Document text
U.S. Food & Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 2099 3
w ww.fda.gov
Our STN: BL 125742/0 BLA APPROVAL
BioNTech Manufacturing GmbH August 23, 2021
Attention: Amit Patel
Pfizer Inc.
235 East 42nd Street
New York, NY 10017
Dear M r. Patel :
Please refer to your Biologics License Application (BLA) submitted and received on
May 18, 2021, under section 351(a) of the Publ ic Health Service Act (PHS Act) for
COVID- 19 Vaccine, mRNA.
LICENSING
We are issuing Department of Health and Human Services U.S. License No. 2229 to
BioNTech Manufacturing GmbH , Mainz, Germany, under the provisions of section
351(a) of the PHS Act controlling the manufacture and sale of biological products. The
license authorizes you to introduce or deliver for introduction into interstate commerce, those products for which your company has demonstrated compliance with establishment and product standards.
Under this license, you are authorized to manufacture the product , COVID- 19 Vaccine,
mRNA, which is indicated for active immunization to prevent coronavirus disease 2019 (COVID -19) caused by severe acute respiratory syndrome coronavirus 2 (SARS -CoV- 2)
in individuals 16 years of age and older .
The review of this product was associated with the following National Clinical Trial
(NCT) numbers: NCT04368728 and NCT 04380701.
MANUFACTURING LOCATIONS Under this license, you are approved to manufacture COVID- 19 Vaccine, mRNA drug
substance at Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC , 1 Burtt Road,
Andover , Massachusetts . The final formulated product will be manufactured, filled,
labeled and packaged at Pfizer Manufacturing Belgium NV , Rijksweg 12 , Puurs,
Belgium and at Pharmacia & Upjohn Company LLC, 7000 Portage Road, Kalamazoo,
Michigan. The diluent , 0.9% Sodium Chloride Injection, USP, will be manufactured at
Hospira , Inc., and at Fresenius Kabi
USA, LLC, .
(b) (4)
(b) (4)
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You may label your product with the proprietary name, COMIRNATY, and market it in
2.0 mL glass vials, in packages of 25 and 195 vials .
We did not refer your application to the Vaccines and Related Biological Products
Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues
that would have benefited from an advisory committee discussion.
DA
TING PERIOD
The dat
ing period for COVID- 19 Vaccine, mRNA shall be 9 months from the date of
manufacture when stored b etween -90ºC to - 60ºC ( -130ºF to - 76ºF) . The date of
manufacture shall be no later than the date of final sterile filtration of the formulated drug product (at Pharmacia & Upjohn Company LLC in Kalamazoo, Michigan , the date
of manufacture is defined as the date of sterile filtration for the final drug product ; at
Pfizer Manufacturing Belgium NV in Puurs , Belgium , it is defined as the date of the
Following the final sterile filtration,
, no
reprocessing/r eworking is allowed without prior approval from the Agency . The dating
period for your drug substance shall be when stored at We have
approved the stability protocol s in your license application for the purpose of extending
the expiration dating period of your drug substance and drug product under 21 CFR 601.12.
F
DA LOT RELEASE
P
lease submit final container samples of the product in final containers together with
protocols showing results of all applicable tests. You may not distribute any lots of
product until you receive a notification of release from the Director, Center for Biologics Evaluation and Research (CBER).
BI
OLOGICAL PRODUCT DEVIATIONS
Y
ou must submit reports of biological product deviations under 21 CFR 600.14. You
should identify and investigate all manufacturing deviations promptly, including those associated with processing, testing, packaging, labeling, storage, holding and distribution. If the deviation involves a distributed product, may affect the safety, purity,
or potency of the product, and meets the other criteria in the regulation, you must submit a report on Form FDA 3486 to the Director, Office of Compliance and Biologics Quality , electronically through the eBPDR web application or at the address below.
Links for the instructions on completing the electronic form (eBPDR) may be found on CBER's web site at
https://www.fda.gov/vaccines -blood -biologics/report -problem -center -
biologics -evaluation- research/biological -product -deviations :
Food and
Drug Administration
Center for Biologics Evaluation and Research Document Control Center
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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10903 New Hampshire Ave.
WO71- G112
Silver Spring, MD 20993- 0002
MANUFACTURING CHANGES
You must submit information to your BLA for our review and written approval under 21 CFR 601.12 for any changes in, including but not limited to, the manufacturing, testing,
packaging or labeling of COVID- 19 Vaccine, mRNA, or in the manufacturing facilities.
