
+Placebo+
+65/M
+2
+COVID-19* and multi-organ
+82
+failure
+Placebo
+65/M
+2
+COVID-19*
+69
+(cardiac arrest)
+Placebo
+Placebo
+82/F
+57/F
+2
+124
+Dementia due to Alzheimer's
+COVID-19*
+2
+80
+(pneumonia, respirator failure)
+Placebo
+Placebo
+Placebo
+Placebo
+66/M
+42/F
+53/M
+64/M
+2
+1
+101
+7
+Pneumonia s/p MI
+Undetermined cause of death
+Drug overdosel
+2
+2
+31
+respiratory arrest
+64
+Aortic rupture
+Cardiac arrest due to bacterial
+Placebo
+65/M
+2
+75
+pneumonia
+Placebo
+55/F
+(COVID test negative)
+2
+75
+COVID-19 pneumonia^*
+Placebo
+61/F
+2
+15
+Hemorrhagic stroke
+(COVID test negative)
+Placebo
+47/M
+2
+81
+Cardiac arrest
+Placebo
+58/F
+2
+155
+COVID-19 with septic shock*
+Source: FDA generated
+Total Deaths =38
+* positive COVID-test
+B = black W = white NH = non-Hispanic non-Latino H/L = Hispanic / Latino M = male F = female
++ subject had received one dose of Moderna Covid vaccine during the study
+& on an unspecified date following a report of the subject of having "sniffles", a blood sample was positive for COVID ant bodies (~4 months after vaccination)
+^ HIV population
+t = Turkey sa = South Africa a = Argentina
+COPD = chronic obstructive pulmonary disease
+6.1.12.4 All Serious Adverse Events (SAEs)
+Dose 1 through 1 month after Dose 2
+SAEs were reported by 127 (0.6%) and 116 (0.5%) of participants in the BNT162b2 and placebo groups, respectively. The numbers of participants who reported at least 1 SAE were lower in the younger age group (52 0.4%1 and 49 0.4%1 for the BNT162b2 and placebo groups, respectively) than in the older age group (75 [0.8%] and 67 [0.8%] for the BNT162b2 and placebo groups, respectively). Three of the SAEs in the BNT162b2 group and none in the placebo group were assessed by the investigator as related to vaccine or vaccine administration (ventricular arrhythmia, lymphadenopathy, shoulder injury related to vaccine administration).
+Reviewer Comment: Following clinical review of the adverse event narratives, two of these SAEs were considered by FDA as possibly related to vaccine: shoulder injury possibly related to vaccine administration or to the vaccine itself, and lymphadenopathy involving the axilla contralateral to the vaccine injection site. For
+72
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+lymphadenopathy, the event was temporally associated and biologically plausibly related.
+Deep Vein Thrombosis (DVT)
+Two BNT162 recipients reported a DVT (unspecified location [n =1], leg [n =1]) 11 days after Dose 1 and 19 days after Dose 2, respectively. The first participant consequently developed a pulmonary embolism (PE). The DVT and PE resolved; the study investigator attributed the DVT to the participant's pre-existing type 1 diabetes mellitus.
+For the second participant, the event was ongoing at the time of the data cutoff date (March 13, 2021); the study investigator attributed the DVT to a recent ankle fracture in the same limb. No further information was provided for either participant.
+Dose 1 to data cutoff date or participant's unblinding date (whichever was earlier)
+SAEs were reported by 268 (1.2%) and 268 (1.2%) of participants in the BNT162b2 and placebo groups, respectively. The numbers of participants who reported at least 1 SAE were lower in the younger age group (103 [0.8%] and 117 [0.9%] for the BNT1622 and placebo groups, respectively than in the older age group (165 [1.8%1 and 151 [1.7%1 for the BNT162b2 and placebo groups, respectively). In these analyses, 58.2% of study participants had at least 4 months of follow-up after Dose 2.
+Four SAEs in the BNT162b2 group and 1 in the placebo group were assessed by the investigator as related to the study intervention. Three of these SAEs in the BNT162b2 group were discussed in the subsection above (Dose 1 through 1 month after Dose 2) and the other SAE that occurred prior to unblinding was a report of paresthesia of the right leg (symptoms consistent with radicular nerve pain per the SAE narrative) occurring 47 days after Dose 2 in a participant 16-55 years of age who had other significant neurologic medical history. According to the SAE narrative, a spinal MRI obtained while the participant was symptomatic was unremarkable. A subsequent neurology evaluation and laboratories did not reveal a cause, and the symptoms resolved spontaneously. The investigator considered it a reasonable possibility that the right leg paresthesia was related to BNT162b2; however, the Applicant disagreed and stated that there was not enough evidence to establish a causal relationship apart from chronological association at the time of the report, and that was more likely that the paresthesia was associated with the participant's underlying known neurological conditions. FDA agrees with the Applicant that there is no clear basis to support a causal relationship between BNT1622 and the SAE of paresthesia. Thus, FDA considers this SAE to be unlikely related to the vaccine.
+Appendicitis
+During the evaluation of safety data for the issuance of the EUA (November 2020), an imbalance was noted in the number of reported cases of appendicitis. Appendicitis was reported as a SAE for 12 participants, and numerically higher in the vaccine group: 8 vaccine participants (appendicitis [n =71, appendicitis perforated [n =11) and 4 placebo participants (appendicitis n =21, appendicitis perforated [n =11, complicated appendicitis [n =1]). All of the vaccine participants (n=8) and 2 placebo participants were younger than 65 years of age.
+As a follow-up to this analysis, an evaluation of cases of appendicitis from Dose 1 to data end date was performed. A total of 29 (15 vaccine recipients and 14 placebo recipients) cases of appendicitis were reported and included acute, perforated and complicated cases of appendicitis. Of the 21 participants reporting appendicitis in the
+73
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+16-55-year age group, 12 were in the BNT162b2 cohort/ 9 in the placebo cohort. Cases in those participants >55 ears included 3 participants in the vaccine cohort and 5 in the placebo cohort. The majority of participants who experienced appendicitis were ≤65 years of age. No subject who received BNT162b2 and experienced appendicitis was older than 65 years of age.
+During the placebo-controlled portion of the study, from Dose 1 to unblinding, appendicitis was reported as a SAE for 27 participants, with reports balanced between treatment groups: 14 vaccine participants (appendicitis [n =14], appendicitis perforated [n =1]) and 13 placebo participants (appendicitis [n =9], appendicitis perforated [n =1], complicated appendicitis [n =2], appendix disorder [n =1]). There were two cases of appendicitis from unblinding to the time of data cutoff (March 13, 2021): one case in the vaccine group and one case in the placebo group of perforated appendicitis.
+Table 33. Analysis of Appendicitis Events, Phase 2/3, Dose 1 to Data Cutoff Date
+BNT162b2
+Placebo
+Total
+N=15
+N=14
+N=29
+Time to Event
+n (%)
+n (%)
+n (%)
+Appendicitis within 7
+davs of Dose 1
+2 (13.3%)
+0 (0.0%)
+2 (6.9%)
+Appendicitis within 28
+davs of Dose 1
+5 (33.3%)
+0 (0.0%)
+5 (33.3%)
+Appendicitis within 28
+davs of Dose 2
+3 (20.0%)
+6(42.9%)
+9 (31.0%)
+Appendicitis within 28
+davs of Dose 3
+0 (0.0%)
+1 (7.1%)
+1(7.1%)
+Median number of
+22
+50
+29
+days to event
+Reviewer modified from OCS provided JMP clinical analysis
+Reviewer Comment: While the number of cases reported during blinded follow-up within 28 days after Dose 1 was 7 vs. O for the vaccine and placebo groups, respectively, a reverse case split (6 vs. 3) was observed within 28 days after Dose
+2. Furthermore, only 1 case of appendicitis was reported within 28 davs after Dose
+3 (open label administration of BNT1622 to placebo recipients who were unblinded and crossed over). Thus, there is no clear temporal pattern to suggest a causal relationship.
+All cases were considered unrelated to vaccination by the study investigators and occurred no more frequently than expected in the given age groups. FDA agrees that there is no clear basis upon which to suspect that cases of appendicitis represent a vaccine-related event.
+Deep Vein Thrombosis (DVT)
+A total of 5 participants (2 BNT1622 recipients, 3 placebo recipients) developed DVTs
+71-115 days after study intervention Dose 2. The 2 BNT1622 recipients both reported DVTs in the legs bilaterally with consequent PEs; all events resolved, and the causes of the DVTs are unknown. Two placebo recipients both reported DVTs in the leg, which the study investigator attributed to sport-related trauma and reduced mobility during quarantine, respectively; the event is ongoing for the first placebo recipient and resolved for the second placebo recipient. The third placebo recipient reported DVT in the arm, the cause is unknown, and the event was ongoing at the time of the data cutoff
+74
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+date. No hematologic results or treatment intervention information was provided for any of the 7 participants.
+The clinical features of these thromboembolic SAEs do not appear to be similar to cases of thrombosis with thrombocytopenia syndrome (TTS) observed following vaccination with adenovirus-vectored COVID-19 vaccines. During post-authorization surveillance, a safety signal for TTS has not been identified following vaccination with BNT162b2.
+Myocarditis and Pericarditis
+One report of pericarditis was identified in the vaccine group, occurring in a male participant >55 years of age with no medical history, 28 days after Dose 2 of vaccine; the event was assessed by the investigator as not related to the study intervention and was ongoing at the time of the data cutoff. FDA agrees with the investigator assessment. One report of myocarditis was identified in a participant 16-55 years of age in the placebo group, occurring 5 days after their second placebo dose.
+Open-label follow-up: from participant unblinding to the March 13, 2021 data cutoff
+Original BNT162b2 recipients
+Overall, 20,309 original BNT162b2 recipients were followed after unblinding. Of these, 55 (0.3%) participants reported at least 1 SAE, 1 of which was considered related.
+One SAE (myocardial infarction), which occurred 71 days after Dose 2 and resolved within one day, was reported by a participant ≤55 years of age and was considered possibly related to the study intervention by the investigator. FDA disagrees with the investigator regarding the possible relatedness of an acute myocardial infarction occurring 71 days following the last vaccine dose; the long-time interval decreases the likelihood of relatedness, in our opinion. Three other participants, all of whom were >65 years of age, experienced acute myocardial infarction after unblinding, occurring at a range of 128-145 days after Dose 2; none of these events were considered related to the study intervention by the investigator and FDA agrees with those assessments.
+Placebo recipients who were unblinded and received BNT162b2
+Overall, 19,525 original placebo participants were unblinded and received BNT162b2.
+The number of participants reporting SAEs and As leading to withdrawal was 65/19,525 (0.03%), and 19/19,525 (0.01%), respectively. The number of participants who discontinued from the study because of related As was 12/19,525 (<0.01%), and 2 participants died. These AEs are discussed in more detail in Section 6.1.12.7
+(Dropouts and Discontinuations) and Section 6.1.12.3 (Deaths).
+Allergy to vaccine, anaphylactoid reaction, and deep vein thrombosis were reported in 1 participant each from Dose 3 to 7 days after Dose 1 of BNT162b2.
+• One participant reported an A of Grade 2 allergy to vaccine, which occurred on the day of Dose 3 vaccination, had a duration of 2 days, and resolved; this AE was assessed by the investigator as related to the study intervention. No additional information was available.
+• One participant with an ongoing medical history significant for drug hypersensitivity and food and seasonal allergies reported a life-threatening SAE of anaphylactoid reaction, which occurred 2 days after Dose 3 and was resolved that same day; this SAE was assessed by the investigator as related to the study intervention (described in Section 6.1.12.5).
