Church v. Biden, Case 1:21-cv-02815-CKK Declaration of Peter Marks, MD, PHD

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IN THE UNITED STATES DISTRICT COURT

FOR THE NORTHERN DISTRICT OF FLORIDA
____________________________________
)
JANE DOE #1, et al. )
)
)
Plaintiffs, )
)
v. ) Case No. 1:21-cv-01211-AW-HTC
)
LLOYD AUSTIN, III, in his official )
capacity as Secretary of Defense, et al. )
)
Defendants. )
)
DECLARATION OF PETER MARKS, M.D., Ph.D.

I, Peter Marks, declare as follows:
1. I am the Director of the Center for Biologics Evaluation and Research ( BER
United States 2016. In this
role, I direct the development and implementation of programs and policies for assuring the
safety, purity, and potency of biological products, including vaccines, allergenic products, blood
and blood products, and cellular, tissue, and gene therapies.
2. I joined FDA in 2012 as the Deputy Director for CBER, after practicing medicine, and
working in industry and academia for several years. I received my graduate degree in cell and
molecular biology and my medical degree at New York University, am board certified in internal
medicine, hematology and medical oncology, and am a Fellow of the American College of
Physicians.
3. In my capacity as Director of CBER, I am fully familiar with the instant matter and the
facts stated herein. This declaration is based on my personal knowledge, my background,
training, and experience and my review and consideration of information available to me in my
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official capacity, including information furnished by FDA personnel in the course of their
official duties. My conclusions have been reached in accordance therewith.
4. Vaccines are biological products that are regulated under the Public Health Service
U.S.C. § 321(g)(1)(B). Vaccines are approved for
; a vaccine
that is the subject of an approved BLA need not also obtain approval of a new drug application
C. § 355. 42 U.S.C. § 262(a), (j).
5. Under the PHSA, FDA approves a BLA on the basis of a demonstration that: (1) the
1
; (2) the facility in which the vaccine is produced meets
standards designed to assure that the vaccine continues to be safe, pure, and potent; and (3) the
applicant consents to inspection of the manufacturing facility. 42 U.S.C. § 262(a)(2)(C). FDA
may, but is not required to, consult with its standing advisory committee with scientific expertise
in biological products, the Vaccines and Related Biological Products Advisory Committee, as
part of the approval process. See 21 C.F.R. § 14.171(a). FDA has also issued several guidances
and other public documents on biologics and vaccine development. See generally Biologics
License Applications (BLA) Process, https://www.fda.gov/vaccines-blood-
biologics/development-approval-process-cber/biologics-license-applications-bla-process-cber;
Guidance, Compliance & Regulatory Information (Biologics), https://www.fda.gov/vaccines-
blood-biologics/guidance-compliance-regulatory-information-biologics; Vaccine and Related
1
The standard for licensure of a biological product as potent under 42 U.S.C. § 262 has long
been interpreted by FDA to include effectiveness. See 21 C.F.R. § 600.3(s); FDA Guidance,
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products at 4 (May
1998), available at https://www.fda.gov/media/71655/download.
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Biological Product Guidances, https://www.fda.gov/vaccines-blood-biologics/biologics-
guidances/vaccine-and-related-biological-product-guidances; Vaccine Development 101,
https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-
development-101.
6. On August 23, 2021, FDA approved a BLA for a COVID-19 vaccine known as
Comirnaty, 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. See Comirnaty Approval Letter (August 23, 2021), attached as Exhibit A.
7. Prior to approval, beginning in December 2020, the same formulation of the vaccine,
known as Pfizer-BioNTech Covid-19 vaccine, was available under an emergency use
See https://www.fda.gov/news-events/press-announcements/fda-takes-
key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19. FDA has
discretion to issue an EUA for an FDA-regulated product if: (1) the Secretary of the Department
of Health and Human Services has declared a public health emergency involving a biological or
other agent that can cause a serious or life-threatening disease or condition; (2) it is reasonable to
believe that the product may be effective in diagnosing, treating, or preventing that disease or
condition, and the known and potential benefits of the product outweigh the known and potential
risks of the product; and (3
product. 21 U.S.C. § 360bbb-3(c).2
for clinical trials conducted under an

§§ 360bbb-3(k); 355(i). Clinical trials must be conducted in accordance with an approved IND
and involve only enrolled study participants. Only clinical trial participants enrolled in a clinical
study conducted according to an approved IND receive the study drug.
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8. Even after FDA approved Comirnaty, FDA authorized continued use of the Pfizer-
BioNTech Covid-19 vaccine under an EUA for indications that included the approved use. FDA
determined that there is not sufficient approved vaccine available for distribution to the 16 years
of the EUA. See Letter to
Pfizer, Inc. reissuing EUA authorization for Covid-19 vaccine, p. 7, n.13 (October 20, 2021),
attached as Exhibit B. FDA also determined that there are no products that are approved to
prevent COVID-19 in additional populations covered by the EUA, as the vaccine remains
available under the EUA for uses that have not been approved, specifically for individuals ages
12 through 15 years old; for a third dose in certain populations
certain circumstances.
9. Additionally, FDA determined
as the EUA-authorized vaccine and the products can be used interchangeably to provide the
reissuing EUA authorization for Covid-19 vaccine, p. 2, n.8 (August 23, 2021), attached as
Exhibit C. FDA provided this information in the Letter of Authorization to make clear that
pharmacies and other healthcare practitioners could provide the vaccination series to recipients
using Pfizer-BioNTech, Comirnaty, or both (e.g., first dose of Pfizer-BioNTech followed by
second dose of Comirnaty, or vice versa), since the products have an identical formulation and
are made by the same manufacturer under current good manufacturing practice
requirements. FDA included this clarification in the authorization letter to avoid the unnecessary
operational complications that may have resulted if pharmacies or other healthcare practitioners
had believed that individuals who had received Pfizer-BioNTech for the first dose were not
authorized to receive Comirnaty for the second dose, or vice versa.
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10. The determination that FDA made for Comirnaty and Pfizer-BioNTech Covid-19
vaccine should not be confused with the statutory interchangeability determination that FDA
may make when reviewing a BLA for a biological product manufactured by one company and
comparing it with a biological product manufactured by a different company. Under 42 U.S.C.
§ 262(k)(4), FDA may determine that a biological product
product. is defined at 42 U.S.C. § cal product
licensed under [42 U.S.C. § 262(a)] against which a biological product is evaluated in an
The statutory interchangeability
determination requires a licensed reference product and a subsequent applicant seeking licensure,
which is not present here. The PHSA interchangeability provision also contains obligations
related to exclusivity and exchange of patent information for interchangeable products, which
would not make sense for two products produced by a single company. See 42 U.S.C.
§ 242(k)(6), (l).
11. While FDA determined Comirnaty and Pfizer-BioNTech Covid-19 vaccine are
medically interchangeable, there are legal distinctions between BLA-approved and EUA-
authorized products. For example, products approved under BLAs are required to have the
labeling that was approved as part of the BLA, whereas products authorized under the EUA
would have the EUA labeling, and there may also be differences in manufacturing sites for BLA
and EUA vaccine. Both the EUA and BLA processes have required the sponsor to identify
specific facilities that will manufacture the vaccine. See Summary Basis for Regulatory Action
Comirnaty, pp. 12-13 (August 23, 2021), available at
https://www.fda.gov/media/151733/download.
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12. Vaccine manufactured at sites listed in the BLA also undergoes lot release, which is
designed to ensure conformity with standards applicable to the product. 21 C.F.R. § 610.1; see
also https://www.fda.gov/vaccines-blood-biologics/biologics-post-market-activities/lot-
release#lotrelease. Vaccine manufactured at sites that are not listed in the BLA is not subject to
the lot release requirement.3 Both BLA and EUA manufacturing of this vaccine must adhere to
the
products meet specified standards of purity and potency. See 21 C.F.R. Part 211 (CGMP
regulations for drugs), § 211.1(b) (applicability of CGMP regulations to drugs that are also
biological products); EUA Reauthorization at 11 (Sept. 22, 2021), available at
13. In conjunction with the approval of Comirnaty, FDA asked the applicant to identify
available lots of vaccine that were manufactured at facilities listed in the BLA that had
undergone lot release. For these lots and other lots produced at facilities listed in the BLA, at this
time, FDA is exercising its enforcement discretion with respect to certain labeling requirements,
in that FDA is not taking enforcement with respect to vials that bear the EUA label. 4 FDA
considers these lots to be manufactured in compliance with the BLA and they are not subject to
the EUA requirements when used for the approved indication. Thus, the conditions in the Letter
3
Although not subject to lot release, as a condition of the EUA, Pfizer submits to the EUA file
Certificates of Analysis for each drug product lot at least 48 hours prior to vaccine distribution;
these Certificates include the established specifications and specific results for each quality
control test performed on the final drug product lot. Additionally, also as a condition of the
EUA, Pfizer submits quarterly manufacturing reports to the EUA file that include specified
information about each lot of vaccine manufactured. See Exhibit B at 11-12.
4
Each vial contains six doses of vaccine and a dose is withdrawn from the vial immediately
before injection into a recipient, who would not ordinarily be handling the vial or viewing its
label. Fact Sheet for Healthcare Providers Administering Vaccine, pp. 6-8 (Sept. 22, 2021),
available at https://www.fda.gov/media/144413/download.
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of Authorization for the EUA including the condition requiring vaccination providers to
EUA, it is your choice to receive or do not apply when these lots or
other BLA-compliant lots are used for the approved indication. FDA worked with the Applicant
to develop a Dear Healthcare Provider letter and website to identify those lots. Summary Basis
for Regulatory Action ttached as Exhibit D.
Also, for operational efficiency, to account for the fact that recipients may receive either the
BLA or EUA vaccine, after licensure of Comirnaty, vaccine has been distributed with unified
Fact Sheets, one for providers and one for recipients, that provide information regarding the
EUA product, as well as information about the licensed product. See Fact Sheet for Recipients
(Sept. 22, 2021), available at https://www.fda.gov/media/144414/download.
14. FDA has programs to expedite the development of drugs that are being studied to
treat life-threatening or severely debilitating diseases. 21 U.S.C. § 356. These programs, one of
are designed to help ensure that therapies for serious
conditions are approved and available for patients as soon as it can be concluded that the
See Guidance for Industry, Expedited Programs for
Serious Conditions Drugs and Biologics (May 2014), available at
https://www.fda.gov/media/86377/download. Fast Track designation was granted for Comirnaty
on July 7, 2020. See Exhibit D, SBRA at 5.
receives Fast Track designation, early and frequent communication between the FDA and a drug
company is encouraged throughout the entire drug development and review process. The
frequency of communication assures that questions and issues are resolved quickly, often leading
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https://www.fda.gov/patients/fast-track-
breakthrough-therapy-accelerated-approval-priority-review/fast-track.
15. In addition to granting
speed development and review of COVID-19 vaccines in response to the urgent public health
threat posed by SARS-CoV-2, without sacrificing the stringent statutory requirements for
approval. Vaccines typically undergo three phases of clinical trial. See
https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-
development-101. Phase 1 generally involves 20 to 100 healthy volunteers and focuses on safety.
Id. Phases 2 and 3 studies typically enroll more subjects and are designed to gather more safety
information on common short-term side effects and risks, examine the relationship between the
dose administered and the immune response, and generate critical efficacy data. Id. In the case
of the COVID-19 vaccines, those phases overlapped to speed the development process; no
phases were skipped. See 21 C.F.R. § 312.21 Although in general the phases are conducted
sequentially, they may overlap. . Also, because COVID-19 continues to be widespread, the
vaccine clinical trials have been conducted more quickly than if the disease were less common.
16. The Comirnaty BLA was approved based on six months of safety and efficacy data
from two ongoing clinical trials, C4591001 and BNT162-01, as well as safety information from
the millions of vaccine doses administered under the EUA. C4591001 is a randomized, placebo-
controlled, combined Phase 1, 2, and 3 study that has enrolled more than 43,000 participants.
See Exhibit D, SBRA at 15. Initially, during Phases 2 and 3, study participants, as well as study
investigators/personnel collecting and evaluating safety and efficacy information were blinded to
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-blinded).5 The study population for Phase 2/3
includes participants at higher risk for acquiring COVID-19 and at higher risk of severe COVID-
19, such as participants working in the healthcare field, participants with autoimmune disease,
and participants with chronic but stable medical conditions such as hypertension, asthma,
diabetes, and infection with HIV, hepatitis B or hepatitis C. Id. at 16.
17. In accordance with protocol (the plan that describes the
objectives, design, methodology, statistical considerations, and organization of a clinical trial,
see Glossary of Clinical Trial Terms, available at
https://www.fda.gov/media/108378/download#:~:text=A%20document%20that%20describes%2
0the,in%20other%20protocol%20referenced%20documents), participants ages 16 and older in
since the December 2020 issuance of the EUA
for the Pfizer-BioNTech Covid-19 vaccine and offered the vaccine if they were randomized to
the placebo group. Exhibit D, SBRA at 17. The study was unblinded in stages, either when
participants were eligible according to local recommendations for vaccination or after conclusion
of their six-month post Dose 2 study visit (whichever was earlier). Id. Despite the unblinding,
the data collected during the clinical trial still allowed FDA to evaluate the safety and
assignment. Study participants, investigators, and health care providers may all be blinded to the
treatment a participant is receiving, for example, whether a study participant is receiving the
study drug or a placebo. Glossary of Clinical Trial Terms, available at
https://www.fda.gov/media/108378/download#:~:text=A%20document%20that%20describes%2
0the,in%20other%20protocol%20referenced%20documents). Blinding may be done to prevent
skewing of the data by the placebo effect, by risk-seeking behavior, by unconscious bias or by
other factors. Blinding may impose a significant burden on the volunteer trial participants, and
medical ethicists generally agree that researchers are sometimes ethically bound to unblind a
study and permit placebo recipients to receive an effective treatment at some point. The
availability of effective treatment also encourages participation in clinical trials. Overall, the
priorities.
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effectiveness of the vaccine, considering the data collected during the blinded stage and the other
information submitted supporting safety and effectiveness. Although C4591001 is ongoing and
safety will be evaluated for the duration of the study for blinded and unblinded participants,
because most adverse events linked to vaccination occur within two months of vaccination (see
Table VI. National Vaccine Injury Compensation Program. Rockville, MD: Health Resources
and Services Administration, 2017 (https://www.hrsa.gov/sites/default/files/hrsa/vaccine-
compensation/vaccine-injury-table.pdf.), FDA determined that a BLA for a COVID-19 vaccine
could be supported by six months of safety data.6 See FDA Guidance, Development and
Licensure of Vaccines to Prevent COVID-19, at 15 (June 2020), attached as Exhibit E. Because
the applicant submitted sufficient safety and efficacy data, the ongoing nature of the phase 3
clinical trial was not a basis for declining to license Comirnaty. The estimated completion date
for C4591001 is May 2023, see
https://www.clinicaltrials.gov/ct2/show/NCT04368728?term=C4591001&draw=2&rank=4).
18. BNT162-01 an ongoing Phase 1/2, open-label, dose-finding study with 24
participants, designed to evaluate the safety and immunogenicity of several candidate vaccines,
including the dose that was approved by FDA on August 23, 2021. See Exhibit D, SBRA at 15.
Safety data from the study was included in the BLA for Comirnaty and supported selection of the
6
Indeed, requesting six-months of follow-up safety data is not unique to Covid-19 vaccines.
See Guidance for Industry Clinical Data Needed to Support the Licensure of Pandemic Influenza
Vaccines, at 5,7, 10 (May 2007), available at Guidance for Industry: Clinical Data Needed to
Support the Licensure of Pandemic Influenza Vaccines (fda.gov) (generally recommending six-
months of safety data to support influenza vaccines). FDA explained the rationale for requesting
at least six-months of safety data to support licensure of Comirnaty in its response to a Citizen
to those raised by Plaintiffs. See Response to ICAN Citizen Petition, Docket FDA-2021-P-0529,
at 9-10 (August 23, 2021), available at https://www.regulations.gov/document/FDA-2021-P-
0529-1077.
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final vaccine candidate and dose level. Id. at 21. Although FDA did not refer the BLA to its
considering the EUA for the Pfizer-BioNTech Covid-19 vaccine. Id. at 26-27.
19. In addition to reviewing clinical data, before approving the Comirnaty BLA, FDA
assessed, among other things, its
and clinical pharmacology and nonclinical toxicology data; safety and pharmacovigilance data;
labeling; and manufacturing facilities. See 21 C.F.R. § 601.2 (requirements for contents of BLA
application). Along with the Summary Basis for Regulatory Action for Comirnaty, also
available are three Statistical Reviews; an
assessment of Real World Evidence; two Pharmacovigilance Plan Reviews; two CMC Reviews,
Clinical Review; CBER Sentinel Program Sufficiency Review; Bioresearch Monitoring Review;
Benefit-Risk Assessment Review; Analytical Method Review; and Toxicology Review. See
https://www.fda.gov/vaccines-blood-biologics/comirnaty (click on Approval History, Letters,
Reviews, and Related Document COMIRNATY).
20. Based on the data from the two clinical studies, FDA determined that the overall
efficacy rate in the 16 and older subject population was 91.1% for the prevention of COVID-19
infection and between 95% and 100% for the avoidance of severe infection. Exhibit D, SBRA at
19-20. FDA also considered the safety data from the two clinical studies, in addition to safety
information from EUA use. Id. at 22-25. In sum, based on its review of the clinical, pre-clinical,
and product-related data submitted in the Comirnaty BLA, FDA determined that the product had
a favorable benefit/risk balance, and was safe, pure, and potent. The agency approved the
license for Comirnaty on August 23, 2021. Id. at 27-28; Exhibit A, FDA Approval Letter (Aug.
23, 2021).
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21. Comirnaty is subject to specified post market requirements and commitments. See
21 U.S.C. §§ 355(o)(2)(B)(ii) and 356b. Those requirements and commitments are: (1) Study
-Interventional Post-Approval Safety Study of the Pfizer-BioNTech
COVID-
Conditional Approval Active Surveillance Study Among Individuals in Europe Receiving the
Pfizer-BioNTech Coronavirus Disease 2019 (COVID-
of myocarditis and pericarditis following administration of COMIRNATY; (3) Study C4591021
sub-study 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; (5) Study C4591007
sub-study 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; (6) Study C4591031 sub-study to prospectively assess the incidence of subclinical
myocarditis following administration of a third dose of COMIRNATY in a subset of participants
16 to 30 years of age; (7) -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
; (8) Study C4591007 sub-study to evaluate the
immunogenicity and safety of lower dose levels of COMIRNATY in individuals 12 through < 30
-emergency Use Authorization Active Safety
BioNTech Coronavirus Disease 2019 (COVID-
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-BioNTech COVID-19 BNT162b2 Vaccine Effectiveness Study - Kaiser Permanente
effectiveness of COMIRNATY in children 12 years through 15 years of age; (12) Deferred
pediatric study C4591007 to evaluate the safety and effectiveness of COMIRNATY in children 6
months to < 12 years of age; and (13) Deferred pediatric study C4591023 to evaluate the safety
and effectiveness of COMIRNATY in infants < 6 months of age. Exhibit D, SBRA at 29-30.
22. On the same day that FDA approved the license for Comirnaty, the agency
responded to a Citizen Petition submitted by the Coalition Advocating for Adequately Licensed
Medicines (CAALM) on July 23, 2021. CAALM Petition, Docket FDA-2021-P-0786, attached
as Exhibit F.
of clinical effectiveness that outweighs harms in special populations such as: infants, children,
and adolescents; those with past SARSCoV-2 infection; immunocompromised; pregnant women;
nursing women; frail older adults; and individuals with cancer, autoimmune disorders, and
before licensing a Covid-19 vaccine, and that there should be
risk of symptomatic COVID- Id. at 2. Some
of the populations identified by petitioners participated in the clinical trials and additional
information will be obtained from post-marketing studies. For example, approximately 3% of
the clinical trial participants had evidence of prior Covid-19 infection (see Clinical Review
Memo at 35, referenced in paragraph 19, above). Additionally, although pregnant individuals
were excluded from participation in the trial and the applicant has committed to study the
vaccine in this population segment as described in paragraph 21 above, participants in both the
treatment and placebo arms of the trial became pregnant during the trial, and pregnancy
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outcomes of spontaneous abortion, miscarriages and elective abortions was similar between the
vaccine and the placebo group. Id. at 84. In response to
concluded that petitioners had not provided sufficient scientific justification for requiring
effectiveness data from clinical trials specific to each population group and specifically designed
to evaluate disease endpoints of varying severity, and
with
immunobridging or extrapolation across population groups. CAALM Petition Response at 7-8
(August 23, 2021), attached as Exhibit G.
23.
affected with COVID-
also be at heightened risk for adverse
from the vaccine, finding there was scientific uncertainty about the duration of immunity
from natural infection and that petitioners had not provided sufficient scientific support for the
latter claim. CAALM Petition Response at 8-9, n.31. In reaching that conclusion, FDA
evaluated each study put forward by petitioners and carefully explained why the studies did not
Id.; see also Response to ICAN Citizen Petition at 13-15.
24. In approving the BLA for Comirnaty, FDA applied its scientific expertise to evaluate
the data contained in the application and determined that benefits outweigh its risks
and that it is safe, pure, potent, and effective for its proposed use. In response to the urgent
public health emergency presented by COVID-19, FDA worked expeditiously to provide
guidance to entities seeking to develop vaccines for this disease, and to review the BLA for
Comirnaty once it was submitted to the agency to ensure it fully met the statutory standards for
approval, to further the objective of protecting the public health.
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25. I have reviewed the Declaration of Jane Ruby submitted in this matter. ECF No. 1-
18. Although I have not attempted to exhaustively analyze her conclusions, the declaration is
rife with error and appears to reflect a lack of basic knowledge of the field. For example, I
renders th ompletely compromised. See id. at ¶12. As explained above in
paragraph 17 , referenced in Paragraph 19 above, that
participants initially assigned to the placebo arm of the study were unblinded in phases in
accordance with the protocol does not invalidate the data generated in the trial. Ms. Ruby
declaration also erroneously sion criteria, id. at ¶15,
without regard to subsequent protocol amendments to add study populations, interventions, and
analyses not included in the original design, one of which permitted enrollment of HIV-infected
trial participants. See Review at 23, referenced in Paragraph 19 above. Ms. Ruby
is also incorrect in stating that FDA did not consider the pharmacokinetics of the vaccine (Ruby
Decl. at ¶16). See In
Paragraph 24 of her declaration, Ms. Ruby evidences a fundamental misunderstanding of the
clinical trial process when she impliedly criticizes the protocol for C4591001 for permitting
doses of the vaccine greater than 3 times the dose that was approved. In fact, one of the purposes
of clinical trials to establish the appropriate dose of a medication and the very protocol cited by
Ms. Ruby explains precisely how clinical data led to the dose that was ultimately approved. See
Ruby Decl. Exhibit E at 40 (ECF No. 1-18 at 83). These examples are just illustrative of the
many
26. An injunction against the licensure of Comirnaty would cause irreparable harm. Safe
and effective vaccines are currently the most powerful tool we have against the pandemic and
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Marks Decl.
Exhibit A
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Page 3 – STN BL 125742/0 – Elisa Harkins
10903 New Hampshire Ave.