LABELING
We hereby approve the draft content of labeling including Package Insert , submitted
under amendment 74, dated August 21, 2021, and the draft carton and container label s
submitted under amendment 63, dated August 19, 2021.
CONTENT OF LABELING
As soon as possible, but no later than 14 days from the date of this letter, please submit the final content of labeling (21 CFR 601.14) in Structured Product Label ing (SPL)
format via the FDA automated drug registration and listing system , (eLIST) as described
at
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/
default.htm . Content of labeling must be identical to the Package Insert submitted on
August 21, 2021. Information on submitting SPL files using eLIST may be found in the
guidance for industry SPL Standard for Content of Labeling Technical Qs and As at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM072392.pdf .
The SPL will be accessible via publicly available labeling repositories.
CARTON AND CONTAINER LABELS
Please electronically submit final printed carton and container labels identical to the
carton and container labels submitted on August 19, 2021, according to the guidance
for industry Providing Regulatory Submissions in Electronic Format — Certain Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications at
https://www.fda.gov/regulatory -information/search- fda-guidance-
documents/providing- regulatory -submissions -electronic -format -certain- human-
pharmaceutical -produc t-applications .
All final labeling should be submitted as Product Correspondence to this BLA STN BL
125742 at the time of use and include implementation information on Form FDA 356h.
ADVERTISING AND PROMOTIONAL LABELING
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You may submit two draft copies of the proposed introductory advertising and
promotional labeling with Form FDA 2253 to the Advertising and Promotional Labeling
Branch at the following address:
Food and Drug Administration Center for Biologics Evaluation and Research Document Control Center
10903 New Hampshire Ave.
WO71- G112
Silver Spring, MD 20993- 0002
You must submit copies of your final advertising and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).
All promotional claims must be consistent with and not contrary to approved labeling. You should not make a comparative promotional claim or claim of superiority over other products unless you have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).
ADVERSE EVENT REPORTING
You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80), and you must submit distribution reports at monthly intervals as described in 21 CFR
600.81. For information on adverse experience reporting, please refer to the guidance
for industry Providing Submissions in Electronic Format —Postmarketing Safety Reports for Vaccines at
https://www.fda.gov/regulatory -information/search- fda-
guidance- documents/providing- submissions -electronic -format -postmarketing- safety -
reports -vaccines . For information on distribution reporting, please refer to the guidance
for industry Electronic Submission of Lot Distribution Reports at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation
/Post -MarketActivities/LotRelea ses/ucm061966.htm .
PEDIATRIC REQUIREMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.
We are deferring submission of y our pediatric studies for ages younger than 16 years
for this application because this product is ready for approval for use in individuals 16
years of age and older , and the pediatric studies for younger ages have not been
completed.
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Your deferred pediatric studies required under section 505B(a) of the Federal Food,
Drug, and Cosmetic Act (FDCA) are required postmarketing studies. The status of
these postmarketing studies must be reported according to 21 CFR 601.28 and section 505B(a)( 4)(C) of the FDCA. In addition, section 506B of the FDCA and 21 CFR 601.70
require you to report annually on the status of any postmarketing commitments or required studies or clinical trials.
Label your annual report as an “ Annual Status Report of Postmarketing Study
Requirement/Commitments” and submit it to the FDA each year within 60 calendar days of the anniversary date of this letter until all Requirements and Commitments subject to the reporting requirements under section 506B of the FDCA are released or fulfilled. These required studi es are listed below:
1. Deferred pediatric S tudy C4591001 to evaluate the safety and effectiveness of
COMIRNATY in children 12 years through 15 years of age.
Final Protocol Submission: October 7, 2020
Study Completion: May 31, 2023
Final Report Submission: October 31, 2023
2. Deferred pediatric Study C4591007 to evaluate the safety and effectiveness of
COMIRNATY in infants and children 6 months to < 12 years of age.
Final Protocol Submission: February 8, 2021
Study Completion: November 30, 2023
Final Report Submission: May 31 , 2024
3. Deferred pediatric Study C45910 23 to evaluate the safety and effectiveness of
COMIRNATY in infants <6 month s of age.
Final Protocol Submission: January 31, 2022
Study Completion: July 31, 2024
Final Report Submission: October 31, 2024
Submit the protocols to your IND 19736, with a cross -reference letter to this BLA STN
BL 125742 explaining that these protocols were submitted to the IND. Please refer to
the PMR sequential number for each study/clinical trial and the submission number as
shown in this letter.