+75
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+• One participant with a past medical history significant for deep vein thrombosis, hypertension, pulmonary arterial hypertension, right ventricular enlargement, hypercholesteremia, atherosclerosis and bilateral peripheral neuropathy reported a Grade 2 SAE of deep vein thrombosis (lower right extremity) and Grade 1 SAE of pulmonary embolism, which both occurred 2 days after Dose 3 and had both resolved with a duration of 3 days; both SAEs were assessed by the investigator as not related to the study intervention.
+FDA agrees with the investigator assessments of relatedness to the study interventions listed for the three participants above.
+Placebo recipients who had COVID-19 occurrence after Dose 1 and then received
+BNT16262 after unblinding
+A total of 852 participants originally received placebo, had protocol-confirmed COVID-19 during the blinded follow-up period, and then received BNT162b2 after unblinding.
+Of these, the following SAEs occurred in 3 participants:
+• One participant, who was ≤55 years of age with a significant past history of a deep vein thrombosis, had a Grade 3 SAE of pulmonary embolism 6 days post Dose 4, which lasted 2 days and resolved with sequelae. The SAE was assessed as not related to the study intervention by the investigator.
+• One participant, who was >55 years of age with a past medical history of hypertension, hypercholesterolemia, coronary artery disease, and a coronary artery bypass in 2006, had a Grade 3 SAE of myocardial infarction 16 days post Dose 3, which lasted 4 days and resolved with sequelae. The SAE was assessed and not related to the study intervention by the investigator.
+• One participant, who was >55 years of age had 4 SAEs (none of which were assessed as related to the study intervention by the investigator):
+• 2 Grade 3 SAEs, urosepsis and acute hypoxic respiratory failure, both occurred 7 days post Dose 3, lasted 5 days, and resolved.
+Grade 3 SAE of non-small cell lung cancer (stage III) occurred 31 days post
+Dose 4 and was continuing at the data cutoff date.
+o Grade 2 SAE of Clostridium difficile infection occurred 47 das post Dose 4
+and was continuing at the data cutoff date.
+FDA agrees with the investigator assessments listed for the three participants above
+Placebo-controlled and Open-label follow up from Dose 1 to 6 Months after Dose 2:
+Original BNT162b2 Participants
+A total of 12,006 participants originally received BNT1622 and had at least 6 months of follow-up. SAEs were reported by 190 (1.9%) participants. The number of participants who reported at least 1 SAE was 73 (1.1%) and 117 (2.2%) in the younger and older age groups, respectively. In the first month after vaccination, 58 (0.5%) participants reported SAEs. From 1 month post Dose 2 to 6 months after Dose 2, the frequency of SAEs increased to 1.1% (n=133 participants). The following SOCs had the largest increase in SAEs (Dose 1 to 1 month after Dose 2 vs 1 month after Dose 2 to 6 months after Dose 2):
+• Neoplasms, benign, malignant, and unspecified (including cysts and polyps): 4 (0.0%) vs 21 (0.2%)
+• Injury, poisoning, and procedural complications: 2 (0.0%) vs 14 (0.1%)
+• Infections and infestations: 14 (0.1%) vs 22 (0.2%)
+• Gastrointestinal disorders: 4 (0.0%) vs 10 (0.1%)
+• Respiratory, thoracic, and mediastinal disorders: 2 (0.0%) vs 8 (0.1%)
+76
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+None of these SAEs were considered related to the study intervention and FDA agrees with the investigator's assessment.
+No deaths or AEs leading to withdrawal were reported during the blinded and open-label follow-up periods in the group of original BNT162b2 recipients with at least 6 months of follow-up after Dose 2.
+Subgroup Analyses
+There were no specific safety concerns identified in subgroup analyses by age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection, and occurrence of non-fatal serious adverse events in these subgroups were generally consistent with the overall study population.
+6.1.12.5 Additional Exploratory Analyses
+Please refer to Sections 6.1.12.2 and 6.1.12.4 for AEs of clinical interest, by category, included among reported non-serious As and serious As, respectively.
+MedDRA Queries of CDC AESIs
+After a review of As using the CDC's list of COVID-19-related adverse events of special interest (ASI), the Applicant reported that the following terms were not reported in the study: acute disseminated encephalomyelitis, transverse myelitis, multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, encephalitis, myelitis, encephalomyelitis, meningoencephalitis, ataxia, narcolepsy, cataplexy, immune thrombocytopenia, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, Kawasaki disease, multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A), and acute respiratory distress syndrome.
+Terms that were present in the safety population are summarized below. For a given SMQ, if there was no imbalance between the BNT162b2 group versus placebo, the PTs within the SMQ were not further examined. In the case of an imbalance, the PTs /SMQs responsible for the imbalance are further described and the nature of the events characterized with regard to plausible association with vaccination.
+Overall, the number and percentage of participants with any unsolicited As within the selected SMQs was similar in the BNT162b2 (224 [1.02%1) and placebo (217 [0.99%1) groups from Dose 1 to the unblinding date.
+Table 34. Selected Standardised MedDRA Queries From Dose 1 to Unblinding Date, Blinded Placebo-controlled Follow-up Period, Phase 2/3 Participants 6 Years of Age and Older, Safety Population
+SMQ/System Organ Class
+Particioants with an unsolicited adverse events within one or more SMQs
+An unsolicited adverse events within SMQ
+Angioedema
+An unsolicited adverse events within SMO
+Arthritis
+Any unsolicited adverse events within SMQ
+Convulsions
+BNT16262
+N=21926 n (%)
+224 (1.02)
+Placebo
+N=21921 n (%)
+217 (0.99)
+30 (0.14)
+29 (0.13)
+35 (0.16)
+48 (0.22)
+2 (0.01)
+2 (0.01)
+77
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+BNT162b2
+Placebo
+N=21926
+N=21921
+SMQ/System Organ Class
+n (%)
+n (%)
+Any unsolicited adverse events within
+2 (0.01)
+1 (0.00)
+Demvelination (SMQ)
+Any unsolicited adverse events within SOC
+87 (0.4)
+78 (0.4)
+Cardiac disorders
+Any unsolicited adverse events within SMQ
+27 (0.1)
+22 (0.1)
+Hepatobiliary disorders
+An unsolicited adverse events within SMQ
+182 (0.83)
+161 (0.73)
+Hypersensitivity
+Any unsolicited adverse events within SOC Skin
+134 (0.61)
+119 (0.54)
+and subcutaneous tissue disorders
+Any unsolicited adverse events within Peripheral
+3 (0.01)
+6 (0.03)
+neuropathy
+Source: ST 125742.0 Study C4591001-interim-mth6-report body.pdf, Section 12.2.4.4.2, adapted from Table 45, pages
+281-285.
+N = number of participants in the specified group.
+Cardiac Disorders
+Considering the observed risk of myocarditis/pericarditis, FDA analyzed adverse events within the SOC Cardiac disorders (see Appendix B) by evaluating the related narrow SMQs of Cardiac arrythmia, Ischemic heart disease and Cardiac failure. These SMQs were analvzed at 7 and 28 davs after an vaccination to assess for temporal relationship. More cardiac events were reported in the older age group when compared to the younger age group, with the greatest imbalances observed in Ischemic heart disease, as expected based on age-related risk factors. A total of 16 study participants experienced cardiac events during overall blinded and unblinded follow up through March 13, 2021. Of these 16 participants, 10 vaccine recipients (8 males and 2 females) and 6 placebo recipients (4 males and 2 females) reported ischemic cardiac events and/or cardiac failure. During the first 30 days post vaccination, 5 participants in the vaccine group reported ischemic or cardiac failure events, and 2 participants in the placebo group reported myocardial infarction. Only one event occurred within 7 days of vaccination with BNT162b2. The age range was similar in both study arms (35 to 49 years in the vaccine group and 46 to 48 years in the placebo group). Individual review of these cases revealed that all subiects had at least one of the following predisposing conditions: diabetes, hyperlipidemia, and/or hypertension. No imbalances were noted between treatment groups for any of the other preferred terms within the Cardiac disorders SOC. Of note, for the 8 participants who reported 'cardiac failure congestive' at any time during follow-up, four entered into the study with this pre-existing condition
+(1 BNT162b2: 3 Placebo).
+The occurrence of cardiac events (cardiac arrythmias, ischemic events and cardiac failure) with close temporal association to vaccination is similar between BNT16262 and placebo groups, and any imbalances are small. Because of the small numbers of events observed, the lack of a clear temporal association, and the presence of other factors that could have explained these events, these are unlikely to be related to vaccination. There is considerable uncertainty in making a definitive causality assessment.
+Hepatobiliary Disorders
+An analvsis of hepatobiliarv-related reports demonstrated that Gallstone related disorders (SMQ) were more common in the BNT16262 cohort when compared to
+78
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+placebo (20 BNT162b2: 11 placebo). Within the BNT162b2 group, these events were more common in subiects >55 vears of age (8 events reported by participants 16-55 years of age and 12 events reported by participants >55 years of age). Events occurred
+3-97 days following any vaccination, with a median time to event of 19 days for the BNT162b2 group. The clinical significance of this finding of numerically higher cases of gallstone disorders is not clear.
+6.1.12.6 Clinical Test Results
+Clinical laboratory tests (hematology, chemistries) were assessed in Phase 1. The only common laboratory abnormality reported was transient decreases in lymphocytes 1-3 days after Dose 1, which increased in frequency with increasing dose, were mostly Grade 1-2, generally normalized at the next laboratory assessment 6-8 days after Dose 1 and did not occur after Dose 2. Among Phase 1 participants who received the 30 ug dose of BNT162b2, transient decreases in lymphocytes post-Dose 1 occurred in 5 of 12 participants 18-55 years of age and in 4 of 12 participants 65-85 years of age. These transient hematological changes were not associated with clinical symptoms.
+6.1.12.7 Dropouts and/or Discontinuations
+Dose 1 to data cutoff date or participant's unblinding date (whichever was earlier)
+Of the 43,847 enrolled participants, 352 (1.6%) participants in the BNT162b2 group and 528 (2.4%) participants in the placebo group discontinued from the study prior to unblinding; most were due to withdrawals by the participant (n=109 [0.5%] and n=181 [0.8%], respectively), or loss to follow-up (n=151 [0.7%] and n=152 [0.7 %], respectively). A total of 146 participants (n=26 [0.1%] in the BNT162b2 group and (n=120 [0.5%] in the placebo group) were discontinued because they no longer met eligibility criteria.
+Dropouts due to pregnancy were balanced between the treatment groups (6 per group).
+Study Withdrawal due to an AE
+Of the 43,847 enrolled participants, 45 (0.21%) vaccine recipients and 51 (0.23%) placebo recipients withdrew from the study due to an AE.
+Adverse events in the SOC Cardiac disorders were the most common As leading to withdrawal, with 10 events in the BNT162b2 group (8 of which resulted in death) and 8 in the placebo group (4 of which resulted in death):
+• BNT162b2 group:
+• Did not result in death: coronary arter disease in a participant >55 vears of age occurring 12 days post Dose 2, and tachycardia in a participant >55 years of age occurring 2 days post Dose 1.
+• Resulted in death: cardiac arrest in 4 participants, all >55 years of age, occurring from 31 to 117 days after vaccination, cardiac failure congestive in 1 particioant 16-55 ears of age occurring 69 days after Dose 2, cardio-respiratory arrest in 1 participant 16-55 years of age occurring 86 days after Dose 2, hypertensive heart disease in a participant >55 years of age occurring 71 days after Dose 2, sudden cardiac death in a participant >55 vears of age occurring 42 davs after Dose 2.