WO71-G112
Silver Spring, MD 20993-0002
MANUFACTURING CHANGES
You must submit information to your BLA for our review and written approval under 21
CFR 601.12 for any changes in, including but not limited to, the manufacturing, testing,
packaging or labeling of COVID-19 Vaccine, mRNA, or in the manufacturing facilities.
LABELING
We hereby approve the draft content of labeling including Package Insert, submitted
under amendment 74, dated August 21, 2021, and the draft carton and container labels
submitted under amendment 63, dated August 19, 2021.
CONTENT OF LABELING
As soon as possible, but no later than 14 days from the date of this letter, please submit
the final content of labeling (21 CFR 601.14) in Structured Product Labeling (SPL)
format via the FDA automated drug registration and listing system, (eLIST) as described
at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/
default.htm. Content of labeling must be identical to the Package Insert submitted on
August 21, 2021. Information on submitting SPL files using eLIST may be found in the
guidance for industry SPL Standard for Content of Labeling Technical Qs and As at
http://www.fda.gov/downloads/Drugs/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-product-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/LotReleases/ucm061966.htm.
PEDIATRIC REQUIREMENTS
Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
new active ingredients, new indications, new dosage forms, new dosing regimens, or
new routes of administration are 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 your pediatric studies for ages younger than 16 years
for this application because this product is ready for approval for use in individuals 16
years of age and older, and the pediatric studies for younger ages have not been
completed.
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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 studies are listed below:
1. Deferred pediatric Study C4591001 to evaluate the safety and effectiveness of

COMIRNATY in children 12 years through 15 years of age.
Final Protocol Submission: October 7, 2020
Study Completion: May 31, 2023
Final Report Submission: October 31, 2023

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

COMIRNATY in infants <6 months of age.
Final Protocol Submission: January 31, 2022
Study Completion: July 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 through 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 risks of myocarditis and pericarditis and identify an unexpected serious risk of
subclinical myocarditis.
Furthermore, the pharmacovigilance system that FDA is required to maintain under

section 505(k)(3) of the FDCA is not sufficient to assess these serious risks.
Therefore, based on appropriate scientific data, we have determined that you are
required to conduct the following studies:
4. Study C4591009, entitled “A Non-Interventional Post-Approval Safety Study of

the Pfizer-BioNTech COVID-19 mRNA Vaccine in the United States,” to evaluate
the occurrence of myocarditis and pericarditis following administration of
COMIRNATY.
We acknowledge the timetable you submitted on August 21, 2021, which states
that you will conduct this study according to the following schedule:
Final Protocol Submission: August 31, 2021
Monitoring Report Submission: October 31, 2022
Interim Report Submission: October 31, 2023
Study Completion: June 30, 2025
5. Study 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.
Progress Report Submission: September 30, 2021
Interim Report 1 Submission: March 31, 2022
Interim Report 2 Submission: September 30, 2022
Study Completion: March 31, 2024
Final Report Submission: September 30, 2024
6. Study C4591021 substudy to describe the natural history of myocarditis and

pericarditis following administration of COMIRNATY.
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).
Final Protocol Submission: November 30, 2021
Study Completion: December 31, 2026

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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.
that you will conduct this assessment according to the following schedule:
Final Protocol Submission: September 30, 2021

myocarditis following administration of a third dose of COMIRNATY in a subset of
participants 16 to 30 years of age.
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
subject to the reporting requirements of section 506B of the FDCA are fulfilled or
released. The status report for each study should include:
the sequential number for each study as shown in this letter;

information to identify and describe the postmarketing requirement;
the original milestone schedule for the requirement;
the revised milestone schedule for the requirement, if appropriate;
the current status of the requirement (i.e., pending, ongoing, delayed, terminated,
or submitted); and,
an explanation of the status for the study or clinical trial. The explanation should
include how the study is progressing in reference to the original projected
schedule, including, the patient accrual rate (i.e., number enrolled to date and the
total planned enrollment).
As described in 21 CFR 601.70(e), we may publicly disclose information regarding

these postmarketing studies on our website at http://www.fda.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)(ii) 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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11. Study C4591007 substudy to evaluate the immunogenicity and safety of lower
dose levels of COMIRNATY in individuals 12 through <30 years of age.
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.”
13. Study C4591014, entitled “Pfizer-BioNTech COVID-19 BNT162b2 Vaccine

Effectiveness Study - Kaiser Permanente Southern California.”
Final Protocol Submission: March 22, 2021
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
subject to the reporting requirements of section 506B of the FDCA are fulfilled or
released. The status report for each study should include:
the sequential number for each study as shown in this letter;

information to identify and describe the postmarketing commitment;
the original schedule for the commitment;
the status of the commitment (i.e., pending, ongoing, delayed, terminated, or
submitted); and,
an explanation of the status including, for clinical studies, the patient accrual rate
(i.e., number enrolled to date and the total planned enrollment).
As described in 21 CFR 601.70(e), we may publicly disclose information regarding

these postmarketing studies on our website at http://www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/Post-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 Marion F. Gruber, PhD

Director Director
Office of Compliance Office of Vaccines
and Biologics Quality Research and Review
Center for Biologics Center for Biologics
Evaluation and Research Evaluation and Research
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Marks Decl.
Exhibit B
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October 20, 2021
Pfizer Inc.
Attention: Mr. Amit Patel
235 East 42nd St
New York, NY 10017
Dear Mr. Patel:
On February 4, 2020, pursuant to Section 564(b)(1)(C) of the Federal Food, Drug, and Cosmetic
Act (the FD&C Act or the Act), the Secretary of the Department of Health and Human Services
(HHS) determined that there is a public health emergency that has a significant potential to affect
national security or the health and security of United States citizens living abroad, and that
involves the virus that causes Coronavirus Disease 2019 (COVID-19). 1 On the basis of such
determination, the Secretary of HHS on March 27, 2020, declared that circumstances exist
justifying the authorization of emergency use of drugs and biological products during the
COVID-19 pandemic, pursuant to Section 564 of the Act (21 U.S.C. 360bbb-3), subject to terms
of any authorization issued under that section. 2
On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use
Authorization (EUA) for emergency use of Pfizer-
prevention of COVID-19 for individuals 16 years of age and older pursuant to Section 564 of the
Act. FDA reissued the letter of authorization on: December 23, 2020, 3 February 25, 2021, 4 May
1
U.S. Department of Health and Human Services, Determination of a Public Health Emergency and Declaration that
Circumstances Exist Justifying Authorizations Pursuant to Section 564(b) of the FD&C Act, 21 U.S.C. § 360bbb-3,
February 4, 2020.
2
U.S. Department of Health and Human Services, Declaration that Circumstances Exist Justifying Authorizations
Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3, 85 FR 18250
(April 1, 2020).
3
In the December 23, 2020 revision, FDA removed reference to the number of doses per vial after dilution from the
letter of authorization, clarified the instructions for vaccination providers reporting to VAERS, and made other
technical corrections. FDA also revised the Fact Sheet for Healthcare Providers Administering Vaccine
(Vaccination Providers) to clarify the number of doses of vaccine per vial after dilution and the instructions for
reporting to VAERS. In addition, the Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination
Providers) and the Fact Sheet for Recipients and Caregivers were revised to include additional information on safety
monitoring and to clarify information about the availability of other COVID-19 vaccines.
4
In the February 25, 2021 revision, FDA allowed flexibility on the date of submission of monthly periodic safety
reports and revised the requirements for reporting of vaccine administration errors by Pfizer Inc. The Fact Sheet for
Health Care Providers Administering Vaccine (Vaccination Providers) was revised to provide an update to the
storage and transportation temperature for frozen vials, direct the provider to the correct CDC website for
information on monitoring vaccine recipients for the occurrence of immediate adverse reactions, to include data
from a developmental toxicity study, and add adverse reactions that have been identified during post authorization
use. The Fact Sheet for Recipients and Caregivers was revised to add adverse reactions that have been identified
during post authorization use.
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Page 2 – Pfizer Inc.
10, 2021, 5 June 25, 2021, 6 August 12, 2021, 7 and on August 23, 2021, FDA approved
COMIRNATY (COVID-19 Vaccine, mRNA) 8 and reissued the letter in its entirety for both
Pfizer- Vaccine and certain uses of COMIRNATY (COVID-19 Vaccine,
mRNA). Subsequently, FDA reissued the letter of authorization on September 22, 2021. 10
9
On October 20, 2021, having concluded that revising this EUA is appropriate to protect the
public health or safety under Section 564(g)(2) of the Act, FDA is reissuing the September 22,
2021 letter of authorization in its entirety with revisions incorporated to clarify eligibility for the
booster dose of COMIRNATY (COVID-19 Vaccine, mRNA) or Pfizer-BioNTech COVID-19
Vaccine and to authorize for emergency use the administration of a single booster dose of Pfizer-
BioNTech or COMIRNATY (COVID-19 Vaccine, mRNA) as a
heterologous booster dose following completion of primary vaccination with another authorized
COVID-19 vaccine. The eligible population(s) and dosing interval for the heterologous booster
5
In the May 10, 2021 revision, FDA authorized Pfizer-BioNTech Vaccine for the prevention of COVID-19 in
individuals 12 through 15 years of age, as well as for individuals 16 years of age and older. In addition, FDA
revised the Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination Providers) to include the
following Warning: “Syncope (fainting) may occur in association with administration of injectable vaccines, in
particular in adolescents. Procedures should be in place to avoid injury from fainting.” In addition, the Fact Sheet
for Recipients and Caregivers was revised to instruct vaccine recipients or their caregivers to tell the vaccination
provider about fainting in association with a previous injection.
6
In the June 25, 2021 revision, FDA clarified terms and conditions that relate to export of Pfizer-BioNTech
In addition, the Fact Sheet for Healthcare Providers Administering
Vaccine (Vaccination Providers) was revised to include a Warning about myocarditis and pericarditis following
administration of the Pfizer-BioNTech COVID-19 Vaccine. The Fact Sheet for Recipients and Caregivers was
updated to include information about myocarditis and pericarditis following administration of the Pfizer-BioNTech
7
In the August 12, 2021 revision, FDA authorized a third dose of the Pfizer-BioNTech COVID-19 Vaccine
administered at least 28 days following the two dose regimen of this vaccine in individuals 12 years of age or older
who have undergone solid organ transplantation, or individuals 12 years of age or older who are diagnosed with
conditions that are considered to have an equivalent level of immunocompromise.
8
COMIRNATY (COVID-19 Vaccine, mRNA) was approved 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.
9
In the August 23, 2021 revision, FDA clarified that, subsequent to the FDA approval of COMIRNATY (COVID-
19 Vaccine, mRNA) for the prevention of COVID-19 for individuals 16 years of age and older, this EUA would
remain in place for the Pfizer-BioNTech COVID-19 vaccine for the previously-authorized indication and uses. It
also authorized COMIRNATY (COVID-19 Vaccine, mRNA) under this EUA for certain uses that are not included
in the approved biologics license application (BLA). In addition, the Fact Sheet for Healthcare Providers
Administering Vaccine (Vaccination Providers) was revised to provide updates on expiration dating of the
authorized Pfizer-BioNTech COVID-19 Vaccine and updated language regarding warnings and precautions related
to myocarditis and pericarditis. The Fact Sheet for Recipients and Caregivers was updated as the Vaccine
Information Fact Sheet for Recipients and Caregivers, which comprises the Fact Sheet for the authorized Pfizer-
BioNTech COVID-19 Vaccine and information about the FDA-licensed vaccine, COMIRNATY (COVID-19
Vaccine, mRNA).
10
In the September 22, 2021 revision, FDA authorized the administration of a single booster dose of COMIRNATY
(COVID-19 Vaccine, mRNA) or Pfizer-BioNTech COVID-19 Vaccine at least 6 months after completing the
primary series of this vaccine in individuals: 65 years of age and older; 18 through 64 years of age at high risk of
severe COVID-19; and 18 through 64 years of age whose frequent institutional or occupational exposure to SARS-
CoV-2 puts them at high risk of serious complications of COVID-19 including severe COVID-19.
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dose are the same as those authorized for a booster dose of the vaccine used for primary
vaccination.
COMIRNATY (COVID-19 Vaccine, mRNA) is the same formulation as the Pfizer-BioNTech

