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From: Naik, Ramachandra <[email protected]>
Sent: Friday, August 13, 2021 7:12 PM
To: Harkins Tull, Elisa <[email protected]>
Cc: Smith, Michael (CBER) <[email protected]>; Gottschalk, Laura
<[email protected]>; Aghajani Memar, Neda <[email protected]>; Devlin,
Carmel M <[email protected]>
Subject: STN 125742/0 – COMIRNATY (COVID -19 Vaccine, mR NA) - Safety -related Postmarketing
Requirement/Postmarketing Commitment studies
Dear Ms. Harkins,
Our review of your pharmacovigilance plan for COMIRNATY (COVID -19 Vaccine, mRNA) under BLA STN
125742/0 is ongoing.
Should this product be approved, we have determined that an analysis of spontaneous postmarketing
adverse events reported under section 505(k)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) will
not be sufficient to identify:
• known serious risks of myocarditis and pericarditis
• an unexpe cted 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, should this product be approved, we
have determined that you will be required to conduct the following studies as postmarketing
requirements (PMRs) under Section 505(o) of FDCA: 1. Epidemiologic studies using large electronic healthcare databases to evaluate the occurrence of
myocarditis and pericarditis following administration of COMIRNATY
a. US – Sentinel system (C4591009)
b. EU active surveillance study (C4591021)
c. EU active surveillance substudy (C4591021)
2. A prospective cohort study with at least 5 years of follow -up for potential long -term se quelae of
myocarditis after vaccination (in collaboration with Pediatric Heart Network)
3. A prospective study to assess the incidence of subclinical myocarditis following vaccination
Regarding the study to further characterize subclinical myocarditis, we acknowledge that you are in the
process of analyzing Troponin I levels in serum samples to determine the background rate of abnormality of this biomarker in the relevant population. We acknowledge the challenge in projecting a
definitive sample size or dates for a future study to assess the incidence of subclinical myocarditis.
However, we request that you propose your plans for a future prospective study to assess the incidence
of subc linical myocarditis, including projected study milestone dates.
Additionally, should this product be approved, your proposed studies listed below will be postmarketing commitments (PMCs) as agreed upon between FDA and the applicant:
FDA-CBER-2021-5683-1024784
1. A pregnancy registry for COMIRNATY to assess pregnancy and infant outcomes after exposure of
COMIRNATY during pregnancy in the Organization of Teratology Information Specialists
(OTIS)/Mother to Baby Pregnancy Registry (C4591022)
2. A placebo -controlled, randomized, observer -blind study to evaluate the safety, tolerability, and
immunogenicity of BNT162b2 in healthy pregnant women ≥18 years of age (C4591015)
3. An active safety surveillance study among individuals in the Veteran’s Affairs Health System
(C4591012)
4. Study C4591014, Pfizer -BioNTech COVID -19 BNT162b2 Vaccine Effectiveness Study - Kaiser
Permanente Southern California
For Study C4591014, please comment on the feasibility of revising or amending the protocol to also collect information on the incidence of myocarditis and pericarditis and to include individuals 12
through 15 years of age.
For study C4591015, please comment on recruitment and retention of study participants to date, including any barriers that you have encountered. Please comment on the feasibility of completing the trial, as planned, considering CDC’s recommendation of COVID -19 vaccination for all people 12 years
and older, including people who are pregnant ( https://www.cdc.gov/coronavirus/2019 -
ncov/vaccines/recommendations/pregnancy.html#anchor 1628692562866) .
Please confirm the study milestone dates (mm/dd/yyyy) in the tables below, and populate the projected
study milestone dates for PMR#3 (subclinical myocarditis) as per the above request.
Note that we have also included dates for interim reports when applicable.
Milestone
dates PMR #1a:
C4591009
(Sentinel) PMR #1b: C4591021
(EU) PMR #1c:
C4591021
substudy (EU) PMR#2: PHN
registry PMR#3:
subclinical
myocarditis
Final protocol
submission 8/31/2021 8/11/2021 12/31/2021 11/30/2021
Study
completion 06/30/2025 9/30/2024 9/30/2024 12/01/2026
Interim
reports Monitoring
report:
10/31/2022
Interim report:
10/31/2023 Progress report:
09/30/2021
Interim report 1:
03/31/2022 Interim report 2:
09/30/2022 Interim report 3:
03/31/2023
Interim report 4:
09/30/2023
Interim report 5:
03/31/2024
FDA-CBER-2021-5683-1024785
Final study
report 10/31/2025 9/30/2024 09/30/2024 10/31/2025
Milestone dates PMC #1: C4591022
pregnancy registry PMC#2: C4591015
RCT pregnant women
PMC#3: C4591012
VA study PMC #4: C4591014
Kaiser study
Final protocol
submission 7/1/2021 12/22/2020 1/29/2021 3/22/2021
Study completion 08/01/2025 10/31/2022 06/10/2023
Interim reports Interim report 1:
06/30/2021
Interim report 2:
12/31/2021 Interim report 3: 06/30/2022
Interim report 4:
12/31/2022
Final study
report 12/1/2025 5/31/2023 12/31/2023
Please also propose study(ies) in adolescents 12 through 17 years of age to evaluate the safety and immunogenicity of lower doses of COMIRNATY.
Voluntary sponsor studies
For the following voluntary sponsor studies, please provide study status updates in your periodic safety
reports:
• C4591011: Active safety surveillance of the Pfizer -BioNTech COVID -19 vaccine in the U.S.
Department of Defense population following Emergency Use Authorization
• 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
Please provide your responses in an amendment to STN 125742/0 by COB Monday, August 16, 2021. We recommend that you restate each item an d follow it with your explanation or clarification.
Use of this format helps organize the relevant information and provides a self -contained document that
facilitates future reference. Please confirm receipt of this email and let me know if you have any questions or need additional information.
Regards,
Ram
Ramachandra S. Naik, Ph.D.
Biologist (Regulatory) / Primary Reviewer
Center for Biologics Evaluation and Research
Office of Vaccines Research and Review
FDA-CBER-2021-5683-1024786
U.S. Food and Drug Administration
Tel: 301- 796-2640
ramachandra.naik @fda.hhs.gov
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FDA-CBER-2021-5683-1024787