+• placebo group:
+• Did not result in death: atrial fibrillation (participants), cardiac failure congestive, and coronary artery occlusion (1 participant each).
+79
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+• Resulted in death: myocardial infarction (2 participants each); cardiac arrest, cardiorespiratory arrest (1 participant each).
+AEs in the SOC General disorders and administration site conditions were the next most common AEs leading to withdrawal (6 vaccine, 2 placebo):
+• BNT162b2 groups: injection site pain in 2 participants 16-55 years of age occurring
+1-2 days after Dose 1, chills and pyrexia in 1 participant >55 years of age occurring on the day of Dose 1, facial pain and swelling in 1 participant >55 years of age occurring 4 days after Dose 1, injection site dermatitis in 1 participant 16-55 years of age occurring 3 days after Dose 1, and injection site swelling in 1 participant 16-55 years of age occurring on the day of Dose 1.
+• Placebo group: death and fatigue (1 participant each).
+Please refer to Section 6.1.12.3 for additional details regarding deaths reported in the study.
+To better characterize these study withdrawals due to As, an analysis of the time period from Dose 1 to 1 Month after Dose 2 was also evaluated.
+Of the 43,847 enrolled participants, 32 (0.1%) participants in the BNT1622 group and 36 (0.2%) participants in the placebo group had an AE leading to study withdrawal.
+AEs in the SOC General disorders and administration site conditions were most common with 6 participants in the BNT162b2 group and 2 participants in the placebo group who withdrew from the study due to an AE:
+• BNT162b2 group: injection site pain (2 participants) and chills, facial pain, injection site dermatitis, injection site swelling, pyrexia, and swelling face (1 participant each).
+• placebo group: death and fatigue (1 participant each).
+AEs in the SOC Cardiac disorders also occurred in 3 participants in the BNT162b2 group and 5 participants in the placebo group who withdrew from the study due to an AE:
+• BNT162b2 group (1 participant each): cardiac arrest (resulted in death), coronary artery disease and tachycardia.
+• placebo group: atrial fibrillation (2 participants), cardiac failure congestive, coronary artery occlusion, and myocardial infarction (1 participant each).
+As noted on page 65 in Section 6.1.12.2 above, 1 vaccine recipient >55 years of age reported unilateral deafness which occurred 19 days after Dose 1 and resolved 9 days later. The participant was discontinued from study intervention and remained in the study for safety evaluation.
+Open-label follow-up: from participant unblinding to the March 13. 2021 data cutoff
+Placebo recipients who unblinded to receive BNT162b2
+During the open-label follow-up period, most participants originally randomized in the placebo group remained in the study and received Doses 3 and 4 (88.8% and 72.4%, respectively) of BNT162b2. Overall, 19,525 original placebo participants were unblinded and received BNT162b2. The number of participants who discontinued from the study because of related As was 19/19,525 (0.1%). AEs in the SOC of General disorders and administration site conditions (n=7) were common, with injection site pain the most frequent (n=3), followed by chills (n=2) and fatigue (n=2).
+80
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Placebo recipients who had COVID-19 occurrence after Dose 1, then received
+BNT162b2 after unblinding
+A total of 852 participants who originally received placebo had COVID-19 and then received BNT162b2 after unblinding. Among these, 3 participants reported As leading to withdrawal, all of which were assessed as related to BNT162b2:
+• 1 participant with an AE of allergy to vaccine, who had a known history of asthma and allergy to arthropods, experienced the following 5 minutes after vaccine administration: facial swelling and flushing, followed by nausea and urticaria hours later; nausea resolved the same day; other symptoms resolved the next day);
+•
+•
+1 participant with an AE of pain on the day of vaccination.
+1 participant with 5 AEs (chills, injection site pain, myalgia, headache, and diarrhea) on the day of vaccination.
+Original BNT162b2 Participants
+Overall, 20,309 original BNT1622 recipients, including 12,006 with at least 6 months of total follow-up, were followed after unblinding. Of these, 4 participants were withdrawn due to an AE: 1 participant reporting each of the following PTs: myocardial infarction, acute hepatic failure, injury, road traffic accident, and lung cancer with metastases to the brain. For three participants, withdrawal was due to death (myocardial infarction, road traffic accident and brain metastases). None of these events were considered related to the study intervention and FDA agrees with the assessment.
+6.1.13 Study Summary and Conclusions
+This randomized, blinded, placebo-controlled multinational clinical trial evaluated the safety and efficacy of BNT162b2 in >40,000 participants 16 years of age and older.
+In the updated efficacy analysis, vaccine efficacy after 7 days post Dose 2 was 91.1%, (95% CI 88.8; 93.1) in participants without prior evidence of SARS-CoV-2 infection and 90.9% (95% CI: 88.5, 92.8) in the group of participants with or without prior infection.
+Efficacy estimates were consistently high across demographic and geographic subgroups, although interpretation of some subgroup analyses was limited by low number of cases and/or participants. Updated vaccine efficac against severe COVID-19 occurring after 7 days after Dose 2 was 95.3% (95% Cl 71.0, 99.9), with 1 case in BNT162b2 group and 21 cases in placebo group. Overall, the updated efficacy analysis results show that BNT162b2 provided high VE in preventing symptomatic COVID-19 and severe COVID-19 cases during the blinded, placebo-controlled follow-up period.
+Solicited local reactions and systemic reactions after vaccination were frequent in the BNT162b2 group; these were mostly mild to moderate, generally of short duration, and more frequent in the younger age group than the older age group. The most common solicited adverse reactions, by age group, were injection site reactions (88.6% and 78.2%), fatigue (70.1% and 56.9%), headache (64.9% and 45.9%), muscle pain (45.5% and 32.5%), chills (41.5% and 24.8%), joint pain (27.5% and 21.5%), fever (17.8% and 11.5%) in the younger and older age groups, respectively. Severe adverse reactions occurred in up to 5.3% of participants, were more frequent after Dose 2 than after Dose 1 and were generally less frequent in adults ≥55 ears of age as compared to younger participants.
+Imbalances in unsolicited adverse events between treatment groups from Dose 1
+through 1 month after Dose 2 included hypersensitivity-related adverse events (272
+81
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+participants [1.1%] in the vaccine group vs. 225 participants [0.9%] in the placebo group) and lymphadenopathy (83 participants [0.4%] in the vaccine group and 7 participants [<0.1%] in the placebo group). Bell's palsy was reported by four vaccine participants and 2 placebo recipients during the blinded study period, and an additional 3 placebo/BNT162b2 recipients following unblinding, which suggests a potential causal association between vaccine and the rare occurrence of Bell's palsy. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2 vaccine.
+Overall, deaths and SAEs were reported by similar proportions of participants in both treatment groups. A total of 38 deaths occurred in the reporting period (19 deaths in the BNT162b2 group, 17 in placebo and 2 in the placebo/BNT162b2 group). More deaths occurred in the older age group, as expected due to increased age and comorbidities.
+All deaths represent events that occur in the general population of the age groups where they occurred, at a similar rate. The frequency of non-fatal serious adverse events was low (<1.2%), without meaningful imbalances between treatment groups.
+The number of participants who reported at least 1 SAE was higher in the older age group than in the younger age group, again as expected due to increased age and comorbidities and representing events that occur in the general population of the age groups where they occurred.
+The clinical data submitted exceed FDA's expectations for data to support licensure of vaccines for prevention of COVID-19, including relevant efficacy success criteria and numbers of vaccinated study participants and follow-up time (i.e., at least 3,000 vaccinated participants in each age group with at least 6 months of total safety follow-up) for an acceptable safety database.
+6.2 Study BNT162-01
+NCT04380701
+Title: A multi-site, Phase I/II, 2-part, dose-escalation trial investigating the safety and immunogenicity of four prophylactic SARS-CoV-2 RNA vaccines against COVID-19 using different dosing regimens in healthy and immunocompromised adults
+Desian
+Study BNT162-01 is an ongoing Phase 1, dose-level finding study to evaluate the safety and immunogenicity of several candidate vaccines, including BNT162b2 (1, 3, 10, 20, and 30 g), conducted in healthy German adults. The 30-ug dose level of BNT162b2 was administered to 12 adults age 18-55 years of age (inclusive) and 12 adults age 56-85 years of age (inclusive).
+The primary objective was to evaluate the safety the BNT162 candidate vaccines.
+Secondary and exploratory obiectives 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.
+82
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+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).
+Results
+Disposition of 30ug BNT162b2 group:
+• Safety: Of a total of 24 participants, 12 participants 18-55 years of age 12 participants 56-85 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 30ug 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 geometric mean tiers at baseline (pre-Dose 1), and most pronounced at the 30-ug dose level. The Th1 polarization of the T-helper response was characterized by the IN and IL-2 production, and only minor IL-4, production upon antigen-specific (SARS-CoV-2 S protein peptide pools) re-stimulation.
+Reviewer Conclusions
+Immunogenicity data supported the final dose selection and prospect of benefit for the enrollment of larger numbers of participants in study C4591001. The number of participants was too small to make definitive conclusions about antibody persistence at ~6 months after Dose 2. Also, the analyses of humoral responses in this study were exploratory and not germane to the interpretation of the primary efficacy endpoint in study C4591001.
+7. INTEGRATED OVERVIEW OF EFFICACY
+Not applicable because Study C4591001 was the only study that evaluated the efficacy of BNT612b2.
+8. INTEGRATED OVERVIEW OF SAFETY
+The number of participants who received the 30-ug dose of BNT162b2 in Study
+BNT162-01 (n=24) was small and would not change to the overall safety conclusions.
+Thus, an integrated overview of safety was not applicable.
+9. ADDITIONAL CLINICAL ISSUES
+9.1 Special Populations
+9.1.1 Human Reproduction and Pregnancy Data
+Pregnancy
+During study C4591001 from Dose 1 through the data cutoff date of March 13, 2021, pregnancy was reported by 42 participants who received BNT162b2. For those participants who received BNT162b2 during the open-label period (originally randomized to placebo), 8 participants reported maternal exposure during pregnancy
+83
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+prior to the data cutoff date. Data on Birth Outcomes, Unknown Pregnancy Outcomes and Ongoing Pregnancies is not included in the study report as the Applicant did not collect this information in their standard clinical database.
+The disposition of participants 16 years of age or older who became pregnant from Dose 1 through the data cutoff date of March 13, 2021, is shown below in Table 35 (original treatment groups as randomized, N=44,047) and Table 36 (participants originally randomized to placebo who were unblinded and received BNT162b2,
+N=19,611). No subject in the 16-17-year-old group reported a pregnancy. One subject in the older age group (62 years of age) reported a pregnancy 139 days relative to the last dose of vaccine. Withdrawals due to pregnancy during blinded follow-up were balanced between the vaccine and placebo groups.
+The known pregnancy outcomes of spontaneous abortion, miscarriages and elective abortions was similar between the vaccine and the placebo group.
+Table 35. Disposition of Participants 16 Years of Age and Older Who Experienced
+Pregnancy, Phase 2/3 Safety Population (Data Cutoff Date March 13, 2021)
+BNT162b2a
+Placebob
+(N=22026)
+(N=22021)
+n (%)
+n (%)
+42 (0.2)
+47 (0.2)
+Total
+(N=44047)
+n (%)
+89 (0.2)
+Total number of pregnancies
+Timing of pregnancy
+Completed 1 dose
+Completed 2 doses
+5 (0.0)
+37 (0.2)
+8 (0.0)
+39 (0.2)
+Timing of last dose relative to pregnancy
+Within 30 days of pregnancy
+>30 days after pregnancy
+Spontaneous Abortions
+Miscarriages
+13 (0.1)
+29 (0.1)
+3 (0.0)
+3 (0.0)
+Elective Abortions
+21 (0.1)
+26 (0.1)
+7 (0.0)
+5 (0.0)
+1 (0.0)
+Source: ST 125742, amendment 23, Table 1, IR Réponse, page 4-5.