COVID-19 Vaccine and can be used interchangeably with the Pfizer-BioNTech COVID-19
Vaccine to provide doses for COVID-19 primary vaccination or a booster dose. 11
For the December 11, 2020 authorization for individuals 16 years of age and older, FDA
reviewed safety and efficacy data from an ongoing Phase 1/2/3 trial in approximately 44,000
participants randomized 1:1 to receive Pfizer-BioNTech accine or saline control.
The trial enrolled participants 12 years of age and older. FDA’s review at that time considered
the safety and effectiveness data as they relate to the request for emergency use authorization in
individuals 16 years of age and older. FDA’s review of the available safety data from 37,586 of
the participants 16 years of age and older, who were followed for a median of two months after
receiving the second dose, did not identify specific safety concerns that would preclude issuance
of an EUA. FDA’s analysis of the available efficacy data from 36,523 participants 12 years of
age and older without evidence of SARS-CoV-2 infection prior to 7 days after dose 2 confirmed
that the vaccine was 95% effective (95% credible interval 90.3, 97.6) in preventing COVID-19
occurring at least 7 days after the second dose (with 8 COVID-19 cases in the vaccine group
compared to 162 COVID-19 cases in the placebo group). Based on these data, and review of
manufacturing information regarding product quality and consistency, FDA concluded that it is
reasonable to believe that Pfizer- may be effective. Additionally,
FDA determined it is reasonable to conclude, based on the totality of the scientific evidence
available, that the known and potential benefits of Pfizer-
outweigh the known and potential risks of the vaccine, for the prevention of COVID-19 in
individuals 16 years of age and older. Finally, on December 10, 2020, the Vaccines and Related
Biological Products Advisory Committee voted in agreement with this conclusion.
For the May 10, 2021 authorization for individuals 12 through 15 years of age, FDA reviewed
safety and effectiveness data from the above-referenced, ongoing Phase 1/2/3 trial that enrolled
approximately 46,000 participants, including 2,260 participants 12 through 15 years of age.
Trial participants were randomized 1:1 to receive Pfizer-BioNTech COVID-19 Vaccine or saline
control. FDA’s review of the available safety data from 2,260 participants 12 through 15 years
of age, who were followed for a median of 2 months after receiving the second dose, did not
identify specific safety concerns that would preclude issuance of an EUA. FDA’s analysis of
SARS-CoV-2 50% neutralizing antibody titers 1 month after the second dose of Pfizer-
BioNTech COVID-19 Vaccine in a subset of participants who had no serological or virological
evidence of past SARS-CoV-2 infection confirm that the geometric mean antibody titer in
participants 12 through 15 years of age was non-inferior to the geometric mean antibody titer in
participants 16 through 25 years of age. FDA’s analysis of available descriptive efficacy data
from 1,983 participants 12 through 15 years of age without evidence of SARS-CoV-2 infection
11
The licensed vaccine has the same formulation as the EUA-authorized vaccine and the products can be used
interchangeably to provide doses for primary vaccination or a booster dose without presenting any safety or
effectiveness concerns. The products are legally distinct with certain differences that do not impact safety or
effectiveness.
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prior to 7 days after dose 2 confirm that the vaccine was 100% effective (95% confidence
interval 75.3, 100.0) in preventing COVID-19 occurring at least 7 days after the second dose
(with no COVID-19 cases in the vaccine group compared to 16 COVID-19 cases in the placebo
group). Based on these data, FDA concluded that it is reasonable to believe that Pfizer-
Additionally, FDA determined it is reasonable to conclude, based on the totality of the scientific
evidence available, that the known and potential benefits of Pfizer-
Vaccine outweigh the known and potential risks of the vaccine, for the prevention of COVID-19
in individuals 12 through 15 years of age.
For the August 12, 2021 authorization of a third primary series dose in individuals 12 years of
age or older who have undergone solid organ transplantation, or individuals 12 years of age or
older who are diagnosed with conditions that are considered to have an equivalent level of
immunocompromise, FDA reviewed safety and effectiveness data reported in two manuscripts
on solid organ transplant recipients. The first study was a single arm study conducted in 101
individuals who had undergone various solid organ transplant procedures (heart, kidney, liver,
lung, pancreas) a median of 97±8 months earlier. A third dose of the Pfizer-BioNTech COVID-
19 Vaccine was administered to 99 of these individuals approximately 2 months after they had
received a second dose. Levels of total SARS-CoV-2 binding antibodies meeting the pre-
specified criteria for success occurred four weeks after the third dose in 26/59 (44.0%) of those
who were initially considered to be seronegative and received a third dose of the Pfizer-
BioNTech COVID-19 Vaccine; 67/99 (68%) of the entire group receiving a third vaccination
were subsequently considered to have levels of antibodies indicative of a significant response. In
those who received a third vaccine dose, the adverse event profile was similar to that after the
second dose and no grade 3 or grade 4 events were reported. A supportive secondary study
describes a double-blind, randomized-controlled study conducted in 120 individuals who had
undergone various solid organ transplant procedures (heart, kidney, kidney-pancreas, liver, lung,
pancreas) a median of 3.57 years earlier (range 1.99-6.75 years). A third dose of a similar
messenger RNA vaccine (the Moderna COVID-19 vaccine) was administered to 60 individuals
approximately 2 months after they had received a second dose (i.e., doses at 0, 1 and 3 months);
saline placebo was given to 60 individuals for comparison. The primary outcome was anti-RBD
antibody at 4 months greater than 100 U/mL. This titer was selected based on NHP challenge
studies as well as a large clinical cohort study to indicate this antibody titer was protective.
Secondary outcomes were based on a virus neutralization assay and polyfunctional T cell
responses. Baseline characteristics were comparable between the two study arms as were pre-
intervention anti-RBD titer and neutralizing antibodies. Levels of total SARS-CoV-2 binding
antibodies indicative of a significant response occurred four weeks after the third dose in 33/60
(55.0%) of the Moderna COVID-19 vaccinated group and 10/57 (17.5%) of the placebo
individuals. In the 60 individuals who received a third vaccine dose, the adverse event profile
was similar to that after the second dose and no grade 3 or grade 4 adverse events were reported.
Despite the moderate enhancement in antibody titers, the totality of data (i.e., supportive paper
by Hall et al. demonstrated efficacy of the product in the elderly and persons with co-
morbidities) supports the conclusion that a third dose of the Pfizer-BioNTech COVID-19
Vaccine may be effective in this population, and that the known and potential benefits of a third
dose of Pfizer-BioNTech COVID-19 Vaccine outweigh the known and potential risks of the
vaccine for immunocompromised individuals at least 12 years of age who have received two
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doses of the Pfizer-BioNTech COVID-19 Vaccine and who have undergone solid organ
transplantation, or who are diagnosed with conditions that are considered to have an equivalent
level of immunocompromise.
For the September 22, 2021 authorization of a single booster dose administered at least 6 months
after completing the primary series in individuals: 65 years of age and older; 18 through 64 years
of age at high risk of severe COVID-19; and 18 through 64 years of age whose frequent
institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious
complications of COVID-19 including severe COVID-19, FDA reviewed safety and
effectiveness data from the above-referenced, ongoing Phase 1/2/3 trial in which 329 participants
18 through 75 years of age received a booster dose of the Pfizer-BioNTech COVID-19 Vaccine
approximately 6 months (range 4.8 to 8.8 months) after completion of the primary series. FDA’s
review of the available safety data from 329 participants 18 through 75 years of age, who had
been followed for a median of 2.6 months after receiving the booster dose, did not identify
specific safety concerns that would preclude issuance of an EUA. The effectiveness of the
booster dose of the Pfizer-BioNTech COVID-19 Vaccine is based on an assessment of 50%
neutralizing antibody titers (NT50) against SARS-CoV-2 (USA_WA1/2020). FDA’s analysis of
SARS-CoV-2 NT50 one month after the booster dose compared to 1 month after the primary
series in study participants 18 through 55 years of age who had no serological or virological
evidence of past SARS-CoV-2 infection up to 1 month after the booster dose confirmed
noninferiority for both geometric mean ratio and difference in seroresponse rates. Based on the
totality of the scientific evidence available, including data from the above-referenced clinical
trial, FDA concluded that a booster dose the Pfizer-BioNTech COVID-19 Vaccine may be
effective, and that the known and potential benefits of a single booster dose at least 6 months
after completing the primary series outweigh the known and potential risks for individuals 65
years of age and older; individuals 18 through 64 years of age at high risk of severe COVID-19;
and individuals 18 through 64 years of age whose frequent institutional or occupational exposure
to SARS-CoV-2 puts them at high risk of serious complications of COVID-19 including severe
COVID-19.
For the October 20, 2021 authorization of a single booster dose as a heterologous booster dose
following completion of primary vaccination with another authorized COVID-19 vaccine, FDA
reviewed data from an ongoing Phase1/2 clinical trial in participants 19-85 years of age. In this
trial, adults who had completed primary vaccination with a Moderna COVID-19 Vaccine 2-dose
series (N=151), a Janssen COVID-19 Vaccine single dose (N=156), or a Pfizer-BioNTech
COVID-19 Vaccine 2-dose series (N=151) at least 12 weeks prior to enrollment and who
reported no history of SARS-CoV-2 infection were randomized 1:1:1 to receive a booster dose of
one of three vaccines: Moderna COVID-19 Vaccine, Janssen COVID-19 Vaccine, or Pfizer-
BioNTech COVID-19 Vaccine. Adverse events were assessed through 28 days after the booster
dose. An overall review of adverse reactions reported following the Pfizer-BioNTech COVID-19
Vaccine heterologous booster dose did not identify any new safety concerns, as compared with
adverse reactions reported following Pfizer-BioNTech COVID-19 Vaccine primary series doses
or homologous booster dose. Neutralizing antibody titers, as measured by a pseudovirus
neutralization assay using a lentivirus expressing the SARS-CoV-2 Spike protein with D614G
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mutation, were assessed on Day 1 prior to administration of the booster dose and on Day 15 after
the booster dose. A booster response to the Pfizer-BioNTech COVID-19 Vaccine was
demonstrated regardless of primary vaccination. Based on the on the totality of the scientific
evidence available, including data from the above-referenced clinical trial, FDA concluded that a
heterologous booster dose of the Pfizer-BioNTech COVID-19 Vaccine may be effective, and
that the known and potential benefits of a heterologous booster dose of the Pfizer-BioNTech
COVID-19 Vaccine following completion of primary vaccination with another authorized
COVID-19 vaccine outweigh the known and potential risks.
Having concluded that the criteria for issuance of this authorization under Section 564(c) of the
Act are met, I am authorizing the emergency use of Pfizer-BioNTech COV for the
prevention of COVID-19, as described in the Scope of Authorization section of this letter
(Section II) and subject to the terms of this authorization. Additionally, as specified in
subsection III.BB, I am authorizing use of COMIRNATY (COVID-19 Vaccine, mRNA) under
this EUA when used to provide: (1) a two-dose regimen for individuals aged 12 through 15
years; (2) a third dose to individuals 12 years of age or older who have undergone solid organ
transplantation or who are diagnosed with conditions that are considered to have an equivalent
level of immunocompromise; (3) a single homologous booster dose at least 6 months after
completing a primary series to individuals 65 years of age and older, 18 through 64 years of age
at high risk of severe COVID-19, and 18 through 64 years of age with frequent institutional or
occupational exposure to SARS-CoV-2; and (4) a heterologous booster dose to certain
individuals who have completed primary vaccination with a different authorized COVID-
19 vaccine as described in the Scope of Authorization section of this letter (Section II).
I. Criteria for Issuance of Authorization

12
I have concluded that the emergency use of Pfizer- for the
prevention of COVID-19 when administered as described in the Scope of Authorization (Section
II) meets the criteria for issuance of an authorization under Section 564(c) of the Act, because:
A. SARS-CoV-2 can cause a serious or life-threatening disease or condition, including

severe respiratory illness, to humans infected by this virus;
B. Based on the totality of scientific evidence available to FDA, it is reasonable to believe

that Pfizer- may be effective in preventing COVID-19,
and that, when used under the conditions described in this authorization, the known and
potential benefits of Pfizer- when used to prevent
COVID-19 outweigh its known and potential risks; and
12
In this section (Section I), references to Pfizer- also apply to COMIRNATY
(COVID-19 Vaccine, mRNA).
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C. There is no adequate, approved, and available alternative 13 Pfizer-BioNTech

to prevent COVID-19. 14
II. Scope of Authorization
I have concluded, pursuant to Section 564(d)(1) of the Act, that the scope of this authorization is
limited as follows:
Pfizer Inc. will supply Pfizer- either directly or through

authorized distributor(s), to emergency response stakeholders 16 as directed by the U.S.
15
government, including the Centers for Disease Control and Prevention (CDC) and/or
other designee, for use consistent with the terms and conditions of this EUA;
The Pfizer- covered by this authorization will be
17
administered by vaccination providers and used only to prevent COVID-19 in
individuals ages 12 and older with a two-dose primary regimen and to provide:
13
Although COMIRNATY (COVID-19 Vaccine, mRNA) is approved to prevent COVID-19 in individuals 16 years
of age and older, there is not sufficient approved vaccine available for distribution to this population in its entirety at
the time of reissuance of this EUA. Additionally, there are no COVID-19 vaccines that are approved to provide:
COVID-19 vaccination in individuals age 12 through 15; a third primary series dose to certain immunocompromised
populations described in this EUA; a homologous booster dose to the authorized population described in this EUA;
or a heterologous booster dose following completion of primary vaccination with another authorized COVID-19
vaccine.
14
No other criteria of issuance have been prescribed by regulation under Section 564(c)(4) of the Act.
15
“Authorized Distributor(s)” are identified by Pfizer Inc. or, if applicable, by a U.S. government entity, such as the
Centers for Disease Control and Prevention (CDC) and/or other designee, as an entity or entities allowed to
distribute authorized Pfizer-
16
For purposes of this letter, “emergency response stakeholder” refers to a public health agency and its delegates
that have legal responsibility and authority for responding to an incident, based on political or geographical
boundary lines (e.g., city, county, tribal, territorial, State, or Federal), or functional (e.g., law enforcement or public
health range) or sphere of authority to administer, deliver, or distribute vaccine in an emergency situation. In some
cases (e.g., depending on a state or local jurisdiction’s COVID-19 vaccination response organization and plans),
there might be overlapping roles and responsibilities among “emergency response stakeholders” and “vaccination
providers” (e.g., if a local health department is administering COVID-19 vaccines; if a pharmacy is acting in an
official capacity under the authority of the state health department to administer COVID-19 vaccines). In such
cases, it is expected that the conditions of authorization that apply to emergency response stakeholders and
vaccination providers will all be met.
17
For purposes of this letter, “vaccination provider” refers to the facility, organization, or healthcare provider
licensed or otherwise authorized by the emergency response stakeholder (e.g., non-physician healthcare
professionals, such as nurses and pharmacists pursuant to state law under a standing order issued by the state health
officer) to administer or provide vaccination services in accordance with the applicable emergency response
stakeholder’s official COVID-19 vaccination and emergency response plan(s) and who is enrolled in the CDC
COVID-19 Vaccination Program. If the vaccine is exported from the United States, a “vaccination provider” is a
provider that is authorized to administer this vaccine in accordance with the laws of the country in which it is
administered. For purposes of this letter, “healthcare provider” also refers to a person authorized by the U.S.
Department of Health and Human Services (e.g., under the PREP Act Declaration for Medical Countermeasures
against COVID-19) to administer FDA-authorized COVID-19 vaccine (e.g., qualified pharmacy technicians and
State-authorized pharmacy interns acting under the supervision of a qualified pharmacist). See, e.g., HHS. Fourth
Amendment to the Declaration Under the Public Readiness and Emergency Preparedness Act for Medical
Countermeasures Against COVID-19 and Republication of the Declaration. 85 FR 79190 (December 9, 2020).
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o a third primary series dose to individuals 12 years of age or older who have
undergone solid organ transplantation, or who are diagnosed with conditions that
are considered to have an equivalent level of immunocompromise;
o a single booster dose at least 6 months after completion of a primary series of the
vaccine to individuals: 65 years of age or older; 18 through 64 years of age at high
risk of severe COVID-19; and 18 through 64 years of age with frequent
institutional or occupational exposure to SARS-CoV-2; and
o a single booster dose as a heterologous booster dose following completion of
primary vaccination with another authorized COVID-19 vaccine, where the
eligible population(s) and dosing interval for the heterologous booster dose are
the same as those authorized for a booster dose of the vaccine used for primary
vaccination.
Pfizer- may be administered by a vaccination provider
without an individual prescription for each vaccine recipient.
This authorization also covers the use of the licensed COMIRNATY (COVID-19 Vaccine,
mRNA) product when used to provide: (1) a two-dose primary regimen (0.3 mL each, 3 weeks
apart) for individuals aged 12 through 15 years; (2) a third primary series dose at least 28 days
following the second dose to individuals 12 years of age or older who have undergone solid
organ transplantation or who are diagnosed with conditions that are considered to have an
equivalent level of immunocompromise; (3) a single booster dose (0.3 mL) at least 6 months
after completion of the primary series to individuals 65 years of age and older, 18 through 64
years of age at high risk of severe COVID-19, and 18 through 64 years of age with frequent
institutional or occupational exposure to SARS-CoV-2; and (4) a single booster dose (0.3 mL) as
a heterologous booster dose following completion of primary vaccination with another
authorized COVID-19 vaccine, where the eligible population(s) and dosing interval for the
heterologous booster dose are the same as those authorized for a booster dose of the vaccine used
for primary vaccination.
Product Description 18
The Pfizer-BioNTech COVID-19 Vaccine is supplied as a frozen suspension in multiple dose

vials; each vial must be diluted with 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP
prior to use to form the vaccine. The Pfizer-BioNTech COVID-19 Vaccine does not contain a
preservative.
Each 0.3 mL dose of the Pfizer-BioNTech COVID-19 Vaccine contains 30 mcg of a nucleoside-
modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2.
Each dose of the Pfizer-BioNTech COVID-19 Vaccine also includes the following ingredients:
lipids (0.43 mg (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg
2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-
phosphocholine, and 0.2 mg cholesterol), 0.01 mg potassium chloride, 0.01 mg monobasic
18
For COMIRNATY (COVID-19 Vaccine, mRNA) product description, please see the COMIRNATY (COVID-19
Vaccine, mRNA) prescribing information, found here:
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potassium phosphate, 0.36 mg sodium chloride, 0.07 mg dibasic sodium phosphate dihydrate,
and 6 mg sucrose. The diluent (0.9% Sodium Chloride Injection) contributes an additional 2.16
mg sodium chloride per dose.
The manufacture of the authorized Pfizer- is limited to those

facilities identified and agreed upon in Pfizer’s request for authorization.
The Pfizer-BioNTech COVID-19 Vaccine vial label and carton labels are clearly marked for
“Emergency Use Authorization.” The Pfizer- is authorized to be
distributed, stored, further redistributed, and administered by emergency response stakeholders
when packaged in the authorized manufacturer packaging (i.e., vials and cartons), despite the
fact that the vial and carton labels may not contain information that otherwise would be required
under the FD&C Act.
Pfizer- is authorized for emergency use with the following

product-specific information required to be made available to vaccination providers and
recipients, respectively (referred to as “authorized labeling”):
Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination Providers):

