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1Department of Health and Human Services
Food and Drug Administration
Center for Biologics Eval uation and Research (CBER)
Office of Biostatistics and Pharmacovigilance (OBPV)
REAL WORLD EVIDENCE sBLA MEMORANDUM
From : Yun Lu, PhD
Mathematical Statistician
Analytics and Benefit-Risk Assessment Team (ABRA)
Office of Biostatistics and Pharmacovigilance (OBPV)
CBER, FDA
To: Ramachandra Naik, PhD
Chair of the Review CommitteeOffice of Vaccines Research and Review
Through : Richard Forshee, PhD
Deputy Director, OBPVCBER, FDA
Subject: Review of Clinical Overview, Pharmacovigilance Plan,real world vaccine effectiveness studies against Omicron
variant among adolescents
Sponsor : BioNTech RNA Pharmaceuticals GmbH/Pfizer, Inc.
Product : COMIRNATY; Pfizer-Bio NTech COVID-19 Vaccine*
Application Type/Number: sBLA STN 125742/45
Proposed Indication: Prevention of COVID-19 in individuals 12 years of age
and older
Submission Date : December 16, 2021
*The product was also referred to as BNT162b2 in the clinical development
Yun Lu
-SDigitally signed by Yun Lu -S Date: 2022.05.19
11:48:31 -04'00'
Richard A.
Forshee -SDigitally signed by Richard A. Forshee -S Date: 2022.05.19 12:00:14 -04'00'
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1 OBJECTIVE The purpose of this review is to assess the adequacy of the real world evidence for
supplemental Biologics License Applicat ion (sBLA) 125742/45, which proposes to
extend use of Pfizer-BioNTech coronavir us disease 2019 (COVID-19) Vaccine
COMIRNATY to adolescents 12 through 15 years of age from the cu rrent 16 years of
age and older licensed indication.
Materials Reviewed
x Clinical Overview (STN 125742/45; received December 16, 2021)
x Pharmacovigilance Plan version 1.4.1 (STN 125742/45.9; received May 2, 2022)
x COMIRNATY approval letter (STN 125742/0; dated August 23, 2021)
x Real world effectiveness studies of Pfizer-BioNTech COVID-19 Vaccine against
Omicron variant among adolescents (pub lished on or before May 13, 2022)
x C4591014 protocol amendm ent 2: Pfizer-BioNTech COVID-19 BNT162b2 Vaccine
Effectiveness Study - Kaiser Permanent e Southern California (IND 19736.597;
received December 13, 2021)
x Combined statistical analysis plan (SAP) for studies C4591014, WI235284 and WI255886 (IND 19736.597; received December 13, 2021)
2 PRODUCT INFORMATION 2.1 Product Description The Pfizer-BioNTech COVID-19 Vaccine COMI RNATY contains a nucleoside-modified
messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of severe acute respiratory syndrome coronavir us 2 (SARS-CoV-2). The product is a frozen suspension
for intramuscular injection. The product is administered as a series of two doses (0.3 mL) each 21 days apart by
intramuscular injection. 2.2 Proposed Indication The proposed indication for Pfizer-BioNTech COVID-19 Vaccine COMIRNATY in the United States is for active immunization to prevent COVID-19 caused by SARS-CoV-2
in individuals 12 years of age and older.
3 REAL WORLD EFFECTIVENESS STUDIES
In the Clinical Overview (STN 12 5742/45; received December 16, 2021), the sponsor
referenced six vaccine effectiveness (VE) public ations containing real-world data from
Israel and the United States. The sponsor stated that “Overall, real-world effectiveness data to date indicate high VE against infection and hospitalization following two doses of BNT162b2 in individuals 12-15 y ears of age of approximately 90%.”
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Reviewer comment: The six real world effectiveness (VE) studies in the Clinical
Overview were all from pre-Delt a or Delta predominant periods.1-6 Since the first
Omicron variant COVID-19 case in the United States on December 1, 2021, Omicron
quickly became the predominant strain in th e United States. Real world VE studies in
the Omicron predominant period are more relevant to this sBLA.
As of May 19, 2022, several publications investigated real world VE of Pfizer-
BioNTech COVID-19 BNT162b2 vaccine among adolescents during the Omicron
predominant period.