+Note: Human immunodeficiency virus (HIV)-positive participants are included in this summary a Includes data from Dose 1 through March 13, 2021, for participants who originally received BNT162b2. b Includes data from Dose 1 to before the first dose of BNT162b2 or through March 13, 2021, for participants who originally received placebo.
+13 (0.0)
+76 (0.2)
+34 (0.1)
+55 (0.1)
+10 (0.0)
+8 (0.0)
+1 (0.0)
+Table 36. Disposition of Participants 16 Years of Age and Older Who Experienced
+Pregnancy and Who Had Originally Received Placebo and Then Received BNT162b2 After Unblinding, Phase 2/3 Safety Population (Data Cutoff Date March 13, 2021)
+BNT162b2a (N=19611)
+n (%)
+Total number of pregnancies
+8 (0.0)
+Timing of pregnancy
+Combleted 1 dose
+Completed 2 doses
+3 (0.0)
+5 (0.0)
+Timing of last dose relative to pregnancy
+Within 30 davs of pregnancy
+>30 davs after pregnancy
+Spontaneous Abortions
+Miscarriages
+Elective Abortions
+7 (0.0)
+1 (0.0)
+0 (0.0)
+0 (0.0)
+0
+84
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Source: ST 125742, amendment 23, Table 2, IR Response, page 4-5.
+Note: Human immunodeficiency virus (HIV)-positive participants are included in this summary a Includes data from first dose of BNT1622 through March 13, 2021, for participants who originally received placebo and then received BNT162b2 after unblinding.
+The data on pregnancy and pregnancy outcomes from this study is limited. As part of the postmarketing surveillance, the Applicant will perform a pregnancy registry study to assess pregnancy and infant outcomes after exposure to BNT162b2 during pregnancy among pregnant women aged 18 years or older who reside in the US or Canada.
+(Study C4591022). Additionally, a randomized controlled trial in pregnant women (Study C4591015) will be initiated.
+Further information collected from VAERS using the terms for events related to counts for the SOCs of Pregnancy, puerperium and perinatal conditions can be found in the Pharmacovigilance Plan Review Memorandum (Division of Epidemiology).
+9.1.2 Use During Lactation
+It is not known if BNT1622 is secreted in human breast milk. Data are not available to assess the effects of BNT162b2 on the breastfed infant or on milk production.
+9 1.3 Pediatric Use and PREA Considerations
+To address Pediatric Research Equity Act (PREA) requirements, the Applicant submitted a request for deferral of the following studies in pediatric individuals <16 years to birth, because BNT162b2 would be ready for approval for use before pediatric studies for ages 0 to <16 years are complete. The deferred studies are listed here:
+• Deferred pediatric study C4591001 to evaluate the safety and effectiveness of
+BNT162b2 in children 12 years through 15 years of age
+• Deferred pediatric study C4591007 to evaluate the safety and effectiveness of
+BNT162b2 in children 6 months to <12 years of age
+• Deferred pediatric study C4591023 to evaluate the safety and effectiveness of BNT162b2 in infants <6 months of age
+Clinical data to support the safetv and effectiveness of BNT162b2 in individuals 16-17 years of age were included in this BLA.
+The deferral request and pediatric plans were accepted without revisions by the Pediatric Review Committee on August 3, 2021.
+9.1.4 Immunocompromised Individuals
+Study C4591001 enrolled healthy 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. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratorv/physical examination and individuals with a historv of autoimmune disease or an active autoimmune disease requiring therapeutic intervention were excluded from participation. Examples of conditions resulting in exclusion included but were not limited to: systemic or cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré syndrome, multiple sclerosis, Sjogren's syndrome, idiopathic thrombocytopenia purpura, glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis), psoriasis, and insulin-dependent diabetes mellitus (type 1).
+Individuals on immunosuppressive therapy or planning on receiving
+85
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+immunosuppressive therapy were not enrolled in the study. However, if there was short-term treatment with corticosteroids for an acute illness, the individual's enrollment was delayed for 28 days following the completion of that treatment. The study did enroll a small subgroup (N=200) of participants with HIV infection on stable antiretroviral therapy; these participants all had stable viral load <50 copies/mL and CD4 count >200 cells/mm3 within 6 months before enrollment and are discussed in more detail in Section 9.1.6 below.
+Due to study exclusion criteria described above, data in the BLA submission are insufficient to inform vaccine safetv and effectiveness in immunocompromised populations. Based on published reports of low antibody responses and breakthrough infections among significantly immunocompromised individuals (mainly solid organ transplant recipients) who received the two-dose vaccination series under EUA, FDA amended the EUA for the Pfizer COVID-19 Vaccine in August 2021 to allow for a third dose, at least 28 days following the second dose, in individuals at least 12 years of age who have undergone solid organ transplantation, or who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise.
+9.1.5 Geriatric Use
+Among all participants (N=22,026) who were originally randomized to BNT162b2 in Study C4591001 and included in the safety population, 20.7% (n=4,552) were 65 years of age and older and 4.2% (n=925) were 75 years of age and older. The effectiveness in geriatric participants was consistent with that seen in younger adult participants, and no safety concerns specific to the geriatric age group were identified. The reported frequencies of adverse reactions, including myocarditis/pericarditis, are lower in the geriatric age group compared with younger adults and adolescents.
+9.1.6 Patients with Human Immunodeficiency Virus (HIV) Infection
+As an exploratory objective for study C4591001, the safety, immunogenicity, and efficacv of BNT16262 vaccine was assessed in individuals with confirmed stable HIV disease (protocol amendment 6 dated September 8, 2020) in the Phase 2/3 portion of the study. Confirmed stable HIV disease defined as documented viral load <50 copies/mL and CD4 count >200 cells/mm3 within 6 months before enrollment, and on stable antiretroviral therapy for at least 6 months
+A total of 200 participants ≥16 years of age, who met the prespecified criteria, were randomized 1:1 to receive BNT1622 or placebo.
+Table 37. Participants With Confirmed HIV, Phase 2/3 Safety Population
+Age Group
+BNT162b2 (30 mcg)
+Placebo
+16-55 vears
+74
+69
+>55 vears
+26
+31
+Total
+100
+100
+Total
+143
+57
+200
+Source: ST 125742, Study C4591001, Section 14, Table 14.30 (reviewer modified), pages 357/1584.
+These participants were not included in the overall Phase 3 analvsis for safetv or efficacy for the general population of study participants ≥16 years of age. The safety results for individuals with confirmed stable HIV disease were summarized descriptively. VE was to be assessed if there was a sufficient number of COVID-19 cases in this group of participants.
+86
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+The demographics (sex, race, ethnicity and age) were similar between the BNT162b2 vaccine and placebo cohort of participants with HIV. Baseline SARS-CoV-2 status was positive for 15 participants (15%) in the BNT162b2 vaccine group and 11 participants (11%) in the placebo group. More participants in the placebo group had T-cell counts between 200-500 cells/mm3 than in the vaccine group; 28 (28.0%) compared to 16 (16.0%) respectively. Overall, the participants in the HIV subgroup were younger and more likely to be male than the general population of participants enrolled in the study.
+A higher percentage of participants in the HIV subgroup identified as Black or African American compared to the general study population (54.5% versus 9.5%). The median age at vaccination for the HIV subgroup was 50 years. (This mirrors what was seen in the general study population ≥16 years of age.)
+Table 38. Demographic Characteristics, Blinded Placebo-controlled Follow-up Period, Phase 2/3 HIV-Positive Participants 16 Years of Age and Older, Safety Population
+BNT162b2 (30 ug)
+Placebo
+(Na =100)
+(Na =100)
+nb (%)
+n° (%)
+Total
+(Na =200)
+n' (%)
+Sex
+Male
+Female
+Race
+White
+Black or African American
+American Indian or Alaska Native
+Asian
+Multiracial
+Not reported
+Ethnicity
+Hispanic/Latino
+Non-Hispanic/non-Latino
+Not reported
+Country
+Argentina
+Brazil
+Germany
+South Africa
+Turkey
+USA
+Age group (at vaccination)
+16-55 Years
+>55 Years
+Age at vaccination (vears)
+Mean (SD)
+Median
+Min, max
+Baseline SARS-CoV-2 status
+Positivec
+Negatived
+Missing
+69 (69.0)
+31 (31.0)
+66 (66.0)
+34 (34 0)
+135 (67.5)
+65 (32.5)
+44 (44.0)
+52 (52.0)
+1 (1.0)
+2 (2.0)
+1 (1.0)
+37 (37.0)
+57 (57.0)
+2 (2.0)
+1 (1.0)
+2 (2.0)
+1 (1.0)
+81 (40.5)
+109 (54.5)
+3 (1.5)
+3 (1.5)
+3 (1.5)
+1 (0.5)
+20 (20.0)
+80 (80.0)
+O
+12 (12.0)
+87 (87.0)
+1 (1.0)
+32 (16.0)
+167 (83.5)
+1 (0.5)
+3 (3.0)
+3 (3.0)
+2 (2.0)
+27 (27.0)
+2 (2.0)
+63 (63.0)
+1 (1.0)
+2 (2.0)
+O
+27 (27.0)
+2 (2.0)
+68 (68.0)
+4 (2.0)
+5 (2.5)
+2 (1.0)
+54 (27.0)
+4 (2.0)
+131 (65.5)
+74 (74.0)
+26 (26 0)
+69 (69.0)
+31 (31 0)
+143 (71.5)
+57 (28.5)
+49.0 (9.74) 48.9 (11.15) 48.9 (10.44)
+50.0
+49.0
+(22, 75)
+(26, 68)
+49.5
+(22, 75)
+15 (15.0)
+83 (83.0)
+2 (2.0)
+11 (11.0)
+88 (88.0)
+1 (1.0)
+26 (13.0)
+171 (85.5)
+3 (1.5)
+87
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+BNT162b2 (30 ug)
+(Na =100)
+n° (%)
+Placebo (Na =100)
+n° (%)
+Total
+(Na =2001 nb (%)
+BMI
+Underweight (<18.5 kg/m2)
+Normal weight (218.5 kg/m?
+24.9 kg/m2)
+Overweight (225.0 kg/m? - 29.9 kg/m)
+Obese (≥30.0 kq/m2)
+4 (4.0)
+22 (22.0)
+35 (35.0)
+39 (39.0)
+1 (1.0)
+26 (26.0)
+34 (34.0)
+39 (39.0)
+5 (2.5)
+48 (24.0)
+69 (34.5)
+78 (39.0)
+Cluster of differentiation 4 (CD4) count
+<200 cells/mm3
+200-500 cells/mm3
+>500 cells/mm3
+Missing
+2 (2.0)
+16 (16.0)
+78 (78.0)
+4 (4.0)
+2 (2.0)
+28 (28.0)
+64 (64.0)
+6 (6.0)
+4 (2.0)
+44 (22.0)
+142 (71.0)
+10 (5.0)
+HIV ribonucleic acid (RNA)
+<50 copies/mL
+93 (93.0)
+≥50 copies/mL
+4 (4.0)
+Missing
+3 (3.0)
+96 (96.0)
+0
+4 (4.0)
+189 (94.5)
+4 (2.0)
+7 (3.5)
+Source: ST 125742, Study C4591001, Section 14, Table 14.51, pages 505-6/1584.
+Abbreviation: SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
+Note: Human immunodeficiency virus (HIV)-positive participants are included in this summary but analyzed and reported separately.