Emergency Use Authorization (EUA) of Pfizer- to Prevent
Coronavirus Disease 2019 (COVID-19)
Vaccine Information Fact Sheet for Recipients and Caregivers About COMIRNATY
(COVID-19 Vaccine, mRNA) and Pfizer-BioNTech COVID-19 Vaccine to Prevent
Coronavirus Disease (COVID-19)
I have concluded, pursuant to Section 564(d)(2) of the Act, that it is reasonable to believe that
the known and potential benefits of Pfizer- , 19 when used to
prevent COVID-19 and used in accordance with this Scope of Authorization (Section II),
outweigh its known and potential risks.
I have concluded, pursuant to Section 564(d)(3) of the Act, based on the totality of scientific
evidence available to FDA, that it is reasonable to believe that Pfizer-
Vaccine may be effective in preventing COVID-19 when used in accordance with this Scope of
Authorization (Section II), pursuant to Section 564(c)(2)(A) of the Act.
Having reviewed the scientific information available to FDA, including the information
supporting the conclusions described in Section I above, I have concluded that Pfizer-BioNTech
(as described in this Scope of Authorization (Section II)) meets the criteria set
forth in Section 564(c) of the Act concerning safety and potential effectiveness.
The emergency use of Pfizer- under this EUA must be consistent

with, and may not exceed, the terms of the Authorization, including the Scope of Authorization
(Section II) and the Conditions of Authorization (Section III). Subject to the terms of this EUA and
19
The conclusions supporting authorization stated in this section (Section II) also apply to COMIRNATY (COVID-
19 Vaccine, mRNA).
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under the circumstances set forth in the Secretary of HHS’s determination under Section
564(b)(1)(C) described above and the Secretary of HHS’s corresponding declaration under Section
564(b)(1), Pfizer- is authorized to prevent COVID-19 in individuals
12 years of age and older as described in the Scope of Authorization (Section II) under this EUA,
despite the fact that it does not meet certain requirements otherwise required by applicable federal
law.
III. Conditions of Authorization
Pursuant to Section 564 of the Act, I am establishing the following conditions on this authorization:
Pfizer Inc. and Authorized Distributor(s)
A. Pfizer Inc. and authorized distributor(s) will ensure that the authorized Pfizer-
Vaccine is distributed, as directed by the U.S. government,
including CDC and/or other designee, and the authorized labeling (i.e., Fact Sheets)
will be made available to vaccination providers, recipients, and caregivers consistent
with the terms of this letter.
B. Pfizer Inc. and authorized distributor(s) will ensure that appropriate storage and cold
chain is maintained until delivered to emergency response stakeholders’ receipt sites.
C. Pfizer Inc. will ensure that the terms of this EUA are made available to all relevant
stakeholders (e.g., emergency response stakeholders, authorized distributors, and
vaccination providers) involved in distributing or receiving authorized Pfizer-
. Pfizer Inc. will provide to all relevant stakeholders a
copy of this letter of authorization and communicate any subsequent amendments that
might be made to this letter of authorization and its authorized labeling.
D. Pfizer Inc. may develop and disseminate instructional and educational materials (e.g.,
video regarding vaccine handling, storage/cold-chain management, preparation,
disposal) that are consistent with the authorized emergency use of the vaccine as
described in the letter of authorization and authorized labeling, without FDA’s review
and concurrence, when necessary to meet public health needs during an emergency.
Any instructional and educational materials that are inconsistent with the authorized
labeling are prohibited.
E. Pfizer Inc. may request changes to this authorization, including to the authorized Fact
Sheets for the vaccine. Any request for changes to this EUA must be submitted to
Office of Vaccines Research and Review (OVRR)/Center for Biologics Evaluation
and Research (CBER). Such changes require appropriate authorization prior to
implementation.20
20
The following types of revisions may be authorized without reissuing this letter: (1) changes to the authorized
labeling; (2) non-substantive editorial corrections to this letter; (3) new types of authorized labeling, including new
fact sheets; (4) new carton/container labels; (5) expiration dating extensions; (6) changes to manufacturing
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F. Pfizer Inc. will report to Vaccine Adverse Event Reporting System (VAERS):
Serious adverse events (irrespective of attribution to vaccination);
Cases of Multisystem Inflammatory Syndrome in children and adults; and
Cases of COVID-19 that result in hospitalization or death, that are reported to
Pfizer Inc.
These reports should be submitted to VAERS as soon as possible but no later than
15 calendar days from initial receipt of the information by Pfizer Inc.
G. Pfizer Inc. must submit to Investigational New Drug application (IND) number
19736 periodic safety reports at monthly intervals in accordance with a due date
agreed upon with the Office of Biostatistics and Epidemiology (OBE)/CBER
beginning after the first full calendar month after authorization. Each periodic safety
report is required to contain descriptive information which includes:
A narrative summary and analysis of adverse events submitted during the
reporting interval, including interval and cumulative counts by age groups, special
populations (e.g., pregnant women), and adverse events of special interest;
A narrative summary and analysis of vaccine administration errors, whether or
not associated with an adverse event, that were identified since the last reporting
interval;
Newly identified safety concerns in the interval; and
Actions taken since the last report because of adverse experiences (for example,
changes made to Healthcare Providers Administering Vaccine (Vaccination
Providers) Fact Sheet, changes made to studies or studies initiated).
H. No changes will be implemented to the description of the product, manufacturing

process, facilities, or equipment without notification to and concurrence by FDA.
I. All manufacturing facilities will comply with Current Good Manufacturing Practice
requirements.
J. Pfizer Inc. will submit to the EUA file Certificates of Analysis (CoA) for each drug
product lot at least 48 hours prior to vaccine distribution. The CoA will include the
established specifications and specific results for each quality control test performed
on the final drug product lot.
K. Pfizer Inc. will submit to the EUA file quarterly manufacturing reports, starting in
July 2021, that include a listing of all Drug Substance and Drug Product lots
produced after issuance of this authorization. This report must include lot number,
manufacturing site, date of manufacture, and lot disposition, including those lots that
processes, including tests or other authorized components of manufacturing; (7) new conditions of authorization to
require data collection or study. For changes to the authorization, including the authorized labeling, of the type
listed in (3), (6), or (7), review and concurrence is required from the Preparedness and Response Team
(PREP)/Office of the Center Director (OD)/CBER and the Office of Counterterrorism and Emerging Threats
(OCET)/Office of the Chief Scientist (OCS).
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were quarantined for investigation or those lots that were rejected. Information on the
reasons for lot quarantine or rejection must be included in the report.
L. Pfizer Inc. and authorized distributor(s) will maintain records regarding release of
Pfizer- for distribution (i.e., lot numbers, quantity,
release date).
M. Pfizer Inc. and authorized distributor(s) will make available to FDA upon request any
records maintained in connection with this EUA.
N. Pfizer Inc. will conduct post-authorization observational studies to evaluate the

association between Pfizer-BioNTech COVID-19 Vaccine and a pre-specified list of
adverse events of special interest, including myocarditis and pericarditis, along with
deaths and hospitalizations, and severe COVID-19. The study population should
include individuals administered the authorized Pfizer-BioNTech COVID-19
Vaccine under this EUA in the general U.S. population (12 years of age and older),
individuals who receive a booster dose, populations of interest such as healthcare
workers, pregnant women, immunocompromised individuals, subpopulations with
specific comorbidities. The studies should be conducted in large scale databases with
an active comparator. Pfizer Inc. will provide protocols and status update reports to
the IND 19736 with agreed-upon study designs and milestone dates.
Emergency Response Stakeholders
O. Emergency response stakeholders will identify vaccination sites to receive authorized

Pfizer- and ensure its distribution and administration,
consistent with the terms of this letter and CDC’s COVID-19 Vaccination Program.
P. Emergency response stakeholders will ensure that vaccination providers within their
jurisdictions are aware of this letter of authorization, and the terms herein and any
subsequent amendments that might be made to the letter of authorization, instruct
them about the means through which they are to obtain and administer the vaccine
under the EUA, and ensure that the authorized labeling [i.e., Fact Sheet for Healthcare
Providers Administering Vaccine (Vaccination Providers) and Vaccine Information
Fact Sheet for Recipients and Caregivers] is made available to vaccination providers
through appropriate means (e.g., e-mail, website).
Q. Emergency response stakeholders receiving authorized Pfizer-

Vaccine will ensure that appropriate storage and cold chain is maintained.
Vaccination Providers
R. Vaccination providers will administer the vaccine in accordance with the

authorization and will participate and comply with the terms and training required by
CDC’s COVID-19 Vaccination Program.
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S. Vaccination providers will provide the Vaccine Information Fact Sheet for Recipients
and Caregivers to each individual receiving vaccination and provide the necessary
information for receiving their second dose and/or third dose.
T. Vaccination providers administering the vaccine must report the following

information associated with the administration of the vaccine of which they become
aware to VAERS in accordance with the Fact Sheet for Healthcare Providers
Administering Vaccine (Vaccination Providers):
Vaccine administration errors whether or not associated with an adverse event
Serious adverse events (irrespective of attribution to vaccination)
Cases of Multisystem Inflammatory Syndrome in children and adults
Cases of COVID-19 that result in hospitalization or death
Complete and submit reports to VAERS online at
https://vaers.hhs.gov/reportevent.html. The VAERS reports should include the
words “Pfizer- EUA” in the description section of
the report. More information is available at vaers.hhs.gov or by calling 1-800-822-
7967. To the extent feasible, report to Pfizer Inc. by contacting 1-800-438-1985 or
by providing a copy of the VAERS form to Pfizer Inc.; Fax: 1-866-635-8337.
U. Vaccination providers will conduct any follow-up requested by the U.S

government, including CDC, FDA, or other designee, regarding adverse events to
the extent feasible given the emergency circumstances.
V. Vaccination providers will monitor and comply with CDC and/or emergency
response stakeholder vaccine management requirements (e.g., requirements
concerning obtaining, tracking, and handling vaccine) and with requirements
concerning reporting of vaccine administration data to CDC.
W. Vaccination providers will ensure that any records associated with this EUA are
maintained until notified by FDA. Such records will be made available to CDC,
and FDA for inspection upon request.
Conditions Related to Printed Matter, Advertising, and Promotion
X. All descriptive printed matter, advertising, and promotional material, relating to the
use of the Pfizer- shall be consistent with the
authorized labeling, as well as the terms set forth in this EUA, and meet the
requirements set forth in Section 502(a) and (n) of the FD&C Act and FDA
implementing regulations.
Y. All descriptive printed matter, advertising, and promotional material relating to the
use of the Pfizer- clearly and conspicuously shall state
that:
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This product has not been approved or licensed by FDA, but has been authorized
for emergency use by FDA, under an EUA to prevent Coronavirus Disease 2019
(COVID-19) for use in individuals 12 years of age and older; and
The emergency use of this product is only authorized for the duration of the
declaration that circumstances exist justifying the authorization of emergency use
of the medical product under Section 564(b)(1) of the FD&C Act unless the
declaration is terminated or authorization revoked sooner.
Condition Related to Export
Z. If the Pfizer- is exported from the United States,

conditions C, D, and O through Y do not apply, but export is permitted only if 1) the
regulatory authorities of the country in which the vaccine will be used are fully
informed that this vaccine is subject to an EUA and is not approved or licensed by
FDA and 2) the intended use of the vaccine will comply in all respects with the laws
of the country in which the product will be used. The requirement in this letter that
the authorized labeling (i.e., Fact Sheets) be made available to vaccination providers,
recipients, and caregivers in condition A will not apply if the authorized labeling (i.e.,
Fact Sheets) are made available to the regulatory authorities of the country in which
the vaccine will be used.
Conditions With Respect to Use of Licensed Product
AA. COMIRNATY (COVID-19 Vaccine, mRNA) is licensed for individuals 16 years of

age and older. There remains, however, a significant amount of Pfizer-BioNTech
COVID-19 Vaccine that was manufactured and labeled in accordance with this
emergency use authorization. The authorization remains in place with respect to the
Pfizer-BioNTech COVID-19 Vaccine for this population.
BB. This authorization also covers the use of the licensed COMIRNATY (COVID-19
Vaccine, mRNA) product when used to provide: (1) a two-dose primary regimen for
individuals aged 12 through 15 years; (2) a third primary series dose to individuals 12
years of age or older who have undergone solid organ transplantation or who are
diagnosed with conditions that are considered to have an equivalent level of
immunocompromise; (3) a single booster dose at least 6 months after completing the
primary series to individuals 65 years of age or older, 18 through 64 years of age at
high risk of severe COVID-19, and 18 through 64 years of age with frequent
institutional or occupational exposure to SARS-CoV-2; and (4) a heterologous
booster dose to certain individuals who have completed primary vaccination with a
different authorized COVID-19 vaccine as described in the Scope of Authorization
(Section II) under this EUA. Conditions A through W in this letter apply when
COMIRNATY (COVID-19 Vaccine, mRNA) is provided for the uses described in
this subsection III.BB., except that product manufactured and labeled in accordance
with the approved BLA is deemed to satisfy the manufacturing, labeling, and
distribution requirements of this authorization.
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IV. Duration of Authorization
This EUA will be effective until the declaration that circumstances exist justifying the
authorization of the emergency use of drugs and biological products during the COVID-19
pandemic is terminated under Section 564(b)(2) of the Act or the EUA is revoked under Section
564(g) of the Act.
Sincerely,
--/S/--
____________________________
Jacqueline A. O'Shaughnessy, Ph.D.
Acting Chief Scientist
Enclosures
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Marks Decl.
Exhibit C
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August 23, 2021
Pfizer Inc.
Attention: Ms. Elisa Harkins
500 Arcola Road
Collegeville, PA 19426
Dear Ms. Harkins:
On February 4, 2020, pursuant to Section 564(b)(1)(C) of the Federal Food, Drug, and Cosmetic
Act (the FD&C Act or the Act), the Secretary of the Department of Health and Human Services
(HHS) determined that there is a public health emergency that has a significant potential to affect
national security or the health and security of United States citizens living abroad, and that
involves the virus that causes Coronavirus Disease 2019 (COVID-19). 1 On the basis of such
determination, the Secretary of HHS on March 27, 2020, declared that circumstances exist
justifying the authorization of emergency use of drugs and biological products during the
COVID-19 pandemic, pursuant to Section 564 of the Act (21 U.S.C. 360bbb-3), subject to terms
of any authorization issued under that section. 2
On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use
Authorization (EUA) for emergency use of Pfizer- the
prevention of COVID-19 for individuals 16 years of age and older pursuant to Section 564 of the
Act. FDA reissued the letter of authorization on: December 23, 2020, 3 February 25, 2021, 4 May
1
U.S. Department of Health and Human Services, Determination of a Public Health Emergency and Declaration that
Circumstances Exist Justifying Authorizations Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic
Act, 21 U.S.C. § 360bbb-3. February 4, 2020.
2
U.S. Department of Health and Human Services, Declaration that Circumstances Exist Justifying Authorizations
Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3, 85 FR 18250
(April 1, 2020).
3
In the December 23, 2020 revision, FDA removed reference to the number of doses per vial after dilution from the
letter of authorization, clarified the instructions for vaccination providers reporting to VAERS, and made other
technical corrections. FDA also revised the Fact Sheet for Healthcare Providers Administering Vaccine
(Vaccination Providers) to clarify the number of doses of vaccine per vial after dilution and the instructions for
reporting to VAERS. In addition, the Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination
Providers) and the Fact Sheet for Recipients and Caregivers were revised to include additional information on safety
monitoring and to clarify information about the availability of other COVID-19 vaccines.
4
In the February 25, 2021 revision, FDA allowed flexibility on the date of submission of monthly periodic safety
reports and revised the requirements for reporting of vaccine administration errors by Pfizer Inc. The Fact Sheet for
Health Care Providers Administering Vaccine (Vaccination Providers) was revised to provide an update to the
storage and transportation temperature for frozen vials, direct the provider to the correct CDC website for
information on monitoring vaccine recipients for the occurrence of immediate adverse reactions, to include data
from a developmental toxicity study, and add adverse reactions that have been identified during post authorization
use. The Fact Sheet for Recipients and Caregivers was revised to add adverse reactions that have been identified
during post authorization use.
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10, 2021, 5 June 25, 2021, 6 and August 12, 2021. 7
On August 23, 2021, FDA approved the biologics license application (BLA) submitted by
BioNTech Manufacturing GmbH for COMIRNATY (COVID-19 Vaccine, mRNA) for active
immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 16 years of age and
older.
On August 23, 2021, having concluded that revising this EUA is appropriate to protect the public
health or safety under section 564(g)(2) of the Act, FDA is reissuing the August 12, 2021 letter
of authorization in its entirety with revisions incorporated to clarify that the EUA will remain in
place for the Pfizer-BioNTech COVID-19 vaccine for the previously-authorized indication and
uses, and to authorize use of COMIRNATY (COVID-19 Vaccine, mRNA) under this EUA for
certain uses that are not included in the approved BLA. In addition, the Fact Sheet for
Healthcare Providers Administering Vaccine (Vaccination Providers) was revised to provide
updates on expiration dating of the authorized Pfizer-BioNTech COVID-19 Vaccine and to
update language regarding warnings and precautions related to myocarditis and pericarditis. The
Fact Sheet for Recipients and Caregivers was updated as the Vaccine Information Fact Sheet for
Recipients and Caregivers, which comprises the Fact Sheet for the authorized Pfizer-BioNTech
COVID-19 Vaccine and information about the FDA-licensed vaccine, COMIRNATY (COVID-
19 Vaccine, mRNA).
Pfizer- contains a nucleoside-modified messenger RNA

(modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 formulated in lipid
particles. COMIRNATY (COVID-19 Vaccine, mRNA) is the same formulation as the Pfizer-
BioNTech COVID-19 Vaccine and can be used interchangeably with the Pfizer-BioNTech
COVID-19 Vaccine to provide the COVID-19 vaccination series. 8
5
In the May 10, 2021 revision, FDA authorized Pfizer-BioNTech Vaccine for the prevention of COVID-19 in
individuals 12 through 15 years of age, as well as for individuals 16 years of age and older. In addition, FDA
revised the Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination Providers) to include the
particular in adolescents. Procedures should be in place to avoid injury from

for Recipients and Caregivers was revised to instruct vaccine recipients or their caregivers to tell the vaccination
provider about fainting in association with a previous injection.
6
In the June 25, 2021 revision, FDA clarified terms and conditions that relate to export of Pfizer-BioNTech
In addition, the Fact Sheet for Healthcare Providers Administering
Vaccine (Vaccination Providers) was revised to include a Warning about myocarditis and pericarditis following
administration of the Pfizer-BioNTech COVID-19 Vaccine. The Fact Sheet for Recipients and Caregivers was
updated to include information about myocarditis and pericarditis following administration of the Pfizer-BioNTech
7
In the August 12, 2021 revision, FDA authorized a third dose of the Pfizer-BioNTech COVID-19 Vaccine
administered at least 28 days following the two dose regimen of this vaccine in individuals 12 years of age or older
who have undergone solid organ transplantation, or individuals 12 years of age or older who are diagnosed with
8
The licensed vaccine has the same formulation as the EUA-authorized vaccine and the products can be used
interchangeably to provide the vaccination series without presenting any safety or effectiveness concerns. The
products are legally distinct with certain differences that do not impact safety or effectiveness.
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For the December 11, 2020 authorization for individuals 16 years of age and older, FDA
reviewed safety and efficacy data from an ongoing phase 1/2/3 trial in approximately 44,000
participants randomized 1:1 to receive Pfizer-BioNTech accine or saline control.
The trial has enrolled participants 12 years of review at that time
considered the safety and effectiveness data as they relate to the request for emergency use
authorization in individuals 16 year of the available safety data
from 37,586 of the participants 16 years of age and older, who were followed for a median of
two months after receiving the second dose, did not identify specific safety concerns that would
of the available efficacy data from 36,523
participants 12 years of age and older without evidence of SARS-CoV-2 infection prior to 7 days
after dose 2 confirmed the vaccine was 95% effective (95% credible interval 90.3, 97.6) in
preventing COVID-19 occurring at least 7 days after the second dose (with 8 COVID-19 cases in
the vaccine group compared to 162 COVID-19 cases in the placebo group). Based on these data,
and review of manufacturing information regarding product quality and consistency, FDA
concluded that it is reasonable to believe that Pfizer- may be
effective. Additionally, FDA determined it is reasonable to conclude, based on the totality of the
scientific evidence available, that the known and potential benefits of Pfizer-BioNTech
outweigh the known and potential risks of the vaccine, for the prevention of
COVID-19 in individuals 16 years of age and older. Finally, on December 10, 2020, the
Vaccines and Related Biological Products Advisory Committee voted in agreement with this
conclusion.
For the May 10, 2021 authorization for individuals 12 through 15 years of age, FDA reviewed
safety and effectiveness data from the above-referenced, ongoing Phase 1/2/3 trial that has
enrolled approximately 46,000 participants, including 2,260 participants 12 through 15 years of
age. Trial participants were randomized 1:1 to receive Pfizer-BioNTech COVID-19 Vaccine or
e safety data from 2,260 participants 12 through 15
years of age, who were followed for a median of 2 months after receiving the second dose, did
not identify specific safety concerns that would preclude issuance of
SARS-CoV-2 50% neutralizing antibody titers 1 month after the second dose of Pfizer-
BioNTech COVID-19 Vaccine in a subset of participants who had no serological or virological
evidence of past SARS-CoV-2 infection confirm the geometric mean antibody titer in
participants 12 through 15 years of age was non-inferior to the geometric mean antibody titer in
alysis of available descriptive efficacy data
from 1,983 participants 12 through 15 years of age without evidence of SARS-CoV-2 infection
prior to 7 days after dose 2 confirm that the vaccine was 100% effective (95% confidence
interval 75.3, 100.0) in preventing COVID-19 occurring at least 7 days after the second dose
(with no COVID-19 cases in the vaccine group compared to 16 COVID-19 cases in the placebo
group). Based on these data, FDA concluded that it is reasonable to believe that Pfizer-
Additionally, FDA determined it is reasonable to conclude, based on the totality of the scientific
evidence available, that the known and potential benefits of Pfizer-
Vaccine outweigh the known and potential risks of the vaccine, for the prevention of COVID-19
in individuals 12 through 15 years of age.
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For the August 12, 2021 authorization of a third dose of the Pfizer-BioNTech COVID-19
Vaccine in individuals 12 years of age or older who have undergone solid organ transplantation,
or individuals 12 years of age or older who are diagnosed with conditions that are considered to
have an equivalent level of immunocompromise, FDA reviewed safety and effectiveness data
reported in two manuscripts on solid organ transplant recipients. The first study was a single
arm study conducted in 101 individuals who had undergone various solid organ transplant
procedures (heart, kidney, liver, lung, pancreas) a median of 97±8 months earlier. A third dose
of the Pfizer-BioNTech COVID-19 Vaccine was administered to 99 of these individuals
approximately 2 months after they had received a second dose. Levels of total SARS-CoV-2
binding antibodies meeting the pre-specified criteria for success occurred four weeks after the
third dose in 26/59 (44.0%) of those who were initially considered to be seronegative and
received a third dose of the Pfizer-BioNTech COVID-19 Vaccine; 67/99 (68%) of the entire
group receiving a third vaccination were subsequently considered to have levels of antibodies
indicative of a significant response. In those who received a third vaccine dose, the adverse
event profile was similar to that after the second dose and no grade 3 or grade 4 events were
reported. A supportive secondary study describes a double-blind, randomized-controlled study
conducted in 120 individuals who had undergone various solid organ transplant procedures
(heart, kidney, kidney-pancreas, liver, lung, pancreas) a median of 3.57 years earlier (range 1.99-
6.75 years). A third dose of a similar mRNA vaccine (the Moderna COVID-19 vaccine) was
administered to 60 individuals approximately 2 months after they had received a second dose
(i.e., doses at 0, 1 and 3 months); saline placebo was given to 60 individuals or comparison. The
primary outcome was anti-RBD antibody at 4 months greater than 100 U/mL. This titer was
selected based on NHP challenge studies as well as a large clinical cohort study to indicate this
antibody titer was protective. Secondary outcomes were based on a virus neutralization assay
and polyfunctional T cell responses. Baseline characteristics were comparable between the two
study arms as were pre-intervention anti-RBD titer and neutralizing antibodies. Levels of total
SARS-CoV-2 binding antibodies indicative of a significant response occurred four weeks after
the third dose in 33/60 (55.0%) of the Moderna COVID-19 vaccinated group and 10/57 (17.5%)
of the placebo individuals. In the 60 individuals who received a third vaccine dose, the adverse
event profile was similar to that after the second dose and no grade 3 or grade 4 adverse events
were reported. Despite the moderate enhancement in antibody titers, the totality of data (i.e.,
supportive paper by Hall et al. demonstrated efficacy of the product in the elderly and persons
with co-morbidities) supports the conclusion that a third dose of the Pfizer-BioNTech COVID-19
vaccine may be effective in this population, and that the known and potential benefits of a third
dose of Pfizer-BioNTech COVID-19 Vaccine outweigh the known and potential risks of the
vaccine for immunocompromised individuals at least 12 years of age who have received two
doses of the Pfizer-BioNTech COVID-19 Vaccine and who have undergone solid organ
transplantation, or who are diagnosed with conditions that are considered to have an equivalent
Having concluded that the criteria for issuance of this authorization under Section 564(c) of the
Act are met, I am authorizing the emergency use of Pfizer- for the
prevention of COVID-19, as described in the Scope of Authorization section of this letter
(Section II) and subject to the terms of this authorization. Additionally, as specified in
subsection III.BB, I am authorizing use of COMIRNATY (COVID-19 Vaccine, mRNA) under
this EUA when used to provide a two-dose regimen for individuals aged 12 through 15 years, or
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to provide a third dose to individuals 12 years of age or older who have undergone solid organ
transplantation or who are diagnosed with conditions that are considered to have an equivalent
I. Criteria for Issuance of Authorization
I have concluded that the emergency use of Pfizer- for the

prevention of COVID-19 when administered as described in the Scope of Authorization (Section
II) meets the criteria for issuance of an authorization under Section 564(c) of the Act, because:
A. SARS-CoV-2 can cause a serious or life-threatening disease or condition, including

severe respiratory illness, to humans infected by this virus;
B. Based on the totality of scientific evidence available to FDA, it is reasonable to believe

that Pfizer- may be effective in preventing COVID-19,
and that, when used under the conditions described in this authorization, the known and
potential benefits of Pfizer- when used to prevent
COVID-19 outweigh its known and potential risks; and
C. There is no adequate, approved, and available 9 alternative to the emergency use of

Pfizer- to prevent COVID-19. 10
II. Scope of Authorization
I have concluded, pursuant to Section 564(d)(1) of the Act, that the scope of this authorization is
limited as follows:
Pfizer Inc. will supply Pfizer- either directly or through

authorized distributor(s), 11 to emergency response stakeholders 12 as directed by the U.S.
9
Although COMIRNATY (COVID-19 Vaccine, mRNA) is approved to prevent COVID-19 in individuals 16 years
of age and older, there is not sufficient approved vaccine available for distribution to this population in its entirety at
the time of reissuance of this EUA. Additionally, there are no products that are approved to prevent COVID-19 in
individuals age 12 through 15, or that are approved to provide an additional dose to the immunocompromised
population described in this EUA.
10
No other criteria of issuance have been prescribed by regulation under Section 564(c)(4) of the Act.
11
identified by Pfizer Inc. or, if applicable, by a U.S. government entity, such as the
Centers for Disease Control and Prevention (CDC) and/or other designee, as an entity or entities allowed to
distribute authorized Pfizer-BioNTec
12
that have legal responsibility and authority for responding to an incident, based on political or geographical
boundary lines (e.g., city, county, tribal, territorial, State, or Federal), or functional (e.g., law enforcement or public
health range) or sphere of authority to administer, deliver, or distribute vaccine in an emergency situation. In some
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government, including the Centers for Disease Control and Prevention (CDC) and/or
other designee, for use consistent with the terms and conditions of this EUA;
The Pfizer- covered by this authorization will be
13
administered by vaccination providers and used only to prevent COVID-19 in
individuals ages 12 and older; and
Pfizer- may be administered by a vaccination provider
without an individual prescription for each vaccine recipient.
This authorization also covers the use of the licensed COMIRNATY (COVID-19 Vaccine,
mRNA) product when used to provide a two-dose regimen for individuals aged 12 through 15
years, or to provide a third dose to individuals 12 years of age or older who have undergone solid
organ transplantation or who are diagnosed with conditions that are considered to have an
equivalent level of immunocompromise.
Product Description
The Pfizer-BioNTech COVID-19 Vaccine is supplied as a frozen suspension in multiple dose

vials; each vial must be diluted with 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP
prior to use to form the vaccine. The Pfizer-BioNTech COVID-19 Vaccine does not contain a
preservative.
Each 0.3 mL dose of the Pfizer-BioNTech COVID-19 Vaccine contains 30 mcg of a nucleoside-
modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2.
Each dose of the Pfizer-BioNTech COVID-19 Vaccine also includes the following ingredients:
lipids (0.43 mg (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg
2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-
phosphocholine, and 0.2 mg cholesterol), 0.01 mg potassium chloride, 0.01 mg monobasic
potassium phosphate, 0.36 mg sodium chloride, 0.07 mg dibasic sodium phosphate dihydrate,
and 6 mg sucrose. The diluent (0.9% Sodium Chloride Injection) contributes an additional 2.16
mg sodium chloride per dose.
official capacity under the authority of the state health department to administer COVID-19 vaccines). In such
cases, it is expected that the conditions of authorization that apply to emergency response stakeholders and
vaccination providers will all be met.
13
, organization, or healthcare provider
licensed or otherwise authorized by the emergency response stakeholder (e.g., non-physician healthcare
professionals, such as nurses and pharmacists pursuant to state law under a standing order issued by the state health
officer) to administer or provide vaccination services in accordance with the applicable emergency response
D-19 vaccination and emergency response plan(s) and who is enrolled in the CDC
COVID-19 Vaccination Program. If the vaccine is exported
provider that is authorized to administer this vaccine in accordance with the laws of the country in which it is
administered. For purposes of this lett so refers to a person authorized by the U.S.
Department of Health and Human Services (e.g., under the PREP Act Declaration for Medical Countermeasures
against COVID-19) to administer FDA-authorized COVID-19 vaccine (e.g., qualified pharmacy technicians and
State-authorized pharmacy interns acting under the supervision of a qualified pharmacist). See, e.g., HHS. Fourth
Amendment to the Declaration Under the Public Readiness and Emergency Preparedness Act for Medical
Countermeasures Against COVID-19 and Republication of the Declaration. 85 FR 79190 (December 9, 2020).
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The dosing regimen is two doses of 0.3 mL each, 3 weeks apart. A third dose may be
administered at least 28 days following the second dose of the two dose regimen of this vaccine
to individuals 12 years of age or older who have undergone solid organ transplantation, or
individuals 12 years of age or older who are diagnosed with conditions that are considered to
have an equivalent level of immunocompromise.
The manufacture of the authorized Pfizer- is limited to those

facilities identified and agreed upon in r authorization.
The Pfizer-BioNTech COVID-19 Vaccine vial label and carton labels are clearly marked for
Vaccine is authorized to be
distributed, stored, further redistributed, and administered by emergency response stakeholders
when packaged in the authorized manufacturer packaging (i.e., vials and cartons), despite the
fact that the vial and carton labels may not contain information that otherwise would be required
under the FD&C Act.
Pfizer- is authorized for emergency use with the following

product-specific information required to be made available to vaccination providers and
recipients, respectively (referred
Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination Providers):

Emergency Use Authorization (EUA) of Pfizer- to Prevent
Coronavirus Disease 2019 (COVID-19)
Vaccine Information Fact Sheet for Recipients and Caregivers About COMIRNATY
(COVID-19 Vaccine, mRNA) and Pfizer-BioNTech COVID-19 Vaccine to Prevent
Coronavirus Disease (COVID-19).
I have concluded, pursuant to Section 564(d)(2) of the Act, that it is reasonable to believe that
the known and potential benefits of Pfizer- , when used to prevent
COVID-19 and used in accordance with this Scope of Authorization (Section II), outweigh its
known and potential risks.
I have concluded, pursuant to Section 564(d)(3) of the Act, based on the totality of scientific
evidence available to FDA, that it is reasonable to believe that Pfizer-
Vaccine may be effective in preventing COVID-19 when used in accordance with this Scope of
Authorization (Section II), pursuant to Section 564(c)(2)(A) of the Act.
Having reviewed the scientific information available to FDA, including the information
supporting the conclusions described in Section I above, I have concluded that Pfizer-BioNTech
(as described in this Scope of Authorization (Section II)) meets the criteria set
forth in Section 564(c) of the Act concerning safety and potential effectiveness.
The emergency use of Pfizer- under this EUA must be consistent

with, and may not exceed, the terms of the Authorization, including the Scope of Authorization
(Section II) and the Conditions of Authorization (Section III). Subject to the terms of this EUA and
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under the circumstances set fort determination under Section

564(b)(1)(C) described above and ing declaration under Section
564(b)(1), Pfizer- is authorized to prevent COVID-19 in individuals
12 years of age and older as described in the Scope of Authorization (Section II) under this EUA,
despite the fact that it does not meet certain requirements otherwise required by applicable federal
law.
III. Conditions of Authorization
Pursuant to Section 564 of the Act, I am establishing the following conditions on this authorization:
Pfizer Inc. and Authorized Distributor(s)
A. Pfizer Inc. and authorized distributor(s) will ensure that the authorized Pfizer-
is distributed, as directed by the U.S. government,
including CDC and/or other designee, and the authorized labeling (i.e., Fact Sheets)
will be made available to vaccination providers, recipients, and caregivers consistent
with the terms of this letter.
B. Pfizer Inc. and authorized distributor(s) will ensure that appropriate storage and cold
chain is maintained until delivered to emergency response stakehol
C. Pfizer Inc. will ensure that the terms of this EUA are made available to all relevant
stakeholders (e.g., emergency response stakeholders, authorized distributors, and
vaccination providers) involved in distributing or receiving authorized Pfizer-
. Pfizer Inc. will provide to all relevant stakeholders a
copy of this letter of authorization and communicate any subsequent amendments that
might be made to this letter of authorization and its authorized labeling.
D. Pfizer Inc. may develop and disseminate instructional and educational materials (e.g.,
video regarding vaccine handling, storage/cold-chain management, preparation,
disposal) that are consistent with the authorized emergency use of the vaccine as
described in the letter of authorization and authorized
and concurrence, when necessary to meet public health needs during an emergency.
Any instructional and educational materials that are inconsistent with the authorized
labeling are prohibited.
E. Pfizer Inc. may request changes to this authorization, including to the authorized Fact
Sheets for the vaccine. Any request for changes to this EUA must be submitted to
Office of Vaccines Research and Review (OVRR)/Center for Biologics Evaluation
and Research (CBER). Such changes require appropriate authorization prior to
implementation.14
14
The following types of revisions may be authorized without reissuing this letter: (1) changes to the authorized
labeling; (2) non-substantive editorial corrections to this letter; (3) new types of authorized labeling, including new
fact sheets; (4) new carton/container labels; (5) expiration dating extensions; (6) changes to manufacturing
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F. Pfizer Inc. will report to Vaccine Adverse Event Reporting System (VAERS):
Serious adverse events (irrespective of attribution to vaccination);
Cases of Multisystem Inflammatory Syndrome in children and adults; and
Cases of COVID-19 that result in hospitalization or death, that are reported to
Pfizer Inc.
These reports should be submitted to VAERS as soon as possible but no later than
15 calendar days from initial receipt of the information by Pfizer Inc.
G. Pfizer Inc. must submit to Investigational New Drug application (IND) number
19736 periodic safety reports at monthly intervals in accordance with a due date
agreed upon with the Office of Biostatistics and Epidemiology (OBE)/CBER
beginning after the first full calendar month after authorization. Each periodic safety
report is required to contain descriptive information which includes:
A narrative summary and analysis of adverse events submitted during the
reporting interval, including interval and cumulative counts by age groups, special
populations (e.g., pregnant women), and adverse events of special interest;
A narrative summary and analysis of vaccine administration errors, whether or
not associated with an adverse event, that were identified since the last reporting
interval;
Newly identified safety concerns in the interval; and
Actions taken since the last report because of adverse experiences (for example,
changes made to Healthcare Providers Administering Vaccine (Vaccination
Providers) Fact Sheet, changes made to studies or studies initiated).
H. No changes will be implemented to the description of the product, manufacturing

process, facilities, or equipment without notification to and concurrence by FDA.
I. All manufacturing facilities will comply with Current Good Manufacturing Practice
requirements.
J. Pfizer Inc. will submit to the EUA file Certificates of Analysis (CoA) for each drug
product lot at least 48 hours prior to vaccine distribution. The CoA will include the
established specifications and specific results for each quality control test performed
on the final drug product lot.
K. Pfizer Inc. will submit to the EUA file quarterly manufacturing reports, starting in
July 2021, that include a listing of all Drug Substance and Drug Product lots
produced after issuance of this authorization. This report must include lot number,
manufacturing site, date of manufacture, and lot disposition, including those lots that
processes, including tests or other authorized components of manufacturing; (7) new conditions of authorization to
require data collection or study. For changes to the authorization, including the authorized labeling, of the type
listed in (3), (6), or (7), review and concurrence is required from the Preparedness and Response Team
(PREP)/Office of the Center Director (OD)/CBER and the Office of Counterterrorism and Emerging Threats
(OCET)/Office of the Chief Scientist (OCS).
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were quarantined for investigation or those lots that were rejected. Information on the
reasons for lot quarantine or rejection must be included in the report.
L. Pfizer Inc. and authorized distributor(s) will maintain records regarding release of
Pfizer-BioNTech for distribution (i.e., lot numbers, quantity,
release date).
M. Pfizer Inc. and authorized distributor(s) will make available to FDA upon request any
records maintained in connection with this EUA.
N. Pfizer Inc. will conduct post-authorization observational studies to evaluate the

association between Pfizer-BioNTech COVID-19 Vaccine and a pre-specified list of
adverse events of special interest, along with deaths and hospitalizations, and severe
COVID-19. The study population should include individuals administered the
authorized Pfizer-BioNTech COVID-19 Vaccine under this EUA in the general U.S.
population (12 years of age and older), populations of interest such as healthcare
workers, pregnant women, immunocompromised individuals, subpopulations with
specific comorbidities. The studies should be conducted in large scale databases with
an active comparator. Pfizer Inc. will provide protocols and status update reports to
the IND 19736 with agreed-upon study designs and milestone dates.
Emergency Response Stakeholders
O. Emergency response stakeholders will identify vaccination sites to receive authorized