Submit final study reports to this BLA STN BL 125742. In order for your PREA PMRs to
be considered fulfilled, you must submit and receive approval of an efficacy or a labeling
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supplement. For administrative purposes, all submissions related to these required
pediatric postmarketing studies must be clearly designated as:
• Required Pediatric Assessment(s)
We note that you have fulfilled the pediatric study requirement for ages 16 t hrough 17
years for this application.
POSTMARKETING REQUIREMENTS UNDER SECTION 505(o)
Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C . 355(o)(3)(A)).
We have determined that an analysis of spontaneous postmarketing adverse events reported under section 505(k)(1) of the FDCA will not be sufficient to assess known
serious risk s 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 risk s.
Therefore, based on appropriate scientific data, we have determined that you are required to conduct the following studies:
4. S tudy C4591009,
entitled “ A Non -Interventional Post -Approval Safety Study of
the Pfizer -BioNTech COVID- 19 mRNA Vaccine in the United States ,” to evaluate
the occurrence of myocarditis and pericarditis following administration of
COMIRNATY.
We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule:
Final Protocol Submission: August 31, 2021
Monitoring Report Submission: October 31, 2022
Interim Report Submission: October 31, 2023 Study Completion: June 30, 2025
Final Report Submission: October 31, 2025
5. S tudy C4591021,
entitled “ Post Conditional Approval Active Surveillance Study
Among Individuals in Europe Receiving the Pfizer -BioNTech Coronavirus
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Disease 2019 (COVID -19) Vaccine ,” to evaluate the occurrence of myocarditis
and pericarditis following administration of COMIRNATY.
We acknowledge the timetable you submitted on August 21, 2021, which states
that you will conduct this study according to the following schedule:
Final Protocol Submission: August 11, 2021
Progress Report Submission: September 30, 2021 Interim Report 1 Submission: March 31, 2022 Interim Report 2 Submission: September 30, 2022 Interim Report 3 Submission: March 31, 2023 Interim Report 4 Submission: September 30, 2023 Interim Report 5 Submission : March 31, 2024
Study Completion: March 31, 2024 Final Report Submission: September 30 , 202 4
6. Study C4591021 substudy to describe the natural history of myocarditis and
pericarditis following administration of COMIRNATY.
We acknowledge the timetable you submitted on August 21, 2021, which states
that you will conduct this study according to the following schedule:
Final Protocol Submission: January 31, 2022 Study Completion: March 31, 2024 Final Report Submission: September 30 , 2024
7. Study C4591036, a prospective cohort study with at least 5 years of follow -up for
potential long- term sequelae of myocarditis after vaccination (in collaboration
with Pediatric Heart Network) .
We acknowledge the timetable you submitted on August 21, 2021, which states
that you will conduct this study according to the following schedule:
Final Protocol Submission: November 30, 202 1
Study Completion: December 31, 2026
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Final Report Submission: May 31, 2027
8. Study C4591007 substudy to prospectively assess the incidence of subclinical
myocarditis following administration of the second dose of COMIRNATY in a
subset of participants 5 through 15 years of age.
We acknowledge the timetable you submitted on August 21, 2021, which states
that you will conduct this asse ssment according to the following schedule:
Final Protocol Submission: September 30, 2021
Study Completion: November 30, 2023 Final Report Submission: May 31, 2024
9. Study
C4591031 substudy to prospectively assess the incidence of subclini cal
myocarditis following administration of a third dose of COMIRNATY in a subset of participants 16 to 30 years of age. We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule:
Final Protocol Submission: November 30, 2021
Study Completion: June 30, 2022
Final Report Submission: December 31, 2022
Please submit the protocols to your IND 19736, with a cross -reference letter to this BLA
STN BL 125742 explaining that these protocols were submitted to the IND. Please refer
to the PMR sequential number for each study/clinical trial and the submission number
as shown in this letter.
Please submit final study reports to the BLA. If the information in the final study report supports a change in the label, the final study report must be submitted as a supplement to this BLA STN BL 125742. For administrative purposes, all submissions
related to these postmarketing studies required under section 505(o) must be submitted to this BLA and be clearly designated as:
• Required Postmarketing Correspondence under Section 505(o)
• Required Postmarketing Final Report under Section 505(o)
• Supplement contains Required Postmarketing Final Report under Section
505(o)
Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to
periodically report to FDA on the status of any study or clinical trial otherwise
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undertaken to investigate a safety issue. In addition, section 506B of the FDCA and 21
CFR 601.70 require you to report annually on the status of any postmarketing
commitments or required studies or clinical trials.