+a. N = number of participants in the specified group, or the total sample. This value is the denominator for the percentage
+calculations.
+•. n = Number of participants with the specified characteristic
+c. Positive N-binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
+d. Negative N-binding antibody result at Visit 1, negative NAAT result at Visit 1, and no medical history of COVID-19
+Solicited local reactions in participants with stable HIV disease were similar to those observed for all participants ≥16 years of age by severity, onset day, and median duration (see Table 26 and Table 27 for general population local reactions). In the subgroup of participants with stable HIV, the frequency of pain at the injection site following BNT162b2 was similar after Dose 1 compared with Dose 2 of (63.0% vs 53.3%) The frequency of redness and swelling was similar after Dose 1 compared with Dose 2 (redness: 3.7% vs 6.7%; swelling: 5.6% vs 8.3%, respectively). One (1.7%) severe reaction (pain at the iniection site was reported after Dose 2 of BNT162b2.
+Overall, no Grade 4 reactions were reported for either the vaccine or the placebo group.
+The mean duration of local reactions in those participants who received the BNT162b2 was ≤2 days.
+Solicited systemic adverse reactions in participants with confirmed stable HIV disease were similar to those observed for all participants ≥16 years of age by severity, onset day, and duration Fever, headache, chills, and joint pain increased in frequency from Dose 1 to Dose 2 while fatigue, vomiting, diarrhea, and muscle pain were similar in frequency after each dose. No severe systemic events were reported after Dose 1 of BNT162b2. Following Dose 2 of BNT162b2, severe solicited systemic adverse events included 1 (1.7%) fever (>38.9°C to 40.0°C), 3 (5.0%) fatigue, 2 (3.3%) headache, 1 (1.7%) chills, and 1 (1.7%) diarrhea. No grade 4 solicited systemic adverse events were reported after either dose.
+Table 39 and Table 40 present the frequency and severity of reported solicited local and systemic reactions, respectively, within 7 days of each dose of BNT1622 and placebo for participants 16 years of age and older with confirmed stable HIV infection.
+88
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Table 39. Solicited Local Reactions Among HIV-Positive Participants 16 Years of Age and Older, by Maximum Severity, Within 7 Days After Each Dose, Reactogenicity Subset of the Safety Population*
+BNT162b2
+Dose 1
+Na =54 n° (%)
+Placebo
+Dose 1
+Na =56 n° (%)
+BNT16262
+Dose 2
+Na =60 n° (%)
+Placebo
+Dose 2
+Na =62 n° (%)
+Redness
+Any (>2.0 cm)
+Mild
+2 (3.7)
+2 (3.7)
+3 (5.4)
+1 (1.8)
+Moderate
+Severe
+0
+2 (3.6)
+4 (6.7)
+3 (5.0)
+1 (1.7)
+O
+1 (1.6)
+1 (1.6)
+0
+0
+Swelling~
+Any (>2.0 cm)
+Mild
+Moderate
+3 (5.6)
+2 (3.7)
+1 (1.9)
+1 (1.8)
+Severe
+O
+1 (1.8)
+5 (8.3)
+2 (3.3)
+3 (5.0)
+0
+0
+ooo
+Pain at the injection sited
+Any
+Mild
+Moderate
+34 (63.0)
+26 (48.1)
+8 (14.8)
+Severe
+9 (16.1)
+8 (14.3)
+1 (1.8)
+0
+32 (53.3)
+22 (36.7)
+9 (15.0)
+1 (1.7)
+5 (8.1)
+5 (8.1)
+Source: Modified from Table 14.72 page 546/1584
+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 HIV-positive participants 16 years of age and older.
+* 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.
+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 55.0 cm; Moderate: >5.0 to 510.0 cm; Severe: >10.0 cm.
+d. Mild: does not interfere with activity; Moderate: interferes with activity; Severe: prevents daily activity.
+Table 40. Solicited Systemic Reactions Among HIV-Positive Participants 16 Years of Age and Older, by Maximum Severity, Within 7 Days After Each Dose, Reactogenicity Subset of the Safety Population*
+BNT16262
+Dose 1
+Na =54 nb (%)
+Placebo
+Dose 1
+Na =56 nb (%)
+BNT16262
+Dose 2
+Na =60 nb (%)
+Placebo
+Dose 2
+Na =62 nb (%)
+Fever
+238.0°C
+238.0°C to 38.4°C
+>38.4°C to 38.9°C
+>38 9°C to 40 0°C
+>40.0°C
+Fatique®
+Any
+Mild
+Moderate
+Severe
+Headache
+Any
+Mild
+Moderate
+Severe
+1 (1.9)
+1 (1.9)
+4 (7.1)
+2 (3.6)
+O
+2 (3.6)
+9 (15.0)
+4 (6.7)
+4 (6.7)
+1 (1.7)
+5 (8.1)
+5 (8.1)
+0
+O
+O
+22 (40.7)
+15 (27.8)
+7 (13.0)
+15 (26.8)
+9 (16.1)
+5 (8.9)
+1 (1.8)
+24 (40.0)
+12 (20.0)
+9 (15.0)
+3 (5.0)
+12 (19.4)
+5 (8.1)
+7 (11.3)
+11 (20.4)
+7 (13.0)
+4 (7.4)
+18 (32.1)
+10 (17.9)
+7 (12.5)
+1 (1.8)
+18 (30.0)
+8 (13.3)
+8 (13.3)
+2 (3.3)
+12 (19.4)
+8 (12.9)
+4 (6.5)
+89
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+BNT162b2
+Dose 1
+Na =54 nb (%)
+Placebo
+Dose 1
+Na =56 nb (%)
+BNT162b2
+Dose 2
+Na =60 nb (%)
+Placebo
+Dose 2
+Na =62 n' (%)
+Chills
+Any
+Mild
+Moderate
+6 (11.1)
+5 (9.3)
+1 (1.9)
+Severe
+5 (8.9)
+4 (7.1)
+1 (1.8)
+0
+14 (23.3)
+5 (8.3)
+8 (13.3)
+1 (1.7)
+4 (6.5)
+3 (4.8)
+1 (1.6)
+Vomitingd
+Any
+Mild
+1 (1.9)
+1 (1.9)
+3 (5 4)
+1 (1.8)
+Moderate
+2 (3.3)
+1 (1.7)
+1 (1.7)
+2 (3.2)
+1 (1.6)
+1 (1.6)
+Severe
+2 (3.6)
+Diarrhea
+Any
+Mild
+5 (9.3)
+5 (9.3)
+Moderate
+Severe
+8 (14.3)
+6 (10.7)
+1 (1.8)
+1 (1.8)
+4 (6.7)
+1 (1.7)
+2 (3.3)
+1 (1.7)
+9 (14.5)
+6 (9.7)
+3 (4.8)
+New or worsened muscle pain
+Any
+Mild
+Moderate
+9 (16.7)
+7 (13.0)
+2 (3.7)
+10 (17 9)
+7 (12.5)
+3 (5.4)
+10 (16.7)
+5 (8.3)
+5 (8.3)
+5 (8.1)
+1 (1.6)
+4 (6.5)
+Severe
+New or worsened joint pain
+Anv
+Mild
+Moderate
+5 (9.3)
+5 (9.3)
+O
+7 (12.5)
+4 (7.1)
+3 (5.4)
+10 (16.7)
+4 (6.7)
+6 (10.0)
+5 (8.1)
+1 (1.6)
+4 (6.5)
+Severe
+Use of antipyretic or pain medicationf
+7 (13.0)
+8 (14.3)
+16 (26.7)
+7 (11.3)
+Source: Modified Table 14.79 page 587/1584
+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 HIV-positive participants 16 years of age and older.
+* 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.
+The N for each event 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.
+Reviewer Comment: Regardless of the number of doses of BNT162b2 vaccine, the solicited adverse reactions and systemic adverse events observed in the stable HIV population following any dose of BNT1622 occurred with the same or less frequency than those observed in the general study population.
+Table 41 below presents the rates of adverse events reported in participants with stable
+HIV from dose one of vaccine or placebo until the study unblinding date. While the rate of any related AE in the stable HIV cohort was higher in the BNT162b2 group when compared to the placebo group (attributed to the overall reactogenicity of BNT162b2), rates of related severe and life-threatening events were similar between the two treatment groups.
+90
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Two participants in the vaccine group withdrew secondary to an adverse event, and 1 participant in the placebo group also withdrew from the study. Serious adverse events were similar between the two cohorts (6.6% in the vaccine group and 6.9% in the placebo group) and included one case of COVID pneumonia in the placebo group (see
+Table 41 below).
+Table 41. Occurrence of at Least 1 Adverse Event From Dose 1 to Unblinding Date Among HIV-Positive Participants 16 Years of Age and Older, Blinded Placebo-controlled Follow-up Period, Phase 2/3 Safety Population
+Any event
+Related
+Severe
+Life-threatening
+Any serious adverse event
+BNT162b2
+(Na =100)
+n=% nb
+29
+19
+2
+1
+2
+Related
+Placebo (Na =100)
+n=% nb
+15
+3
+O
+1
+2
+0
+Severe
+Life-threatening
+1
+1
+1
+Any adverse event leading to withdrawal
+Related
+2
+O
+1
+Severe
+0
+Life-threatening
+Death
+1
+1
+1
+1
+Source: ST 125742, Study C4591001, Section 14, modified supplemental Table 14.118, pages 848/1584.
+a. N = number of participants in the specified group.
+b. n = Number of participants reporting at least 1 occurrence of the specified event category. For "any event," n = number
+of participants reporting at least 1 occurrence of any event.
+. Assessed by the investigator as related to investigational product.
+SAEs
+An assessment of the HIV subgroup for the period from Dose 1 to the unblinding date shows that four participants (2 in BNT162b2 group/ 2 in placebo group) reported at least 1 SAE during the blinded, placebo-controlled follow-up period. During this same time period, 2 As leading to withdrawal were reported in the BNT162b2 group (1 life-threatening) and 2 As (life-threatening) leading to withdrawal were reported in the placebo group. These As are summarized in Table 42 below. Only the severe As of nausea, vomiting, chills, injection site pain, fever, myalgia reported by the same participant one day after Dose 2 in the BNT162b2 were thought to be related to the study product. These As were reported to have resolved in 3 days.
+Table 42. Adverse Events That Were Severe, Serious, Life Threatening, or Led to Withdrawal, from Dose 1 to Unblinding Date, HIV-Positive Participants 16 Years of Age and Older, Blinded Placebo-Controlled Follow-up Period, Phase 2/3 Safety Population
+Dose/ Day of
+Onset Relative
+Vaccine Group
+BNT162b2
+BNT16262
+AE Category
+SAE (severe)
+SAE (life threatening)
+Dose
+Dose 2 / Day 86
+Dose 2/ Day 74
+Description pneumonia
+Motor vehicle accident
+91
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Vaccine Group
+BNT162b2
+BNT162b2
+AE Category
+AE exposure
+Severe AE
+Dose/ Day of
+Onset Relative
+Dose
+Dose 1 / Day 22
+Dose 2/Day 1
+Description
+Pregnancy
+Nausea/vomiting/chills/injection
+site pain /fever/ myalgia
+Placebo
+SAE (life-
+Dose 2 / Day 72
+COVID-19 pneumonia
+threatening)
+Dose 2/ Dav 68
+Diabetes mellitus
+Placebo
+SAE
+Dose 2/ Day 71
+Breast cancer
+Source: FDA summary from ST 125742.0. 12, Appendix 3- narratives.
+• A BNT162b2 participant in the >55-year age group experienced an SAE of pneumonia 86 days after Dose 2 which lasted 8 days prior to resolution.