Pfizer- and ensure its distribution and administration,
consistent with the terms of this letter accination Program.
P. Emergency response stakeholders will ensure that vaccination providers within their
jurisdictions are aware of this letter of authorization, and the terms herein and any
subsequent amendments that might be made to the letter of authorization, instruct
them about the means through which they are to obtain and administer the vaccine
under the EUA, and ensure that the authorized labeling [i.e., Fact Sheet for Healthcare
Providers Administering Vaccine (Vaccination Providers) and Vaccine Information
Fact Sheet for Recipients and Caregivers] is made available to vaccination providers
through appropriate means (e.g., e-mail, website).
Q. Emergency response stakeholders receiving authorized Pfizer-

Vaccine will ensure that appropriate storage and cold chain is maintained.
Vaccination Providers
R. Vaccination providers will administer the vaccine in accordance with the

authorization and will participate and comply with the terms and training required by
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S. Vaccination providers will provide the Vaccine Information Fact Sheet for Recipients
and Caregivers to each individual receiving vaccination and provide the necessary
information for receiving their second dose and/or third dose.
T. Vaccination providers administering the vaccine must report the following

information associated with the administration of the vaccine of which they become
aware to VAERS in accordance with the Fact Sheet for Healthcare Providers
Administering Vaccine (Vaccination Providers):
Vaccine administration errors whether or not associated with an adverse event
Serious adverse events (irrespective of attribution to vaccination)
Cases of Multisystem Inflammatory Syndrome in children and adults
Cases of COVID-19 that result in hospitalization or death
Complete and submit reports to VAERS online at
https://vaers.hhs.gov/reportevent.html. The VAERS reports should include the
the report. More information is available at vaers.hhs.gov or by calling 1-800-822-

7967. To the extent feasible, report to Pfizer Inc. by contacting 1-800-438-1985 or
by providing a copy of the VAERS form to Pfizer Inc.; Fax: 1-866-635-8337.
U. Vaccination providers will conduct any follow-up requested by the U.S

government, including CDC, FDA, or other designee, regarding adverse events to
the extent feasible given the emergency circumstances.
V. Vaccination providers will monitor and comply with CDC and/or emergency
response stakeholder vaccine management requirements (e.g., requirements
concerning obtaining, tracking, and handling vaccine) and with requirements
concerning reporting of vaccine administration data to CDC.
W. Vaccination providers will ensure that any records associated with this EUA are
maintained until notified by FDA. Such records will be made available to CDC,
and FDA for inspection upon request.
Conditions Related to Printed Matter, Advertising, and Promotion
X. All descriptive printed matter, advertising, and promotional material, relating to the
use of the Pfizer- shall be consistent with the
authorized labeling, as well as the terms set forth in this EUA, and meet the
requirements set forth in section 502(a) and (n) of the FD&C Act and FDA
implementing regulations.
Y. All descriptive printed matter, advertising, and promotional material relating to the
use of the Pfizer- clearly and conspicuously shall state
that:
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This product has not been approved or licensed by FDA, but has been
authorized for emergency use by FDA, under an EUA to prevent Coronavirus
Disease 2019 (COVID-19) for use in individuals 12 years of age and older; and
The emergency use of this product is only authorized for the duration of the
declaration that circumstances exist justifying the authorization of emergency
use of the medical product under Section 564(b)(1) of the FD&C Act unless the
declaration is terminated or authorization revoked sooner.
Condition Related to Export
Z. If the Pfizer- is exported from the United States,

conditions C, D, and O through Y do not apply, but export is permitted only if 1) the
regulatory authorities of the country in which the vaccine will be used are fully
informed that this vaccine is subject to an EUA and is not approved or licensed by
FDA and 2) the intended use of the vaccine will comply in all respects with the laws
of the country in which the product will be used. The requirement in this letter that
the authorized labeling (i.e., Fact Sheets) be made available to vaccination providers,
recipients, and caregivers in condition A will not apply if the authorized labeling (i.e.,
Fact Sheets) are made available to the regulatory authorities of the country in which
the vaccine will be used.
Conditions With Respect to Use of Licensed Product
AA. COMIRNATY (COVID-19 Vaccine, mRNA) is now licensed for individuals

16 years of age and older. There remains, however, a significant amount of Pfizer-
BioNTech COVID-19 vaccine that was manufactured and labeled in accordance with
this emergency use authorization. This authorization thus remains in place with
respect to that product for the previously-authorized indication and uses (i.e., for use
to prevent COVID-19 in individuals 12 years of age and older with a two-dose
regimen, and to provide a third dose to individuals 12 years of age or older who have
undergone solid organ transplantation, or who are diagnosed with conditions that are
considered to have an equivalent level of immunocompromise).
BB. This authorization also covers the use of the licensed COMIRNATY (COVID-19
Vaccine, mRNA) product when used to provide a two-dose regimen for individuals
aged 12 through 15 years, or to provide a third dose to individuals 12 years of age or
older who have undergone solid organ transplantation or who are diagnosed with
Conditions A through W in this letter apply when COMIRNATY (COVID-19
Vaccine, mRNA) is provided for the uses described in this subsection III.BB, except
that product manufactured and labeled in accordance with the approved BLA is
deemed to satisfy the manufacturing, labeling, and distribution requirements of this
authorization.
IV. Duration of Authorization

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Marks Decl.
Exhibit D
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Summary Basis for Regulatory Action

Date: 08/23/2021
From: Ramachandra Naik, PhD, Review Committee Chair,
DVRPA/OVRR
BLA STN: 125742/0

BioNTech Manufacturing GmbH (in partnership with
Applicant:
Pfizer, Inc.)
Submission Receipt
May 18, 2021
Date:
PDUFA Action Due Date: January 16, 2022
Proper Name: COVID-19 Vaccine, mRNA
Proprietary Name: COMIRNATY
Active immunization to prevent coronavirus disease
2019 (COVID-19) caused by severe acute respiratory
Indication:
syndrome coronavirus 2 (SARS-CoV-2) in individuals 16
years of age and older
Recommended Action: The Review Committee recommends approval of this product.
______________________________________________________________________
Director, Office of Vaccines Research and Review
______________________________________________________________________
Director, Office of Compliance and Biologics Quality
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Table of Contents
1. Introduction .................................................................................................................3
2. Background ................................................................................................................4
3. Chemistry, Manufacturing and Controls (CMC) ..........................................................6
a. Product Quality ............................................................................................. 6
b. Testing Specifications................................................................................. 10
c. CBER Lot Release ..................................................................................... 11
d. Facilities Review / Inspection...................................................................... 11
e. Container/Closure System.......................................................................... 14
f. Environmental Assessment ........................................................................... 14
4. Nonclinical Pharmacology/Toxicology ......................................................................14
5. Clinical Pharmacology ..............................................................................................15
6. Clinical/Statistical......................................................................................................15
a. Clinical Program ......................................................................................... 15
b. Bioresearch Monitoring (BIMO) – Clinical/Statistical/Pharmacovigilance ... 22
7. Safety and Pharmacovigilance .................................................................................22
8. Labeling ....................................................................................................................25
9. Advisory Committee Meetings ..................................................................................26
10. Other Relevant Regulatory Issues ............................................................................27
11. Recommendations and Benefit/Risk Assessment ....................................................27
a. Recommended Regulatory Action .............................................................. 27
b. Benefit/Risk Assessment ............................................................................ 28
c. Recommendation for Postmarketing Activities ........................................... 28
1. Introduction
BioNTech Manufacturing GmbH (in partnership with Pfizer Inc.) submitted a Biologics
License Application (BLA) STN BL 125742 for licensure of COVID-19 Vaccine, mRNA.
The proprietary name of the vaccine is COMIRNATY. COMIRNATY is a vaccine
indicated for active immunization to prevent coronavirus disease 2019 (COVID-19)
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals
16 years of age and older. The vaccine is administered intramuscularly (IM) as a series
of two 30 3 weeks apart.
COMIRNATY (also referred to as BNT162b2 in this document) contains a nucleoside-

modified messenger RNA (mRNA) encoding the viral spike glycoprotein (S) of SARS-
CoV-2 that is formulated in lipids including ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-
diyl)bis(2-hexyldecanoate), 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 1,2-
distearoyl-sn-glycero-3-phosphocholine, and cholesterol.
3
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Study ID C4591001 BNT162-01

Control Saline Placebo None
Phase 2/3: 2 groups, randomized
1 group, randomized received
Groups 1:1 to receive COMIRNATY or
COMIRNATY IM
Placebo IM
Schedule D0, D21 D0, D21
Total follow-up 6 Months (follow-up ongoing) 6 Months (follow-up ongoing)
YOA: years of age; VE: vaccine efficacy; IM: intramuscular; D: day
Study C4591001
Study C4591001 is an ongoing, randomized, placebo-controlled, observer-blind Phase
1/2/3 study being conducted in the U.S., Argentina, Brazil, Germany, South Africa and
Turkey. Initially the study was designed as a Phase 1/2 study in healthy adults in the
U.S. for vaccine candidate and dosage selection, as well as evaluation of
immunogenicity and preliminary efficacy. The protocol was expanded to include a Phase
2/3 portion of the study to evaluate clinical disease efficacy endpoint in individuals 12
years of age and older in the U.S. and additional sites outside of the U.S.
The Phase 1 portion of the study was designed to identify a preferred vaccine candidate,
vaccine dose, and administration schedule for further development based on the
vaccine’s safety, tolerability, and immunogenicity. To this end, two age groups were
evaluated in separate cohorts, younger adults 18 through 55 years of age (N=45) and
older adults 65 through 85 years of age (N=45). The study population included healthy
men and women and excluded participants at high risk of SARS-CoV-2 infection or with
serological evidence of prior or current SARS-CoV-2 infection. Two different vaccine
candidates were evaluated, and younger participants received increasing dose levels
(10, 20 and 30 ) with progression to higher dose levels in a stepwise manner.
Evaluation of increasing doses in the older age group (65 through 85 years) was based
on recommendations from an internal review committee that reviewed safety and
immunogenicity data derived from adults 18 through 55 years of age. For each vaccine
candidate and dose, participants were randomized 4:1, such that 12 participants
received the vaccine candidate and 3 participants received placebo. Review of the safety
and immunogenicity from the Phase 1 portion of Study C4591001, in combination with
data from Study BNT162-01, supported the final vaccine candidate, dose and dosing
regimen (BNT162b2 administered at 3 weeks apart) to proceed to the
Phase 2/3 portion of Study C4591001.
In Phase 2/3, participants were enrolled with stratification by age (younger adults: 18
through 55 years of age; older adults: over 55 years of age) with the goal for the older
age strata to consist of 40% of the entire study population. Adolescents were added to
the protocol, based on review of safety data in younger adults enrolled in the ongoing
study; thus, the age strata were revised as follows: 16 through 55 years of age, and 56
years of age and older. The study population for Phase 2/3 includes participants at
higher risk for acquiring COVID-19 and at higher risk of severe COVID-19, such as
participants working in the healthcare field, participants with autoimmune disease, and
participants with chronic but stable medical conditions such as hypertension, asthma,
diabetes, and infection with HIV, hepatitis B or hepatitis C. Participants were randomized
1:1 to receive 2 doses of either COMIRNATY or placebo, 3 weeks apart. The Phase 2
portion of the study evaluated reactogenicity and immunogenicity of the vaccine in 360
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participants in the early stage of Phase 2/3, and these participants also contribute to the
overall efficacy and safety data in the Phase 3 portion.
The ongoing Phase 3 portion of the study is evaluating the safety and efficacy of
COMIRNATY for the prevention of COVID-19 occurring at least 7 days after the second
dose of vaccine. Efficacy is being assessed throughout a participant’s blinded follow-up
in the study through surveillance for potential cases of COVID-19. If, at any time, a
participant develops acute respiratory illness, an illness visit occurs. Assessments for
illness visits include a nasal (mid-turbinate) swab, which is tested at a central laboratory
using a reverse transcription-polymerase chain reaction (RT-PCR) test (i.e., Cepheid;
FDA- authorized under EUA), or other sufficiently validated nucleic acid amplification-
based test (NAAT), to detect SARS-CoV-2. The central laboratory NAAT result is used
for the case definition, unless it was not possible to test the sample at the central
laboratory. In that case, the following NAAT results are acceptable: Cepheid Xpert
Xpress SARS-CoV-2, Roche cobas SARS-CoV-2 real-time RT-PCR test
(EUA200009/A001), and Abbott Molecular/RealTime SARS-CoV-2 assay
(EUA200023/A001).
The study design included a planned interim analysis of the first primary efficacy
endpoint (the efficacy of BNT162b2 against confirmed COVID-19 occurring from 7 days
after Dose 2 in participants without evidence of SARS-CoV-2 infection before
vaccination) at pre-specified numbers of COVID-19 cases (at least 62, 92, and 120
cases). All primary and secondary efficacy endpoints were analyzed in the final efficacy
analysis after at least 164 COVID-19 cases were accrued. Participants are expected to
participate for a maximum of approximately 26 months.
Per protocol, since December 14, 2020, following issuance of the emergency use
authorization for the Pfizer-BioNTech COVID-19 Vaccine, study participants 16 years of
age and older have been progressively unblinded to their treatment assignment (when
eligible per local recommendations) and offered BNT162b2 vaccination if they were
randomized to placebo.
The study was unblinded in stages as all ongoing participants were either individually
unblinded (when eligible per local recommendations) or the subject had concluded their
6-month post–Dose 2 study visit. Participants 16 years of age and older who participated
in the Phase 2/3 study were given the opportunity to receive COMIRNATY no later than
the 6-month timepoint after the second study vaccination. Participants who originally
received placebo but received COMIRNATY were moved to a new visit schedule to
receive both doses of COMIRNATY, 3 weeks apart.
The primary safety and efficacy endpoints were:
1. Primary safety endpoint (descriptive): Solicited local adverse reactions (injection

site pain, redness, swelling), solicited systemic adverse events (AE) (fever,
fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and
new or worsened joint pain), unsolicited AEs, serious adverse events (SAEs).
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2. First primary efficacy endpoint: COVID-19 incidence per 1000 person-years of

follow-up based on laboratory-confirmed NAAT in participants with no serological
or virological evidence (up to 7 days after Dose 2) of past SARS-CoV-2 infection.
3. Second primary efficacy endpoint: COVID-19 incidence per 1000 person-years of

follow-up based on laboratory-confirmed NAAT in participants with and without
serological or virological evidence (up to 7 days after Dose 2) of past SARS-CoV-
2 infection.
The pertinent secondary endpoint was:
1. Severe COVID-19 incidence per 1000 person-years of follow-up.
Study C4591001 results

The population in the protocol-specified, event-driven final primary efficacy analysis
included all participants 12 years of age and older who had been enrolled from July 27,
2020 and followed for the development of COVID-19 through November 14, 2020. For
participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, VE
against confirmed COVID-19 occurring at least 7 days after Dose 2 was 95.0% (95%
credible interval: 90.0, 97.9), which met the pre-specified success criterion. The case
split was 8 COVID-19 cases in the BNT162b2 group compared to 162 COVID-19 cases
in the placebo group. This protocol-specified, event-driven final primary efficacy analysis
was the basis for issuance of the emergency use authorization for the Pfizer-BioNTech
COVID-19 Vaccine on December 11, 2020.
Therefore, the primary study objective of VE against COVID-19 was met as the point
estimate was above 50% and the lower bound of the 95% CI of the point estimate of VE
was above 30%.
The population for the updated vaccine efficacy analysis per protocol included
participants 16 years of age and older who had been enrolled from July 27, 2020, and
followed for the development of COVID-19 during blinded placebo-controlled follow-up
through March 13, 2021, representing up to ~6 months of follow-up after Dose 2. Overall,
60.8% of participants in the COMIRNATY group and 58.7% of participants in the placebo
-up time after Dose 2 in the blinded placebo-controlled
follow-up period. The overall VE against COVID-19 in participants without evidence of
prior SARS-CoV-2 infection was 91.1% (95% CI: 88.8 to 93.1). The overall VE against
COVID-19 in participants with or without evidence of prior SARS-CoV-2 infection was
90.9% (95% CI: 88.5 to 92.8).
The updated vaccine efficacy information is presented in Tables 7a and 7b.
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Table 7a: First COVID-19 occurrence from 7 days after Dose 2 in participants
without evidence of prior SARS-CoV-2 infection - Evaluable Efficacy (7 Days)
Population During the Placebo-Controlled Follow-up Period *
COMIRNATY Placebo
Na=19,993 Na=20,118
Cases Cases
n1b n1b
Surveillance Timec Surveillance Timec Vaccine Efficacy %
Subgroup (n2d) (n2d) (95% CIe)
77 833 91.1
All participants 6.092 (19,711) 5.857 (19,741) (88.8, 93.1)
70 709 90.5
16 through 64 years 4.859 (15,519) 4.654 (15,515) (87.9, 92.7)
7 124 94.5
65 years and older 1.233 (4192) 1.202 (4226) (88.3, 97.8)
* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2
not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days
after Dose 2 were included in the analysis.
a. N = Number of participants in the specified group.
b. n1 = Number of participants meeting the endpoint definition.
c. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the
endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d. n2 = Number of participants at risk for the endpoint.
e. Two-sided confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the
surveillance time.
Table 7b: First COVID-19 occurrence from 7 days after Dose 2 in participants with
or without* evidence of prior SARS-CoV-2 infection - Evaluable Efficacy (7 Days)
Population During the Placebo-Controlled Follow-up Period *
Placebo
COMIRNATY Na=21,210
Na=21,047 Cases
Cases n1b Vaccine Efficacy
n1b Surveillance Timec %
Subgroup Surveillance Timec (n2d) (n2d) (95% CIe)
81 854 90.9
All participants 6.340 (20,533) 6.110 (20,595) (88.5, 92.8)
74 726 90.2
16 through 64 years 5.073 (16,218) 4.879 (16,269) (87.5, 92.4)
7 128 94.7
65 years and older 1.267 (4315) 1.232 (4326) (88.7, 97.9)
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom
consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or
increased muscle pain; new loss of taste or smell; sore throat; diarrhea; vomiting).
* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and
SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit
prior to 7 days after Dose 2 were included in the analysis.
a. N = Number of participants in the specified group.
b. n1 = Number of participants meeting the endpoint definition.
c. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the
d. n2 = Number of participants at risk for the endpoint.
e. Two-sided confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the
surveillance time.
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Efficacy Against Severe COVID-19

Vaccine efficacy against severe COVID-19 for participants with or without prior SARS-
CoV-2 infection is shown in Tables 8a and 8b. The VE against severe COVID-19 in
participants with or without evidence of prior SARS-CoV-2 infection was 95.3% (95% CI:
71.0 to 99.9) using the protocol definition of severe COVID-19 and 100.0% (95% CI: 87.6
to 100.0) based on the CDC definition of severe COVID-19.
Table 8a: Vaccine Efficacy – First Severe COVID-19 Occurrence in Participants 16