You must describe the status in an annual report on postmarketing studies for this product. Label your annual report as an Annual Status Report of Postmarketing
Requirements/Commitments and submit it to the FDA each year within 60 calendar
days of the anniversary date of this letter until all Requirements and Commitments subject to the reporting requirements of section 506B of the FDCA are fulfilled or released. The status report for each study should include:
• the sequential number for each study as shown in this letter;
• information to identify and describe the postmarketing requirement;
• the original milestone schedule for the requirement;
• the revised milestone schedule for the requirement, if appropriate;
• the current status of the requirement (i.e., pending, ongoing, delayed, terminated, or submitted); and,
• an explanation of the status for the study or clinical trial. The explanation should
include how the study is progressing in reference to the original projected schedule, including, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment).
As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our webs ite at
http://www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/Post -marketingPhaseIVCommitments/default.htm .
We will consider the submission of your annual report under section 506B of the FDCA and 21 CFR 601.70 to satisfy the periodic reporting requirement under section 505(o)(3)(E)(i i) provided that you include the elements listed in section 505(o) and 21
CFR 601.70. We remind you that to comply with section 505(o), your annual report
must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to periodically report on the status of
studies or clinical trials required under section 505(o) may be a violation of FDCA section 505(o)(3)(E)(ii) and could result in regulatory action.
POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS UNDER SECTION 506B
We acknowledge your written commitments as described in your letter of
August 21, 2021 as outlined below:
10. Study C4591022, entitled “ Pfizer -BioNTech COVID- 19 Vaccine Exposure during
Pregnancy: A Non -Interventional Post -Approval Safety Study of Pregnancy and
Infant Outcomes in the Organization of Teratology Information Specialists
(OTIS)/MotherToBaby Pregnancy Registry .”
Final Protocol Submission: July 1, 2021
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Study Completion: June 30, 2025
Final Report Submission: December 31, 2025
11. Study C4591007 substudy to evaluate the immunogenicity and safety of lower
dose levels of COMIRNATY in individuals 12 through <30 years of age.
Final Protocol Submission: September 30, 2021
Study Completion: November 30, 2023 Final Report Submission: May 31, 2024
12. Study C4591012, entitled “Post-emergency Use Authorization Active Safety
Surveillance Study Among Individuals in the Veteran’s Affairs Health System
Receiving Pfizer -BioNTech Coronavirus Disease 2019 (COVID -19) Vaccine.”
Final Protocol Submission: January 29, 2021 Study Completion: June 30, 2023 Final Report Submission: December 31, 2023
13.
Study C4591014, entitled “ Pfizer -BioNTech COVID- 19 BNT162b2 Vaccine
Effectiveness Study - Kaiser Permanente Southern California.”
Final Protocol Submission: March 22, 2021
Study Completion: December 31, 2022
Final Report Submission: June 30, 2023
Please submit clinical protocols to your IND 19736, and a cross -reference letter to this
BLA STN BL 125742 explaining that these protocols were submitted to the IND. Please
refer to the PMC sequential number for each study/clinical trial and the submission
number as shown in this letter.
If the information in the final study report supports a change in the label, the final study report must be submitted as a supplement. Please use the following designators to
prominently label all submissions, including supplements, relating to these postmarketing study commitments as appropriate:
• Postmarketing Commitment – Correspondence Study Update
• Postmarketing Commitment – Final Study Report
• Supplement contains Postmarketing Commitment – Final Study Report
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For each postmarketing study subject to the reporting requirements of 21 CFR 601.70,
you must describe the status in an annual report on postmarketing studies for this
product. Label your annual report as an Annual Status Report of Postmarketing
Requirements/Commitments and submit it to the FDA each year within 60 calendar
days of the anniversary date of this letter until all Requirements and Commitments subject to the reporting requirements of section 506B of the FDCA are fulfilled or released. The status report for each study should include:
• the sequential number for each study as shown in this letter;
• information to identify and describe the postmarketing commitment;
• the original schedule for the commitment;
• the status of the commitment (i.e., pending, ongoing, delayed, te rminated, or
submitted); and,
• an explanation of the status including, for clinical studies, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment).
As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our website at
http://www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/Post -marketingPhaseIVCommitments/default.htm .
POST APPROVAL FEEDBACK MEETING
New biological products qualify for a post approval feedback meeting. Such meetings
are used to discuss the quality of the application and to evaluate the communication process during drug development and marketing application review. The purpose is to
learn from successful aspects of the review process and to identify areas that could benefit from improvement. If you would like to have such a meeting with us, please
contact the Regulatory Project Manager for this application.
Sincerely ,
Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics
Evaluation and Research Marion F. Gruber, PhD
Director
Office of Vaccines
Research and Review
Center for Biologics
Evaluation and Research