+• A BNT162b2 participant in the >55-year age group experienced a fatal SAE of road traffic accident 73 days after Dose 2.
+• A younger participant in the placebo group reported a SAE of breast cancer 71 days after Dose 2. The event is ongoing at the data cutoff date.
+• A younger participant in the placebo group reported a SAE of diabetes mellitus 68
+days after Dose 2, and COVID-19 pneumonia 72 days after Dose 2 which lasted 4 days and resulted in death (South Africa).
+An assessment of the HIV-infected study cohort for the period from Dose 1 to the unblinding date shows that four participants (2 in BNT162b2 group/ 2 in placebo group) reported at least 1 SAE during the controlled follow-up period. During this same time period there were 2 AEs leading to withdrawal in the BNT162b2 group (1 life-threatening) and 2 AEs (life-threatening) leading to withdrawal in the placebo group.
+Deaths
+Two deaths were reported in participants (1 BNT162b2 and 1 placebo) with confirmed stable HIV infection:
+• One female participant in the vounger age group died due to COVID-19 pneumonia reported 75 days after receiving Dose 2 of placebo. This participant was diagnosed based on a local COVID-19 test that could not be confirmed as protocol-approved and was not confirmed by a test result from the central laboratory. Therefore, this participant was not included in efficacy analyses.
+• One female participant in the older age group died due to a road traffic accident occurring 73 days after receiving Dose 2.
+HIV-infected participants were not included in the efficacy population. A separate efficacy analysis was not performed for the HIV-infected population.
+10. CONCLUSIONS
+The data submitted to this BLA provide evidence to support the safety and effectiveness of BNT162b2 (30 g), administered in two doses 3 weeks apart, for prevention of COVID-19 caused by SARS-CoV-2.
+The clinical data submitted to the BLA include results of a randomized, blinded, placebo-controlled multinational clinical trial that evaluated the safetv and efficacv of BNT162b2 in >40,000 participants 16 years of age and older. Overall, the updated efficacy analysis results show that BNT1622 provided >90% VE in preventing symptomatic COVID-19, and >95% VE in preventing severe COVID-19, starting 7 days
+92
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+after Dose 2. 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. These findings are consistent with the VE results reported in the protocol-specified event-driven interim and final analvses that supported issuance of an EUA for this vaccine in December 2020 and provide more robust evidence of vaccine effectiveness based on a much larger number of cases observed over a longer period of placebo-controlled follow-up than was available at the time of the EUA request.
+The clinical safety data submitted exceeded FDA expectations for an acceptable pre-licensure safety database of at least 3000 participants in each age group (16-55 ears of age and >55 years of age) with at least 6 months of total safety follow-up. In the clinical trial, local and/or systemic solicited reactions following vaccination were generally of short duration and occurred more commonly in the BNT162b2 group than the placebo group. Severe events, when they did occur, were more common in the younger age group. Overall, deaths and SAEs were reported by similar proportions of participants in both groups. Adverse reactions other than solicited reactogenicity events identified from the clinical trial data include lvmphadenopathy and potentially Bell's Palsy (the latter from a small numerical imbalance of temporally associated events).
+These imbalances support labeling of both lymphadenopathy and Bell's Palsy as potential adverse reactions. A slight imbalance in hypersensitivity-related events was observed during the trial, and hypersensitivity reactions reported during post-authorization use further supports inclusion of these reactions in labeling. The safety results for individuals with confirmed stable HIV disease were summarized descriptively. The proportion of subjects reporting solicited reactions in the HIV population was similar or lower than those seen in the main study population.
+Post-authorization safety surveillance has identified two additional clinically important but infrequent adverse reactions: anaphylaxis and myocarditis/pericarditis. The risk of myocarditis, observed as highest in males younger than 40 years of age, is being addressed by labeling in the Warnings and Precautions Section of the US package insert, by ongoing monitoring through active and passive surveillance, and by postmarketing studies to be conducted by the Applicant, US Government agencies, and other healthcare stakeholders to further evaluate and understand these risks.
+Based on the totality of data and the benefit-risk considerations as described in Section 11 below, the clinical reviewers conclude that the clinical trial data submitted in this application, and complemented by available post-authorization data and plans for post-licensure studies, support approval of BNT1622 for the indication of active immunization to prevent svmptomatic coronavirus disease 2019 (COVID 19) caused b severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older.
+93
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+11. RISK-BENEFIT CONSIDERATIONS AND RECOMMENDATIONS
+11.1 Risk-Benefit Considerations
+Table 43. STN125742: Risk -Benefit Considerations
+Decision Factor
+Analysis of
+Condition
+Unmet Medical
+Need
+Evidence and Uncertainties
+• SARS CoV-2, a novel respiratory coronavirus causing COVID-19, is currently responsible for a global pandemic that has significantly disrupted human activity on a global scale.
+• COVID-19 is associated with significant morbidity, mortality (>4 million deaths worldwide to date) and long-term sequelae among survivors. In the US, COVID-19 has been responsible for >2.6 million hospitalizations and >600.000 deaths to date.
+• While the greatest risk of severe or fatal COVID-19 is in individuals >65 years of age and those with comorbid conditions (e.g., obesity, diabetes, immunocompromising conditions), significant morbidity and mortality and long-term sequelae from COVID-19 has occurred in healthy individuals of all ages.
+• Individuals with asymptomatic SARS-CoV-2 infection may transmit the virus to others.
+• Multiple genetic variants of the virus are circulating and continue to emerge.
+Evidence of an increase in transmissibility, shorter incubation periods and more severe disease (e.g., increased hospitalizations or deaths) has been associated with some of these variants.
+• Uncertainties include: lack of complete understanding of mechanisms of pathogenesis and individual risk for severe disease; evolving epidemiology of the pandemic: and potential for emergence of SARS-CoV-2 variants with altered infectivity, virulence, and/or capacity to evade immunity from natural infection or vaccination
+�� No therapies are currently licensed for prevention of COVID-19. Remdesivir is the only drug approved for the treatment of COVID-19, and approved use is limited to hospitalized adults and pediatric patients [12 years of age and older and weighing at least 40 kilograms (about 88 pounds)].
+• Monoclonal antibodies are available under EUA for treatment and post-exposure prophylaxis but not for pre-exposure prophylaxis.
+• BNT16262 is one of three COVID-19 vaccines for which an Emergency Use
+Authorization (EUA) has been issued. Currently, no vaccines are FDA
+Conclusions and Reasons
+• COVID-19 is a serious/life-threatening disease responsible for a globally disruptive pandemic.
+• Control of the COVID-19 pandemic will be necessary to return to the normal activities of pre-pandemic times.
+• The emergence of variants of the SARS CoV-2 virus may lead to more transmissible viruses or more severe disease.
+• Further research is needed to understand
+SARS-CoV-2 immunology, COVID-19 pathogenesis, and individual risk factors for severe disease.
+• Public health measures of social distancing and masking are helpful but do not prevent all transmission of the virus.
+• There is an unmet medical need for a FDA-approved vaccine to prevent COVID-19 caused b SARS-CoV-2
+• Ongoing epidemiological and clinical surveillance is needed to inform needs related to development of pharmacologic interventions
+94
+
+Clinical Benefit
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+approved for the prevention of COVID-19, and this has been cited as a reason for vaccine hesitancy and refusal of some individuals to receive EUA vaccines.
+• Public health vaccination goals of immunizing 75% of the population (to achieve herd immunity) have not yet been achieved.
+• Non-pharmacologic measures to prevent transmission of SARS-CoV-2 include masks, social distancing, and avoidance of high-risk situations. These actions do not prevent all infections.
+A recent increase in US incidence of COVID-19, following decreased incidence with the introduction of EU vaccines, involves overwhelmingly unvaccinated individuals (especially among those with severe disease); however, this increased incidence is also associated with breakthrough cases in vaccinated individuals.
+• Uncertainties include whether the recent increased incidence of new infections in the US is due to waning immunity from natural infection or vaccination, to the emergence of the delta variant, or to a combination of these factors
+• In the evaluable efficacy population of >40,000 participants 16 years of age and older without evidence of prior SARS-CoV-2 enrolled in an ongoing multinational, randomized placebo-controlled Phase 1/2/3 trial, vaccine efficacy against symptomatic COVID-19 during the placebo-controlled follow-up period starting from 7 days after Dose 2 was 91.1% [95%Cl: 88.8;93.1]. The efficacy estimate was similar when including participants with evidence of prior SARS-Cov-2 infection. although these participants contributed onlv 2.7% of the total confirmed COVID-19 cases observed during placebo-controlled follow-up.
+• 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, and participants with obesity and medical comorbidities associated with high risk of severe COVID-19.
+• In the same clinical trial population of participants 16 years of age and older without evidence of prior SARS-CoV-2 infection, vaccine efficacy against severe COVID-19 during the placebo-controlled follow-up period starting from 7 days after Dose 2 was 95.3% [95% CI: 70.9%; 99.9%].
+• Uncertainties in clinical benefit include: longer-term duration of protection; effectiveness in certain populations (e.g., significantly immunocompromised) not well represented in the clinical trial; effectiveness against SARS-CoV-2 variants that are antigenically or biologically different from those circulating during vaccine evaluation to date; and effectiveness against asymptomatic infection and transmissibilitv of the virus
+(including vaccines) for treatment and prevention of COVID-19 and public health recommendations for their use.
+• The evidence for clinical benefit of BNT1622 meets the evidentiary standards for approval (i.e., substantial evidence of effectiveness) for use in individuals 16 vears of age and older.
+• Data from additional studies (post-authorization and post-approval), are needed to address uncertainties in clinical benefit.
+95
+
+Risk
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+• The most frequently reported adverse reactions in the ongoing placebo-controlled trial were solicited injection site reactions (redness, swelling, and pain) and systemic adverse reactions (fever, fatigue, headache, chills. vomiting, diarrhea, muscle pain, and joint pain), which were generally less frequent in older (56 years and above) vs. younger (16-55 years) participants.
+Solicited adverse reactions were transient, and severe adverse reactions were infrequent (~5% or less among younger participants and ~1% or less among older participants).
+• Among all unsolicited adverse events reported in the trial, a substantial imbalance in self-limited lymphadenopathy (87 events in vaccine recipients, mostly ipsilateral and regional to the injection site, vs. 8 events in placebo recipients) supports a causal association with the vaccine.
+• A total of 7 cases of temporally associated Bell's Palsy following BNT1622 (4 cases during blinded follow-up and 3 cases during unblinded follow-up all within 9 das post-vaccination) vs. O such cases following placebo suggest a potential causal association. This A was reported infrequently in the clinical trial and is being further investigated in post-authorization studies.
+• 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.
+• Post-authorization safety surveillance has identified the following additional infrequent risks plausibly associated with the vaccine: diarrhea, vomiting, severe allergic reactions including anaphylaxis and other hypersensitivity reactions, and arm pain ipsilateral to the injection site.
+• Extensive clinical and nonclinical experience has vielded no evidence of vaccine-enhanced disease (or more severe COVID-19 as a marker for vaccine-enhanced disease) following vaccination with BNT16262.
+• Uncertainties related to risks of myocarditis and pericarditis include lack of precise estimates for excess risk across various age and gender subgroups. including whether and how frequently subclinical cases occur, and longer-term outcomes and prognoses.
+• Other uncertainties related to risks in general include: more robust characterization of the safety profile through active safety surveillance and/or controlled observational studies in specific populations (e.g., individuals with prior COVID-19. preanant women. and significantly immunocompromised
+• The most commonly manifested risks are mild to moderate, self-limited injection site and systemic adverse reactions.