Years of Age and Older With or Without* Prior SARS-CoV-2 Infection Based on
Protocol† Definition From 7 Days After Dose 2 – Evaluable Efficacy (7 Days)
Population During the Placebo-Controlled Follow-up
COMIRNATY Placebo
Cases Cases
n1a n1a Vaccine Efficacy
Surveillance Timeb Surveillance Timeb %
(n2c) (n2c) (95% CId)
7 days after Dose 2d 1 21 95.3
6.353 (20,540) 6.237 (20,629) (70.9, 99.9)
Table 8b: Vaccine Efficacy – First Severe COVID-19 Occurrence in Participants 16

Years of Age and Older With or Without* Prior SARS-CoV-2 Infection Based on
Centers for Disease Control and Prevention (CDC)‡ Definition From 7 Days After
Dose 2 – Evaluable Efficacy (7 Days) Population During the Placebo-Controlled
Follow-up
COMIRNATY Placebo
Cases Cases
n1a n1a Vaccine Efficacy
Surveillance Timeb Surveillance Timeb %
(n2c) (n2c) (95% CId)
7 days after Dose 2d 0 31 100
6.345 (20,513) 6.225 (20,593) (87.6, 100.0)
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom
consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or
increased muscle pain; new loss of taste or smell; sore throat; diarrhea; vomiting).
* Participants who had no evidence of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at Visit 1 and
SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit
prior to 7 days after Dose 2 were included in the analysis.
†
Severe illness from COVID-19 is defined in the protocol as confirmed COVID-19 and presence of at least 1 of the following:
tional
inspired oxygen <300 mm Hg);
Respiratory failure [defined as needing highflow oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal
membrane oxygenation (ECMO)];
Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or requiring vasopressors);
Significant acute renal, hepatic, or neurologic dysfunction;
Admission to an Intensive Care Unit;
Death.
‡
Severe illness from COVID-19 as defined by CDC is confirmed COVID-19 and presence of at least 1 of the following:
Hospitalization;
Admission to the Intensive Care Unit;
Intubation or mechanical ventilation;
Death.
a. n1 = Number of participants meeting the endpoint definition.
b. Total surveillance time in 1000 person-years for the given endpoint across all participants within each group at risk for the
c. n2 = Number of participants at risk for the endpoint.
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d. Two-side confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted to the
surveillance time
Study BNT162-01
Study BNT162-01 is an ongoing Phase 1/2, open-label, dose-finding study to evaluate
the safety and immunogenicity of several candidate vaccines, including BNT162b2 (1, 3,
10, 20, and 30 g), conducted in Germany in healthy and immunocompromised adults.
Only safety and immunogenicity data in individuals 16 years of age and older, the
population for the intended use and who received the final vaccine formulation (30 µg
BNT162b2) are used to support this application. The 30 µg dosage of BNT162b2 was
administered to 12 adults 18 to 55 years of age and 12 adults 56 to 85 years of age.
The primary objective was to evaluate the safety of the BNT162 candidate vaccines.
Secondary and exploratory objectives were to describe humoral and cellular immune
responses following vaccination, measured at baseline and various time points after
vaccination, specifically 7 days post Dose 2. Adverse event monitoring was the same as
the safety monitoring in study C4591001.
The study started April 23, 2020. The BLA contains safety data (reactogenicity and AE
analyses) up to 1 month after Dose 2 (data cutoff date: October 23, 2020), neutralizing
antibody data up to ~2 months after Dose 2 (data cutoff date: October 23, 2020), and T-
cell data up to ~6 months after Dose 2 (data cutoff date: March 2, 2021).
Study BNT162-01 Results

Disposition of 30 g BNT162b2 group:
- Safety: Of a total of 24 participants, 12 participants 18 to 55 years of age and 12
participants 56 to 85 years of age completed the visit at 1- month post-Dose 2.
- Immunogenicity: Of the 12 participants, serum neutralizing antibody and T-cell
responses were available for 10 and 12 participants, respectively.
Safety: The safety profiles for adult participants 18-55 and 56-85 years of age receiving
30 g 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 GMTs at baseline (pre-Dose 1), and most pronounced at
-helper response was indicated by
-2 production, and only minimal IL-4 production upon antigen-specific
(SARS-CoV-2 S protein peptide pools) re-stimulation.
Review of the safety and immunogenicity from Phase 1 part of Study C4591001, in
combination with data from Study BNT162-01, supported selection of the final vaccine
as two doses 3 weeks apart) to
proceed into Phase 2/3 part of Study C4591001.
Lot Consistency
Consistency of process performance qualification (PPQ) batches manufactured at both
Pfizer Puurs and Pfizer Kalamazoo was demonstrated by verifying process parameters
and in-process testing results as well as DP release testing. Data obtained from the
analytical comparability assessments on the PPQ batches manufactured at both sites
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provide evidence of reproducible and consistent manufacture of COMIRNATY DP of

acceptable product quality across all supply nodes.
b. Bioresearch Monitoring (BIMO) – Clinical/Statistical/Pharmacovigilance

BIMO inspection assignments were issued for a total of nine (9) clinical study sites that
participated in the conduct of study Protocol C4591001. Three (3) of these inspection
assignments focused on clinical study sites that enrolled the pediatric population and six
(6) of the study sites enrolled the adult population. The inspections did not reveal
findings that impact the BLA.
c. Pediatrics
The Applicant’s Pediatric Plan was presented to the FDA Pediatric Review Committee
(PeRC) on August 3, 2021. The committee agreed with the Applicant’s request for a
deferral for studies in participants 0 to <16 years of age because the biological product is
ready for approval for use in individuals 16 years of age and older before pediatric
studies in participants 0 to <16 years of age are completed (Section 505B(a)(3)(A)(i) of
PREA).
The PREA-required studies specified in the approval letter and agreed upon with the
Applicant are as follows:
1. Study C4591001 to evaluate the safety and effectiveness of COMIRNATY in

children 12 years through 15 years of age

children 6 months to <12 years of age

infants <6 months of age
7. Safety and Pharmacovigilance
The solicited adverse reactions in COMIRNATY

recipients 16 through 55 years of age following any dose were pain at the injection site
(88.6%), fatigue (70.1%), headache (64.9%), muscle pain (45.5%), chills (41.5%), joint
pain (27.5%), fever (17.8%), and injection site swelling (10.6%). The most commonly
solicited adverse reactions in COMIRNATY recipients 56 years of age
and older following any dose were pain at the injection site (78.2%), fatigue (56.9%),
headache, (45.9%), muscle pain (32.5%), chills (24.8%), joint pain (21.5%), injection site
swelling (11.8%), fever (11.5%), and injection site redness (10.4%).
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follow-up after Dose 2. There were no notable patterns between treatment groups for
specific categories of serious adverse events (including neurologic, neuro-inflammatory,
and thrombotic events) that would suggest a causal relationship to COMIRNATY.
From Dose 1 through the March 13, 2021 data cutoff date, there were a total of 38
deaths, 21 in the COMIRNATY group and 17 in the placebo group. None of the deaths
were considered related to vaccination.
Since the issuance of the EUA (December 11, 2020), post-authorization safety data has
been reported from individuals 16 years of age and older following any dose of
COMIRNATY. Because these reactions are reported from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal
relationship to vaccine exposure. Below are presented adverse reactions categorized as
important identified risks in the pharmacovigilance plan that have occurred during the
conduct of the clinical trial and have been reported following the issuance of the EUA.
Myocarditis/Pericarditis
During the time from Dose 1 to unblinding in Study C4591001, one report of pericarditis
was identified in the COMIRNATY
age, with no medical history, 28 days after Dose 2; the event was assessed by the
investigator as not related to the study intervention and was ongoing at the time of the
data cutoff. One report of myocarditis was identified in a male participant <55 years of
age in the placebo group, occurring 5 days after his second placebo dose.
Post-EUA safety surveillance reports received by FDA and CDC identified serious risks
for myocarditis and pericarditis following administration of COMIRNATY. Reporting rates
for medical chart-confirmed myocarditis/pericarditis in VAERS have been higher among
males under 40 years of age than among females and older males and have been
highest in males 12-17 years of age (65 cases per million doses administered as per
CDC communication on August 20, 2021), particularly following the second dose, and
onset of symptoms within 7 days following vaccination. Although some cases of vaccine-
associated myocarditis/pericarditis required intensive care support, available data from
short-term follow up suggest that most individuals have had resolution of symptoms with
conservative management. Information is not yet available about potential long-term
sequelae and outcomes in affected individuals. A mechanism of action by which the
vaccine could cause myocarditis and pericarditis has not been established.
These safety findings of increased risk for myocarditis/pericarditis led to warning in

section 5.2 Warning and Precautions of the PI.
Myocarditis and pericarditis are considered important identified risks in the

pharmacovigilance plan included in the BLA. Of note, the Applicant will be required to
conduct postmarketing requirement (PMR) safety studies under Section 505(o) of the
Federal Food, Drug, and Cosmetic Act (FDCA) to assess the known serious risks of
myocarditis and pericarditis as well as an unexpected serious risk for subclinical
myocarditis (see Section 11c Recommendation for Postmarketing Activities, for study
details).
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Moreover, since vaccine-associated myocarditis/pericarditis is the most clinically

significant identified risk, FDA undertook a quantitative benefit-risk assessment to model
the excess risk of myocarditis/pericarditis vs. the expected benefits of preventing COVID-
19 and associated hospitalizations, ICU admissions, and deaths. For estimation of risk,
the model took a conservative approach by relying on non-chart-confirmed cases from a
US healthcare claims database (OPTUM) that could provide a control group and greater
confidence in denominators for vaccine exposures. Thus, the estimates of excess risk in
this model are higher than the rates estimated from reports to VAERS (an uncontrolled
passive surveillance system), with an estimated excess risk approaching 200 cases per
million vaccinated males 16-17 years of age (the age/sex-stratified group with the
highest risk). For estimation of benefit, the model output was highly dependent on the
assumed COVID-19 incidence, as well as assumptions about vaccine efficacy and
duration of protection. The assessment therefore considered a range of scenarios
including but not limited to a “most likely” scenario associated with recent Delta variant
surge and diminished vaccine effectiveness (70% overall, 80% against COVID-19
hospitalization) compared to that observed in the clinical trial. The “worst-case” scenario
with low COVID-19 incidence reflecting the July 2021 nadir and the same somewhat
diminished vaccine effectiveness as in the “most likely” scenario.
For males and females 18 years of age and older and for females 16-17 years of age,
even before accounting for morbidity prevented from non-hospitalized COVID-19, the
model predicts that the benefits of prevented COVID-19 hospitalizations, ICU admissions
and deaths would clearly outweigh the predicted excess risk of vaccine-associated
myocarditis/pericarditis under all conditions examined. For males 16-17 years of age, the
model predicts that the benefits of prevented COVID-19 hospitalizations, ICU admissions
and deaths would clearly outweigh the predicted excess risk of vaccine-associated
myocarditis/pericarditis under the “most likely” scenario, but that predicted excess cases
of vaccine-associated myocarditis/pericarditis would exceed COVID-19 hospitalizations
and deaths under the “worst case” scenario. However, this predicted numerical
imbalance does not account for the greater severity and length of hospitalization, on
average, for COVID-19 compared with vaccine-associated myocarditis/pericarditis.
Additionally, the “worst case” scenario model predicts prevention of >13,000 cases of
non-hospitalized COVID-19 per million vaccinated males 16-17 years of age, which
would include prevention of clinically significant morbidity and/or long-term sequelae
associated with some of these cases. Finally, the model does not account for indirect
societal/public health benefits of vaccination. Considering these additional factors, FDA
concluded that even under the “worst case” scenario the benefits of vaccination
sufficiently outweigh risks to support approval of the vaccine in males 16-17 years of
age.
Mitigation of the observed risks and associated uncertainties will be accomplished

through labeling (including warning statements) and through continued safety
surveillance and postmarketing studies to further assess and understand these risks,
including an immunogenicity and safety study of lower dose levels of COMIRNATY in
individuals 12 through <30 years of age. The Applicant will be required to conduct
postmarketing requirement (PMR) safety studies under Section 505(o) of the Federal
Food, Drug, and Cosmetic Act (FDCA) to assess the known serious risks of myocarditis
and pericarditis and an unexpected serious risk for subclinical myocarditis (see section
11c for study details).
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Anaphylaxis
The risk of anaphylaxis was recognized early in the post-authorization time period and it
is included as an important identified risk in the PVP. The estimated crude reporting rate
for anaphylaxis is 6.0 cases per million doses. Therefore, the incidence of anaphylaxis
after receipt of COMIRNATY is comparable with those reported after receipt of other
vaccines.
There were no reports of anaphylaxis associated with COMIRNATY in clinical study

participants through the cutoff date of March 13, 2021.
A contraindication for individuals with known history of a severe allergic reaction (e.g.,
anaphylaxis) to any component of COMIRNATY is included in section 4 of the PI.
Additionally, a warning statement is included in section 5.1 of the PI instructing that
“appropriate medical treatment used to manage immediate allergic reactions must be
immediately available in the event an acute anaphylactic reaction occurs following
administration of COMIRNATY”
Pharmacovigilance Plan (PVP)

The Applicant’s proposed pharmacovigilance plan (version 1.1) includes the following
important risks and missing information:
Important identified risks: Anaphylaxis; Myocarditis and Pericarditis
Important potential risk: Vaccine-Associated Enhanced Disease (VAED), including
Vaccine-Associated Enhanced Respiratory Disease (VAERD)
Missing information: Use in pregnancy and lactation; Vaccine effectiveness; Use
in pediatric individuals <12 years of age
In addition to routine pharmacovigilance, the Applicant will conduct the postmarketing

studies listed in Section 11c Recommendation for Postmarketing Activities.
Adverse event reporting under 21 CFR 600.80 and the postmarketing studies in Section
11c are adequate to monitor the postmarketing safety for COMIRNATY.
8. Labeling
The proprietary name, COMIRNATY, was reviewed by CBER’s Advertising and

Promotional Labeling Branch (APLB) on July 2, 2021, and found to be acceptable. CBER
communicated this decision to the Applicant on July 6, 2021. The APLB found the PI and
package/container labels to be acceptable from a promotional and comprehension
perspective. The Review Committee negotiated revisions to the PI, including modifying
the proposed proper name from “COVID-19 mRNA vaccine (nucleoside-modified)” to
“COVID-19 Vaccine, mRNA” and including a warning for an increased risk of myocarditis
and pericarditis following administration of COMIRNATY. All labeling issues regarding
the PI and the carton and container labels were acceptably resolved after exchange of
information and discussions with the Applicant.
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9. Advisory Committee Meetings
Vaccines and Related Biological Products Committee (VRBPAC) meetings were

convened on October 22, 2020 to discuss, in general, development for EUA and
licensure of vaccines to prevent COVID-19 and on December 10, 2020, to discuss
BioNTech Manufacturing GmbH/Pfizer’s EUA request for the Pfizer-BioNTech COVID-19
Vaccine.
On October 22, 2020, the VRBPAC was presented with the following items for
discussion (no vote):
1. Please discuss FDA’s approach to safety and effectiveness data as outlined in the
respective guidance documents.
2. Please discuss considerations for continuation of blinded Phase 3 clinical trials if

an EUA has been issued for an investigational COVID-19 vaccine.
3. Please discuss studies following licensure and/or issuance of an EUA for COVID-
19 vaccines to
a. Further evaluate safety, effectiveness and immune markers of protection
b. Evaluate the safety and effectiveness in specific populations
In general, the VRBPAC endorsed FDA’s approach and recommendations on the safety
and effectiveness data necessary to support a BLA and EUA for COVID-19 vaccines as
outlined in the respective guidance documents. VRBPAC members recommended for
the median follow-up of 2 month to be the minimum follow-up period and suggested
longer follow-up periods to evaluate, both safety and efficacy, if feasible. The VRBPAC
endorsed the importance of additional studies to further evaluate safety and
effectiveness of the vaccine after EUA issuance and/or licensure and underscored the
need to evaluate the safety and effectiveness of COVID-19 vaccines in specific
populations.
On December 10, 2020, VRBPAC discussed Pfizer- BioNTech Manufacturing GmbH’s

EUA request for their vaccine to prevent COVID-19 in individuals 16 years of age and
older. The committee discussed the safety and efficacy data derived from the clinical
disease endpoint efficacy study C4591001.
The VRPBAC voted on one question:
1. Based on the totality of scientific evidence available, do the benefits of the Pfizer-
BioNTech COVID-19 Vaccine outweigh its risks for use in individuals 16 years of
age and older?
The results of the vote were as follows:

Yes = 17 No = 4 Abstain = 1
The VRBPAC was presented with the following items for discussion (no vote):
1. Pfizer has proposed a plan for continuation of blinded, placebo-controlled follow-

up in ongoing trials if the vaccine were made available under EUA. Please discuss
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Pfizer’s plan, including how loss of blinded, placebo-controlled follow-up in

ongoing trials should be addressed.
2. Please discuss any gaps in plans described today and in the briefing documents
for further evaluation of vaccine safety and effectiveness in populations who
receive the Pfizer-BioNTech COVID-19 Vaccine under an EUA.
The committee discussed potential implications of loss of blinded, placebo-controlled

follow-up in ongoing trials including how this may impact availability of safety data to
support a BLA. The VRBPAC commented on the need to further assess vaccine effect
on asymptomatic infection and viral shedding, and further evaluation of safety and
effectiveness in subpopulations such as HIV-infected individuals, individuals with prior
exposure to SARS-CoV-2.
FDA did not refer this application to the VRBPAC because our review of the information
submitted to this BLA did not raise concerns or controversial issues that would have
benefited from an advisory committee discussion.
10. Other Relevant Regulatory Issues
a. Identification of BLA Lots

Upon CBER’s request inquiring about what BLA-compliant EUA-labeled lots may be
available for use upon licensure of COMIRNATY, the Applicant submitted information
listing which lots they considered to be manufactured according to the BLA. To address
the issue of these lots not bearing the vial label associated with BLA approval, CBER
worked with the Applicant to develop a Dear HCP letter to be included with lots
considered by CBER to be BLA-compliant. This letter explained that some lots labeled
for EUA use were also considered BLA-compliant and refers HCP to a website for
additional information. CBER requested and the Applicant agreed that only EUA-labeled
lots that had also undergone CBER lot release according to the BLA would be
considered BLA-compliant and listed at the website included in the Dear HCP letter.
b. Exception to the 21 CFR 610.15(a) Requirement for a Preservative

Under 21 CFR 610.15(a), a vaccine product in multiple-dose containers must (absent
certain exceptions) contain a preservative. The Applicant submitted a request for
exception to this requirement and provided a justification for the multi-dose presentation
of COMIRNATY not containing a preservative. CBER considered the Applicant’s request
for an exception to the 21 CFR 610.15(a) for COMIRNATY as a multiple dose
preservative-free presentation acceptable.
11. Recommendations and Benefit/Risk Assessment
a. Recommended Regulatory Action