A prospective cohort study evaluated effectiveness of 2-Dose BNT162b2 in preventing
SARS-CoV-2 infection July 2021 -February 2022 in four states.7 Among adolescents
aged 12-15 years, adjusted VE 14-149 days after dose 2 was 87% (95% CI = 49%-97%)
and 59% (95% CI = 22%-79%) against Delta and Omicron infection, respectively.
A test-negative case-control study invest igated VE against emergency department
(ED) and urgent care (UC) encounters April 2021-January 2022 in ten states.8 Among
adolescents aged 12-15 years, estimated VE 14 -149 days after dose 2 of BNT162b2 was
92% (95% CI = 89%-94%) and 45% (95% CI = 30%-57%) against COVID-19-associated
ED and UC encounters during Delta and Omicron predominant periods, respectively.
Estimated VE 150 days after dose 2 decreased to 79% (95% CI = 68%-86%) and í2%
(95% CI = í25%-17%) during Delta and Omicron predominant periods, respectively.
A test-negative case-control study invest igated VE against laboratory-confirmed
COVID-19 leading to hospitalization (COVID-19 hospitalization) and against COVID-19 leading to receipt of life support or to death (critical COVID-19) July 2021-February
2022 in 23 states.
9 Among adolescents 12-18 years of age during the Omicron
predominant period, estimated VE of BNT1 62b2 was 40% (95% CI, 9%-60%) against
COVID-19 hospitalization, 79% (95% CI, 51%- 91%) against critical COVID-19, and 20%
&,í %-49%) against noncritical COVID-19.
Another study included a total of 22,273 te st-positive COVID-19 cases and 25,471 test-
negative controls from adolescents 12-15 years of age December 2021-February 2022
during Omicron predominant period across the United States.10 At 2 to 4 weeks after
dose 2 of BNT162b2 , the estimated VE against symp tomatic COVID-19 infection was
59.5% (95% CI, 44.3%-70.6%). During mo nth 2 after dose 2, the estimated VE
decreased to 16.6% (95% CI, 8.1%-24.3%). The estimated VE 2 to 6.5 weeks after the
booster dose was 71.1% (95% CI, 65.5%-75.7%).
These recently published real world VE studies among adolescents showed decreased VE of 2-Dose BNT162b2 during Omicron predominant period than Delta predominant
period, higher VE against critical COVID- 19 than noncritical COVID-19, potential
waning effectiveness, and better protection of the booster dose.
In Pharmacovigilance Plan, the sponsor stated “Four post-authorization
effectiveness studies in real-world use are ongoing: 1 interventional study (BNT162-01 cohort 13), 1 non-interv entional study (C4591014) and 2 low-
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interventional studies (WI235284 and WI255886) to determine the effectiveness of
BNT162b2 when administered outside of the clinical setting.”
Reviewer comment: The non-interventional study (C4591014, entitled “Pfizer-
BioNTech COVID-19 BNT162b2 Vaccine Effectiveness Study - Kaiser Permanente
Southern California” ) was postmarketing commitment (PMC) #13 of BLA
125742/0. The study included individu als 12-15 years of age. The amended
protocols and combined statistical anal ysis plan (SAP) for studies C4591014,
WI235284 and WI255886 were submitted to IND 19736.597 (received December
13, 2021), and the documents are acceptable.
4 OBPV REAL WORLD EVIDENCE RECOMMDENDATIONS Should the product be approved in individuals 12-15 years of age, based on the review
of the published real world vaccine effe ctiveness studies among adolescents, OBPV
recommends the following action: Postmarketing commitment (PMC) vaccine effe ctiveness study as outlined in the BLA
125742/0 approval letter: Study C4591014, entitled “Pfizer-BioNTech COVID-19 BNT162b2 Vaccine Effectiveness Study - Ka iser Permanente Sout hern California.”
The study included individuals 12 through 15 years of age.
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REFERENCES
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doi:10.3201/eid2711.211886
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8. Klein NP, Stockwell MS, Demarco M, et al. Effectiveness of COVID-19 Pfizer-BioNTech
BNT162b2 mRNA Vaccination in Preventing COVID-19-Associated Emergency Department and
Urgent Care Encounters and Hospitalizations Among Nonimmunocompromised Children and Adolescents Aged 5-17 Years - VISION Network, 10 States, April 2021-January 2022. MMWR
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doi:10.1056/NEJMoa2202826
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Vaccination With Symptomatic SARS-CoV-2 Infection in Children and Adolescents During
Omicron Predominance. Jama . May 13 2022;doi:10.1001/jama.2022.7493
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