+• Less commonly manifested but potentially serious risks include severe allergic reactions and myocarditis/pericarditis. Additional data are needed to better quantify the risks of myocarditis and pericarditis and to understand long-term prognoses for vaccine-associated myocarditis and pericarditis.
+• Although the potential for vaccine enhanced disease has been evaluated throughout vaccine development and post-authorization use, this theoretical risk is not substantiated by the totality of evidence from nonclinical studies, clinical trials, and post-authorization
+COVID-19 case surveillance and observational studies.
+96
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Risk Management
+individuals); and whether additional rare adverse reactions could be identified with increased exposure and longer follow up.
+Labeling for COMINRATY describes the common and uncommon (but potentially serious risks associated with the vaccine. The labeling includes warning statements for severe allergic reactions and myocarditis/pericarditis.
+• The Applicant will be required to conduct post-approval studies to further evaluate vaccine safety and effectiveness, and specifically to better understand the identified risks of vaccine-associated myocarditis and pericarditis and their long-term sequelae.
+• Risk mitigation strategies for BNT1622 for use in individuals 16 years of age and older include communication of risks and benefits through labeling, directed counseling prior to vaccination according to individual risks and benefits, and a pharmacovigilance plan to further evaluate risks.
+• Ongoing monitoring of COVID-19 epidemiology (including emergence of variants) and vaccine effectiveness will also be critical to updating benefit risk assessments and risk mitigation strategies as the pandemic evolves over time
+97
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+11.2 Risk-Benefit Summary and Assessment
+COVID-19 caused by SARS-CoV-2 is associated with a wide spectrum of manifestations, including mild illness in some individuals but severe morbidity (in some cases with long-term sequelae) and/or mortality in others. Over 4 million deaths attributable to COVID-19 have been reported worldwide since the beginning of the pandemic in late 2019, with >600,000 US deaths since the beginning of the pandemic and >2.6 million US hospitalizations during the year starting in August 2020 and ending in August 2021. Currently, the US is experiencing its third surge of COVID-19, associated with widespread transmission of the SARS-CoV-2 delta variant nationally.
+While the greatest risk of severe or fatal COVID-19 is in individuals >65 years of age and those with comorbid conditions (e.g., obesity, diabetes, immunocompromising conditions), significant morbidity and mortality and long-term sequelae from COVID-19 has occurred in healthy individuals of all ages. In addition to individual-level morbidity and mortality, the COVID-19 pandemic has overwhelmed healthcare systems during periods of high incidence, and the effects of SARS-CoV-2 infection, COVID-19 disease, and the necessary public health measures implemented to prevent infection and illness have severely disrupted human activities on a global scale. While three COVID-19 vaccines have received emergency use authorization in the US based on having met applicable statutory criteria, including authorization of BNT1622 for use in individuals 12 years of age and older, full approval of a COVID-19 vaccine that has met the FDA evidentiary standard for safety, effectiveness, and manufacturing quality and consistency would represent an important step in addressing the unmet need for approved pharmacologic interventions for prevention of COVID-19.
+A randomized, blinded, multinational placebo-controlled trial (C4591001) that enrolled
+>40,000 participants 16 years of age and older demonstrated the clinical benefit of BNT162b2 in preventing PCR-confirmed COVID-19 of any severity during the trial's blinded, placebo-controlled follow-up period, with an estimated vaccine efficacy of >90% from 7 days after completion of the 2-dose vaccination regimen. 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 medical comorbidities associated with high risk of severe COVID-
+19. Data from numerous published observational studies of real-world use of the vaccine, although not independently reviewed and confirmed by FDA, appear to corroborate the high level of protection observed in the clinical trial, including against COVID-19 associated hospitalization and death, across various patient populations and geographic regions. Although some more recently published observational studies that evaluated vaccine effectiveness during emergence of the delta variant appear to suggest decreased protection against less severe COVID-19 caused by this variant, protection against hospitalization and death appears stable at this time. Remaining uncertainties regarding the clinical benefits of BNT162b2 in individuals 16 ears and older include its level of protection against asymptomatic infection and transmission of SARS-CoV-2, including for the delta variant, durability of protection beyond 6-8 months (the current limit of observation in the clinical trial and observational studies), confirmation of more robust estimates of effectiveness in certain populations not well represented in the clinical trial (including individuals with prior SARS-CoV-2 infection), and vaccine effectiveness against future emerging variants.
+98
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+Risks demonstrated to be associated with use of BNT162b2 in individuals 16 ears of age and older include common self-limited local and systemic adverse reactions characterized in the clinical trial, which are mostly mild to moderate but can be severe in some individuals (~5% or fewer, depending on the adverse reaction), and two rare but clinically important serious adverse reactions detected through post-authorization safety surveillance: anaphylaxis and myocarditis/pericarditis. The crude reporting rate for anaphylaxis in VAERS through Jul 2021 (which includes unconfirmed and potentially duplicate reports) has been ~6 cases per million doses, which is similar in magnitude to rates of anaphylaxis reported for other preventive vaccines. 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 as per CDC communication on August
+20, 2021). Although some cases of vaccine-associated myocarditis/pericarditis required intensive care support (with several suspected fatal cases under CDC investigation but not confirmed at the time of this review), available data from short-term follow-up suggest that most individuals affected by vaccine-associated myocarditis/pericarditis have had resolution of symptoms with conservative management. Information is not yet available about potential long-term sequelae and outcomes in affected individuals, and additional uncertainties regarding the risk of myocarditis/pericarditis include: whether and to what extent subclinical cases might occur, and if they do what are the long-term outcomes; the mechanism of pathogenesis; and individual factors conferring increased risk for vaccine-associated myocarditis/pericarditis. Other risk uncertainties for BNT162b2 in general include: more robust characterization of the safety profile through active safety surveillance and/or controlled observational studies in specific populations (e.g., individuals with prior COVID-19, pregnant women, and significantly immunocompromised individuals); and whether additional rare but clinically important adverse reactions could be identified with increased exposure and longer follow up.
+Since vaccine-associated mvocarditis/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 (summarized in Section 4.7 of this review memo, with more details provided in the review memo from the CBER Analytics and Benefit-Risk Assessment Team). 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 age/sex-stratified 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 with incidence rates reflecting the recent delta variant surge and assumption of diminished vaccine effectiveness (70% overall, 80% against COVID-19 hospitalization) compared to that observed in the clinical trial: and a "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.
+99
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+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, ICU admissions 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.
+Uncertainties in the quantitative benefit-risk assessment include those around estimates of excess risk from vaccine-associated myocarditis/pericarditis and those around predicting future COVID-19 incidence and vaccine effectiveness with potential emergence of new SARS-CoV-2 variants. It is possible that the benefit-risk balance could become less favorable than predicted by the model, in particular for males 16-17 years of age, if sustained dramatic decreases in COVID-19 incidence occur, if additional information about vaccine-associated myocarditis/pericarditis demonstrates much higher rates and/or worse outcomes than currently appreciated, or if vaccine efficacy against circulating variants diminishes substantially. However, currently available data support a benefit-risk balance that is clearly favorable for approving BNT162b2 for use in all individuals 16 years of age and older. Mitigation of the observed risks and associated uncertainties will be accomplished through labeling (including warning statements regarding risks of allergic reactions and vaccine-associated myocarditis/pericarditis) and through continued safety surveillance and postmarketing studies (as summarized in Section 11.6) to further assess and understand these risks.
+11.3 Discussion of Regulatory Options
+The BNT162b2 vaccine is currently available under EUA for use in individuals 12 ears of age and older. The Applicant has requested, and the data support, approval of BNT162b2 (trade name COMIRNATY following approval) for use in individuals 16 ears of age and older to prevent COVID-19 caused by SARS-CoV-2. At this time, the Applicant has not vet requested approval of the vaccine for use in adolescents 12-15 years of age because additional safety data, including longer-term follow-up and further characterization of the risk of myocarditis/pericarditis in this age group, are needed to inform a benefit-risk assessment and to meet the evidentiary standard to support approval. As available evidence continues to meet the statutory criteria for EUA (including that available evidence supports the known and potential benefits outweigh the known and potential risks) for adolescents 12-15 years of age, the vaccine will
+100
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+remain available under EU for use in this age group following its full approval for use in individuals 16 years of age and older.
+11.4 Recommendations on Regulatory Actions
+The clinical reviewers recommend approval of BNT162b2 for the prevention of COVID-19 caused by SARS-Cov-2 in individuals 16 years of age and older.
+11.5 Labeling Review and Recommendations
+The package insert was submitted in the format required by FDA's Final Rule titled
+"Content and Format of Labeling for Human Prescription Drug and Biological Products;
+Requirements for Pregnancy and Lactation Labeling", referred to as the "Pregnancy and Lactation Labeling Rule (PLLR)" effective June 30, 2015. Communications between the Applicant and CBER resulted in revisions to the original prescribing information which reflects the data submitted in support of the application for licensure. Of note is the addition to the WARNINGS AND PRECAUTIONS section to describe the occurrence of myocarditis and pericarditis in subjects who receive BNT162b2 and the increase risk observed for adolescents and young adult males.
+The data within the label was found to be consistent with and supported by the information and data in the BLA application.
+11.6 Recommendations on Postmarketing Actions
+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)).
+FDA has determined that an analvsis 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 to include:
+Postmarketing requirement (PMR) safety studies under section 505(o) of the Federal Food, Drug, and Cosmetic Act 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.
+101
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+3. Study C4591021 substudy to describe the natural history of myocarditis and pericarditis following administration of COMIRNATY.
+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).
+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 16-30 years of age.
+Postmarketing commitment (PMC) 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/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 Applicant 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.
+102
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+APPENDIX A CHARLSON COMORBIDITY INDEX
+This index is based on a list of 19 conditions identified from diagnoses in hospital and physician data. Each condition is assigned a weight from 1 to 6. The index score is the sum of the weights for all identified conditions (Charlson et al., 1987). An index score of O indicates no comorbid conditions, while higher scores indicate a greater level of comorbidity.
+Charlson Index Diagnoses: Cancer, Chronic Pulmonary Disease, Diabetes without Complications, Congestive Heart Failure, Cerebrovascular Disease, Dementia, Renal Disease, Peripheral Vascular Disease, Myocardial Infarction, Diabetes with Complications, Paraplegia and Hemiplegia, Connective Tissue Disease-Rheumatic Disease, Peptic Ulcer Disease, Mild Liver Disease, Metastatic Carcinoma, Moderate or Severe Liver Disease, /AIDS.
+Reference: Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5):373- 383. [PubMed: 3558716]
+103
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+APPENDIX B CARDIAC DISORDERS FROM DOSE 1 TO DATE OF UNBLINDING AMONG PHASE 2/3 PARTICIPANTS 16 YEARS OF AGE AND OLDER
+Table 44. Cardiac Disorders, by System Organ Class and Age Group, From Dose 1 to Unblinding Date, Phase 2/3 Subjects 16 Years of Age and Older, Safety Population
+System Organ Class
+Preferred Term
+Cardiac disorders (SOC)
+Tachycardia
+Atrial fibrillation
+Palpitations
+Acute myocardial infarction
+Cardiac arrest
+Coronarv arter disease
+Angina pectoris
+Cardiac failure congestive
+Mvocardial infarction
+Bradvcardia
+Angina unstable
+Left ventricular hypertrophy
+Mvocardial ischaemia
+Ventricular extrasystoles
+Ventricular tachycardia
+Acute coronar syndrome
+Acute left ventricular failure
+Arrhythmia
+Arrhythmia supraventricular
+Arteriospasm coronary
+Atrioventricular block complete
+Atrioventricular block first degree
+Bundle branch block right
+16-55 Years of Age
+BNT16261
+Placebo
+N=12995 N=13026
+n (%)
+n (%)
+30 (0.2)
+31 (0.2)
+10 (0.1)
+4 (0.0)
+2 (0.0)
+3 (0.0)
+3 (0.0)
+13 (0.1)
+2 (0.0)
+^ (0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+1
+(0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+0 (0.0)
+4 (0.0)
+1 (0.0)
+0 (00)
+1 (0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+1 (0.0)
+0 (0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+2 (0.0)
+1 (0 0)
+~ (0.0)
+0 (0.0)
+1 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+1 (0.0)
+~ (00)
+0 (0 0)
+1 (0.0)
+(0 0)
+1 (0.0)
+0 (0.0)
+>55 Years of Age
+Total
+BNT162b1 Placebo
+BNT16261 Placebo
+N=8931
+NE8895
+N=21926 N=21921
+n (%)
+n (%)
+n (%)
+n (%)
+57 (0.6)
+47 (0.5)
+87 (0.4)
+78 (0.4)
+5 (0.1)
+з (0.0)
+15 (0.1)
+7 (0.0)
+11 (0.1)
+14 (0.2)
+13 (0 1)
+17 (0.1)
+4 (0.0)
+3 (0.0)
+7 (0.0)
+16 (0.1)
+4 (0.0)
+3 (0.0)
+6 (0.0)
+4 (0.0)
+2 (0.0)
+6 (0.0)
+2 (0.0)
+5
+(0.1)
+(0.0)
+6 (0 0)
+(0.0)
+4
+(0.0)
+4 (0.0)
+2
+(0.0)
+O - N - N =
+(0.0)
+(0.0)
+(0.0)
+(0.0)
+(0.0)
+(0.0)
+- O
+(0.0)
+(0.0)
+o O.
+(0.0)
+1
+(0.0)
+(0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+5 (0.0)
+1 (0.0)
+3 (0.0)
+5 (0.0)
+3
+(0.0)
+4 (0.0)
+4 (0.0)
+8 (0.0)
+2 (0.0)
+3 (0 0)
+2 (0.0)
+3 (0.0)
+2 (0.0)
+3 (0.0)
+0 (0.0)
+2 (0.0)
+1 (0.0)
+0 (0.0)
+2 (0.0)
+0 (0.0)
+0 (0.0)
+2 (0.0)
+0 (0.0)
+0 (0.0)
+2 (0.0)
+0 (0.0)
+2 (00)
+1 (0.0)
+4 (0.0)
+0 (0.0)
+1 (0 0)
+0 (0.0)
+2 (0.0)
+1 (0.0)
+3 (0.0)
+0 (0.0)
+1
+(0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+1 (0.0)
+1 (0 0)
+1 (0 0)
+1 (0 0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+104
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+16-55 Years of Age
+>55 Years of Age
+Total
+BNT162b^ Placebo
+BNT16261 Placebo BNT162b Placebo
+System Organ Class
+N=12995 N=13026
+N=8931
+N=8895 N=21926 N=21921
+Preferred Term
+n (%)
+n
+(%)
+n (%)
+n (%)
+n (%)
+n (%)
+Cardiac disorder
+1 (0.0)
+0 (0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+Cardio-respiratory arrest
+1 (0.0)
+1 (0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+1 (0.0)
+Cardiomegaly
+0 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+Cardiovascular disorder
+0 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+Coronary artery dissection
+0 (0.0)
+0 (0.0)
+(0.0)
+0 (0.0)
+1 (0.0)
+(0.0)
+Hypertensive heart disease
+0 (0.0)
+0 (0.0)
+1
+(0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+Left ventricular dysfunction
+0 (0.0)
+0 (0.0)
+1
+(0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+Mitral valve incompetence
+(0 0)
+2 (0.0)
+1
+(0.0)
+1 (0.0)
+1 (0.0)
+3 (0.0)
+Mitral valve prolapse
+0 (0.0)
+1 (0.0)
+(0.0)
+0 (0.0)
+1 (0.0)
+1 (0.0)
+Pericarditis
+0 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+Sinus tachvcardia
+1 (0.0)
+1 (0.0)
+0
+(0.0)
+0 (0.0)
+1 (0.0)
+1 (0.0)
+Supraventricular tachycardia
+1 (0.0)
+0 (0.0)
+0
+(0.0)
+1 (0.0)
+1 (0.0)
+1 (0.0)
+Tricusoid valve incompetence
+0 (0.0)
+1 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+1 (0.0)
+Ventricular arrhvthmia
+0 (0.0)
+0 (0.0)
+(0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+Aortic valve incompetence
+0 (0.0)
+0 (0.0)
+(0.0)
+2 (0.0)
+0 (0.0)
+2 (0.0)
+Arteriosclerosis coronary artery
+0 (0.0)
+0 (0.0)
+0
+(0.0)
+1 (0.0)
+(0.0)
+1 (0 0)
+Atrial flutter
+0 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+2 (0.0)
+Bundle branch block left
+0 (0.0)
+0 (0 0)
+(0.0)
+1 (0 0)
+0 (0 0)
+1 (0.0)
+Cardiac failure acute
+0 (0.0)
+0 (0 0)
+(0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+Coronary artery occlusion
+0 (0.0)
+0 (0.0)
+(0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+Junctional ectopic tachvcardia
+0 (0.0)
+(0.0)
+0
+(0.0)
+0 (0.0)
+0 (0.0)
+1 (0 0)
+Left atrial enlargement
+0 (0.0)
+1 (0 0)
+(0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+Mvocarditis
+0 (0.0)
+1 (0.0)
+(0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+Pericardial effusion
+0 (0 0)
+0 (0.0)
+0
+(0.0)
+1 (0.0)
+0 (0.0)
+1 (0 0)
+Postural orthostatic tachvcardia svndrome
+0 (0.0)
+1 (0 0)
+(0.0)
+0 (0.0)
+0 (0 0)
+1 (0 0)
+Sinus bradycardia
+0 (0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+Tachvarrhvthmia
+0 (0.0)
+0 (0.0)
+0 (0.0)
+1 (0.0)
+0 (0.0)
+1 (0.0)
+Source: OCS Analysis Studio, Safety Explorer.
+Demographic Filters: TRT01A = "BNT162b2 Phase 2/3" or "Placebo", AGEGR1 = "16-55 Years" or ">55 Years"; SAF1FL = "Y"
+Adverse Event Filters: VPHASE = "Vaccination 1" or "Vaccination 2" or "Follow Up 1" or "Follow Up 2", AEBODSYS = "CARDIAC DISORDERS"
+105
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+APPENDIX C DEATH NARRATIVES
+Narratives for COVID-19-related deaths
+• 80-year-old white, non-Hispanic male who received two doses of BNT162b2 (b) (6)
+and (6) (6)
+). Pertinent medical history includes systolic
+congestive heart failure (since 2016); hypertension, hyperlipidemia, gastrosophageal reflux disease, and atrial fibrillation (April 2018); hypokalemia (since July 2018); neuropathy and chronic back pain (both since August 2019); and cerebrovascular accident (on (b) (6)
+). Subiect was transported to ER with
+garbled speech, increased confusion, shortness of breath and chest congestion. As part of the medical work-up a SARS-CoV-2 test was performed which was positive.
+The subject was diagnosed with COVID-19 pneumonia on (6) (6)
+days after receiving Dose 2. The subiect died of COVID-19 pneumonia on (b) (6)
+., (6) (o) days after receiving Dose 2).
+• 68-year-old black/ African American female with a pertinent medical history thyroid cancer and thyroidectomy (both in 1982), hyperlipidemia (since 2010), hypertension (since 2013), emphysema (since 2017), and malignant lung neoplasm (in 2017), received Placebo Dose 1 on (b) (6)
+and Placebo Dose 2 on b) (6)
+(Day 22). Two separate COVID-19 tests were reported as positive prior to hospital admission. The subject was diagnosed with acute respiratory failure and COVID-19 on (b) (6)
+days after receiving Dose 2, and died of the
+events on b) (6)
+days after receiving Dose 2.
+• 65-year-old white male with a pertinent medical history of hyperlipidemia and hypertension (since 2010) and pulmonary fibrosis (since 2014), received Placebo Dose 1 on (b) (6)
+and Placebo Dose 2 on (b) (6)
+(Day 22).
+On (b) (6)
+(Day 85), it was noted that the subject received a prohibited
+vaccination (Moderna COVID-19 vaccine [mRNA-1273]) through his employer during the study period. The subject was diagnosed with COVID-19 infection leading to multiple organ dysfunction syndrome on (b) (6)
+days after receiving
+Placebo Dose 2. The subject experienced shortness of breath, fever, cough, fatigue, and muscle aches "a day or so after" exposure to COVID-19 on December 28, 2020 (Day 90). On (b) (6)
+(Day ), the subject received monoclonal
+antibodies from his primary care physician but later that day presented to the emergency department with weakness, dyspnea, nausea, and diarrhea and was subsequently hospitalized with COVID-19 (Positive SARS-CoV-2 test). The subject died from COVID-19 and multiorgan failure on (b) (6)
+davs after the
+second vaccination).
+• 65-year-old white male with a pertinent medical history of coronary artery disease (since 1983); hypercholesterolemia and hypertension (both since 2010); and dyspepsia (since 2012), and obesity. Subject received placebo Dose 1 on (b) (6)
+and placebo Dose 2 on (0) (6)
+(Day 24). The subject was
+diagnosed with COVID-19 by self-swab and local testing (December 1, 2020). The subiect died of COVID-19 complicated by cardiac arrest on b) (6) davs after receiving Dose 2.
+• 57-year-old white female (Hispanic/Latino) with a pertinent medical history of type 2 diabetes mellitus (since 1995); hypothyroidism and asthma (both since 2005);
+106
+
+Clinical Reviewers: Susan Wollersheim, MD and Ann Schwartz, MD
+STN:125742
+hypercholesterolemia (since 2010); vitamin D deficiency (since Jan 2020); and insomnia and sleep apnea (both since May 2020), received placebo Dose 1 on (b) (6)
+and placebo Dose 2 on (b) (6)
+(Day 22). The
+subject developed COVID-19 infection (SARS-CoV-2 nuclei acid amplification test was positive) and pneumonia on November 26, 2020, 58 days after receiving Dose
+2; and acute hypoxemic respiratory failure on November 28, 2020, 60 days after receiving Dose 2. The subject died of the COVID-19 infection, pneumonia, and acute hypoxemic respiratory failure on (b) (6)
+days after receiving Dose 2.
+• 55-year-old black South African female with a pertinent medical history of asthma (since 1997), (b) (6)
+infection (since 2008), and
+hypertension and obesity (both since 2010), received placebo Dose 1 on b) (6)
+and placebo Dose 2 on b) (6)
+(Day 22). The subject was diagnosed
+with diabetes mellitus on December 28, 2020, 68 days after receiving Dose 2. On January 1, 2021, the subject was diagnosed with COVID-19 pneumonia (SARS-CoV-
+2 PC positive), 72 days after receiving Dose 2. The subject died of COVID-19 pneumonia on (6) (6)
+days after receiving Dose 2.
+• 58-year-old white Hispanic/Latino female (Argentina) received placebo Dose 1 on (b) (6)
+and placebo Dose 2 on (b) (6)
+(Day 21). SARS-CoV-
+2 NAAT result at the time of the COVID-19 illness on December 26, 2020 (Day 120) was positive. On (b) (6)
+(Day (b) (6)), she died because of septic shock in
+the context of a severe COVID-19 illness.
+107
+