Based on the review of the clinical, pre-clinical, and product-related data submitted in
the original BLA, the Review Committee recommends approval of COMIRNATY for
the labeled indication and usage.
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b. Benefit/Risk Assessment
Considering the data submitted to support the safety and effectiveness of
COMIRNATY that have been presented and discussed in this document, as well as
the seriousness of COVID-19, the Review Committee is in agreement that the
risk/benefit balance for COMIRNATY is favorable and supports approval for use in
individuals 16 years of age and older.
c. Recommendation for Postmarketing Activities

BioNTech Manufacturing GmbH has committed to conduct the following
postmarketing activities, which will be included in the approval letter.
POSTMARKETING REQUIREMENTS UNDER SECTION 505(o)
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

Monitoring Report Submission: October 31, 2022
Interim Report Submission: October 31, 2023
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

Progress Report Submission: September 30, 2021
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)
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myocarditis following administration of the second dose of COMIRNATY in a subset
of participants 5 through 15 years of age


myocarditis following administration of a third dose of COMIRNATY in a subset of
participants 16 to 30 years of age

POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS

UNDER SECTION 506B
7. Study C4591022, entitled “Pfizer-BioNTech COVID-19 Vaccine Exposure during

Pregnancy: A Non-Interventional Post-Approval Safety Study of Pregnancy and Infant
Outcomes in the Organization of Teratology Information Specialists
(OTIS)/MotherToBaby Pregnancy Registry”
Final Protocol Submission: July 1, 2021

8. Study C4591007 substudy to evaluate the immunogenicity and safety of lower dose
levels of COMIRNATY in individuals 12 through <30 years of age

9. Study C4591012, entitled “Post-emergency Use Authorization Active Safety

Surveillance Study Among Individuals in the Veteran’s Affairs Health System
Receiving Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) Vaccine”

10. Study C4591014, entitled “Pfizer-BioNTech COVID-19 BNT162b2 Vaccine

Effectiveness Study - Kaiser Permanente Southern California”
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Final Protocol Submission: March 22, 2021

Final Report Submission: June 30, 2023
PEDIATRIC REQUIREMENTS
11. Deferred pediatric study C4591001 to evaluate the safety and effectiveness of
COMIRNATY in children 12 years through 15 years of age
Final Protocol Submission: October 7, 2020

Study Completion: May 31, 2023
COMIRNATY in children 6 months to <12 years of age
Final Protocol Submission: February 8, 2021

COMIRNATY in infants <6 months of age

Study Completion: July 31, 2024
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Marks Decl.
Exhibit E
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Contains Nonbinding Recommendations
Development and Licensure of

Vaccines to Prevent COVID-19
Guidance for Industry
U.S. Department of Health and Human Services

Center for Biologics Evaluation and Research
June 2020
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Preface
Public Comment
This guidance is being issued to address the coronavirus disease 2019 (COVID-19) public health
emergency. This guidance is being implemented without prior public comment because the
Food and Drug Administration (FDA or Agency) has determined that prior public participation
for this guidance is not feasible or appropriate (see section 701(h)(1)(C) of the Federal Food,
Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 371(h)(1)(C)) and 21 CFR 10.115(g)(2)). This
guidance document is being implemented immediately, but it remains subject to comment in
accordance with the Agency’s good guidance practices.
Comments may be submitted at any time for Agency consideration. Submit written comments to
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852. Submit electronic comments to https://www.regulations.gov.
All comments should be identified with the docket FDA-2020-D-1137 and complete title of the
guidance in the request.
Additional Copies
Additional copies are available from the FDA webpage titled “COVID-19-Related Guidance
Documents for Industry, FDA Staff, and Other Stakeholders,” available at
https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/covid-19-related-
guidance-documents-industry-fda-staff-and-other-stakeholders, the FDA webpage titled “Search
for FDA Guidance Documents,” available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents, and the FDA webpage titled “Biologics
Guidances,” available at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics/biologics-guidances. You may also send an email request to
[email protected] to receive an additional copy of the guidance. Please include the docket
number FDA-2020-D-1137 and complete title of the guidance in the request.
Questions
For questions about this document, contact the Office of Communication, Outreach, and
Development (OCOD) by email at [email protected] or at 800-835-4709 or 240-402-8010.
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Table of Contents
I. INTRODUCTION..................................................................................................................... 1
II. BACKGROUND ....................................................................................................................... 2
III. CHEMISTRY, MANUFACTURING, AND CONTROLS – KEY CONSIDERATIONS . 3
A. General Considerations ..................................................................................................... 3
B. Manufacture of Drug Substance and Drug Product....................................................... 3
C. Facilities and Inspections................................................................................................... 5
IV. NONCLINICAL DATA – KEY CONSIDERATIONS ......................................................... 6
B. Toxicity Studies (Refs. 10-14)............................................................................................ 6
C. Characterization of the Immune Response in Animal Models ...................................... 7
D. Studies to Address the Potential for Vaccine-associated Enhanced Respiratory
Disease ................................................................................................................................. 8
V. CLINICAL TRIALS – KEY CONSIDERATIONS .............................................................. 9
B. Trial Populations .............................................................................................................. 10
C. Trial Design....................................................................................................................... 12
D. Efficacy Considerations ................................................................................................... 13
E. Statistical Considerations ................................................................................................ 14
F. Safety Considerations ...................................................................................................... 15
VI. POST-LICENSURE SAFETY EVALUATION – KEY CONSIDERATIONS ................ 16
A. General Considerations ................................................................................................... 16
B. Pharmacovigilance Activities for COVID-19 Vaccines ................................................ 16
C. Required Postmarketing Safety Studies......................................................................... 17
VII. DIAGNOSTIC AND SEROLOGICAL ASSAYS – KEY CONSIDERATIONS.............. 17
VIII. ADDITIONAL CONSIDERATIONS ................................................................................... 18
A. Additional Considerations in Demonstrating Vaccine Effectiveness .......................... 18
B. Emergency Use Authorization ........................................................................................ 19
IX. REFERENCES........................................................................................................................ 20
i
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Therefore, within 60 days following the termination of the public health emergency, FDA intends to
revise and replace this guidance with an updated guidance that incorporates any appropriate changes
based on comments received on this guidance and the Agency’s experience with implementation.
In general, FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The
use of the word should in Agency guidance means that something is suggested or recommended, but
not required.
II. BACKGROUND
There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus has
been named “SARS-CoV-2” and the disease it causes has been named “COVID-19.” On January 31,
2020, the Secretary of HHS issued a declaration of a public health emergency related to COVID-19
and mobilized the Operating Divisions of HHS. 1 In addition, on March 13, 2020, the President
declared a national emergency in response to COVID-19. 2
The SARS-CoV-2 pandemic presents an extraordinary challenge to global health. There are
currently no FDA-licensed vaccines to prevent COVID-19. Commercial vaccine manufacturers and
other entities are developing COVID-19 vaccine candidates using different technologies including
RNA, DNA, protein, and viral vectored vaccines.
This guidance describes FDA’s current recommendations regarding the data needed to facilitate
clinical development and licensure of vaccines to prevent COVID-19. There are currently no
accepted surrogate endpoints that are reasonably likely to predict clinical benefit of a COVID-19
vaccine. Thus, at this time, the goal of development programs should be to pursue traditional
approval via direct evidence of vaccine safety and efficacy in protecting humans from SARS-CoV-2
infection and/or clinical disease.
This guidance provides an overview of key considerations to satisfy regulatory requirements set forth
in the investigational new drug application (IND) regulations in 21 CFR Part 312 and licensing
regulations in 21 CFR Part 601 for chemistry, manufacturing, and controls (CMC), and nonclinical
and clinical data through development and licensure, and for post-licensure safety evaluation of
COVID-19 preventive vaccines. 3 FDA is committed to supporting all scientifically sound
approaches to attenuating the clinical impact of COVID-19. Sponsors engaged in the development
of vaccines to prevent COVID-19 should also see the guidance for industry and investigators,
COVID-19 Public Health Emergency: General Considerations for Pre-IND Meeting Requests for
COVID-19 Related Drugs and Biological Products (Ref. 1).
1
Secretary of Health and Human Services Alex M. Azar, Determination that a Public Health Emergency Exists. (Jan. 31,
2020, renewed April 21, 2020), available at https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.
2
Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak
(Mar. 13, 2020), available at https://www.whitehouse.gov/presidential-actions/proclamation-declaring-national-
emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/.
3
Novel devices used to administer COVID-19 vaccines raise additional issues which are not addressed in this guidance.
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There are many COVID-19 vaccines currently in development and FDA recognizes that the
considerations presented here do not represent all the considerations necessary to satisfy statutory
and regulatory requirements applicable to the licensure of vaccines intended to prevent COVID-19.
The nature of a particular vaccine and its intended use may impact specific data needs. We encourage
sponsors to contact the Center for Biologics Evaluation and Research (CBER) Office of Vaccines
Research and Review (OVRR) with specific questions.
III. CHEMISTRY, MANUFACTURING, AND CONTROLS – KEY CONSIDERATIONS
A. General Considerations
COVID-19 vaccines licensed in the United States must meet the statutory and
regulatory requirements for vaccine development and approval, including for
quality, development, manufacture, and control (section 351(a) of the Public
Health Service Act (PHS Act), (42 U.S.C. 262)). The vaccine product must be
adequately characterized and its manufacture in compliance with applicable
standards including current good manufacturing practice (cGMP) (section
501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)( B)) and 21 CFR Parts 210,
211, and 610). It is critical that vaccine production processes for each vaccine are
well defined and appropriately controlled to ensure consistency in manufacturing.
COVID-19 vaccine development may be accelerated based on knowledge gained

from similar products manufactured with the same well-characterized platform
technology, to the extent legally and scientifically permissible. Similarly, with
appropriate justification, some aspects of manufacture and control may be based
on the vaccine platform, and in some instances, reduce the need for product-
specific data. FDA recommends that vaccine manufacturers engage in early
communications with OVRR to discuss the type and extent of chemistry,
manufacturing, and control information needed for development and licensure of
their COVID-19 vaccine.
B. Manufacture of Drug Substance and Drug Product
Data should be provided to show that all source material used in manufacturing is
adequately controlled, including, for example, history and qualification of cell
banks, history and qualification of virus banks, and identification of all animal
derived materials used for cell culture and virus growth.
Complete details of the manufacturing process must be provided in a Biologics

License Application (BLA) to support licensure of a COVID-19 vaccine (21 CFR
601.2). Accordingly, sponsors should submit data and information identifying
critical process parameters, critical quality attributes, batch records, defined hold
times, and the in-process testing scheme. Specifications should be established for
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each critical parameter. Validation data from the manufacture of platform-related

products may provide useful supportive information, particularly in the
identification of critical parameters.
In-process control tests must be established that allow quality to be monitored for
each lot for all stages of production (section 501(a)(2)(B) of the FD&C Act (21
U.S.C. 351(a)(2)(B)) and, as applicable, 21 CFR 211.110(a)).
Data to support the consistency of the manufacturing process should be provided,

including process validation protocols and study reports, data from engineering
lots, and drug substance process performance qualification.
The manufacturing process must be adequately validated (section 501(a)(2)(B) of

the FD&C Act (21 U.S.C. 351(a)(2)(B)) and, as applicable, 21 CFR 211.100(a)
and 211.110). Validation would typically include a sufficient number of
commercial-scale batches that can be manufactured routinely, meeting
predetermined in-process controls, critical process parameters, and lot release
specifications. Typically, data on the manufacture of at least three commercial-
scale batches are sufficient to support the validation of the manufacturing process
(Ref. 2).
A quality control system should be in place for all stages of manufacturing,

including a well-defined testing program to ensure in process/intermediate product
quality and product quality throughout the formulation and filling process. This
system should also include a well-defined testing program to ensure drug
substance quality profile and drug product quality for release. Data on the
qualification/validation for all quality indicating assays should be submitted to the
BLA to support licensure.
All quality-control release tests, including key tests for vaccine purity, identity and
potency, should be validated and shown to be suitable for the intended purpose.
Release specifications are product specific and will be discussed with the sponsor
as part of the review of a BLA.
If adequately justified, final validation of formulation and filling operations may

be completed after product approval if the impact on product quality is not
compromised. It is important that any data that will be submitted after product
approval be agreed upon prior to licensure and be submitted as a postmarketing
commitment using the appropriate submission category.
For vaccine licensure, the stability and expiry date of the vaccine in its final
container, when maintained at the recommended storage temperature, should be
demonstrated using final containers from at least three final lots made from
different vaccine bulks.
Storage conditions, including container closure integrity, must be fully validated

(21 CFR 211.166).
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The vaccine must have been shown to maintain its potency for a period equal to
that from the date of release to the expiry date (21 CFR 601.2 and 610.10). Post
marketing commitments to provide full shelf life data may be acceptable with
appropriate justification.
A product specific stability program should be established to verify that licensed

product maintains quality over the defined shelf life.
C. Facilities and Inspections
Facilities must be of suitable size and construction to facilitate operations and

should be adequately designed to prevent contamination, cross-contamination and
mix-ups (section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)) and, as
applicable,21 CFR 211.42(a)). All utilities (including plumbing and sanitation)
must be validated, and HVAC systems must provide adequate control over air
pressure, micro-organisms, dust, humidity, and temperature, and sufficient
protection or containment as needed (section 501(a)(2)(B) of the FD&C Act (21
U.S.C. 351(a)(2)(B)) and, as applicable, 21 CFR 211.46(c)) (Ref. 3). Facility and
equipment cleaning and maintenance processes must be developed and validated
(section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)) and, as
applicable, 21 CFR 211.56(c) and 211.67(b)) .
Manufacturing equipment should be qualified and sterile filtration and sterilization

processes validated. Aseptic processes should be adequately validated using
media simulations and personnel should be trained and qualified for their intended
duties.
A quality control unit must be established and must have the responsibility for
oversight of manufacturing, and review and release of components, containers and
closures, labeling, in-process material, and final products (section 501(a)(2)(B) of
the FD&C Act (21 U.S.C. 351(a)(2)(B)) and, as applicable, 21 CFR 211.22). The
quality control unit must have the responsibility for approving validation
protocols, reports, investigate deviations, and institute corrective and preventive
actions.
FDA recommends that vaccine manufacturers engage in early communication

with CBER’s Office of Compliance and Biologics Quality, Division of
Manufacturing and Product Quality to discuss facility preparation and inspection
timing.
Pre-license inspections of manufacturing sites are considered part of the review of

a BLA and are generally conducted following the acceptance of a BLA filing (21
CFR 601.20). During the COVID-19 public health emergency, FDA is utilizing
all available tools and sources of information to support regulatory decisions on
applications that include sites impacted by FDA’s ability to inspect due to
COVID-19. During this interim period, we are using additional tools, where
available, to determine the need for an on-site inspection and to support the
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application assessment, such as reviewing a firm’s previous compliance history,

and requesting records in advance of or in lieu of on-site inspections or voluntarily
from facilities and sites.
IV. NONCLINICAL DATA – KEY CONSIDERATIONS
The purpose of nonclinical studies of a COVID-19 vaccine candidate is to define

its immunogenicity and safety characteristics through in vitro and in vivo testing.
Nonclinical studies in animal models 4 help identify potential vaccine related
safety risks and guide the selection of dose, dosing regimen, and route of
administration to be used in clinical studies. The extent of nonclinical data
required to support proceeding to first in human (FIH) clinical trials depends on
the vaccine construct, the supportive data available for the construct and data from
closely related vaccines.
Data from studies in animal models administered certain vaccine constructs

against other coronaviruses (SARS-CoV and MERS-CoV) have raised concerns of
a theoretical risk for COVID-19 vaccine-associated enhanced respiratory disease
(ERD). In these studies, animal models were administered vaccine constructs
against other coronaviruses and subsequently challenged with the respective wild-
type virus. These studies have shown evidence of immunopathologic lung
reactions characteristic of a Th-2 type hypersensitivity similar to ERD described
in infants and animals that were administered formalin-inactivated respiratory
syncytial virus (RSV) vaccine and that were subsequently challenged with RSV
virus due to natural exposure or in the laboratory, respectively (Refs. 4-9).
Vaccine candidates should be assessed in light of these studies as described in
section D, below.
FDA recommends that vaccine manufacturers engage in early communications

with FDA to discuss the type and extent of nonclinical testing required for the
particular COVID-19 vaccine candidate to support proceeding to FIH clinical
trials and further clinical development.
B. Toxicity Studies (Refs. 10-14)
For a COVID-19 vaccine candidate consisting of a novel product type and for
which no prior nonclinical and clinical data are available, nonclinical safety
studies will be required prior to proceeding to FIH clinical trials 21 CFR
312.23(a)(8).
4
The preclinical program for any investigational product should be individualized with respect to scope, complexity, and
overall design. We support the principles of the “3Rs,” to reduce, refine, and replace animal use in testing when feasible.
Proposals, with justification for any potential alternative approaches (e.g., in vitro or in silico testing), should be
submitted during early communication meetings with FDA (see section VI of this document). We will consider if such
an alternative method could be used in place of an animal test method.
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In some cases, it may not be necessary to perform nonclinical safety studies prior
to FIH clinical trials because adequate information to characterize product safety
may be available from other sources. For example, if the COVID-19 vaccine
candidate is made using a platform technology utilized to manufacture a licensed
vaccine or other previously studied investigational vaccines and is sufficiently
characterized, it may be possible to use toxicology data (e.g., data from repeat
dose toxicity studies, biodistribution studies) and clinical data accrued with other
products using the same platform to support FIH clinical trials for that COVID-19
vaccine candidate. Vaccine manufacturers should summarize the findings and
provide a rationale if considering using these data in lieu of performing
nonclinical safety studies.
When needed to support proceeding to FIH clinical trials, nonclinical safety

assessments including toxicity and local tolerance studies must be conducted
under conditions consistent with regulations prescribing good laboratory practices
for conducting nonclincial laboratory studies (GLP) (21 CFR Part 58). Such
studies should be completed and analysed prior to initiation of FIH clinical trials.
When toxicology studies do not adequately characterize risk, additional safety
testing should be conducted as appropriate.
Data from toxicity studies may be submitted as unaudited final draft toxicicologic
reports to accelerate proceeding to FIH clincial trials with COVID-19 vaccine
candidates. The final, fully quality-assured reports should be available to FDA
within 120 days of the start of the FIH clinical trial.
Use of COVID-19 preventive vaccines in pregnancy and in women of

childbearing potential will be an important consideration for vaccination
programs. Therefore, FDA recommends that prior to enrolling pregnant women
and women of childbearing potential who are not actively avoiding pregnancy in
clinical trials, sponsors conduct developmental and reproductive toxicity (DART)
studies with their respective COVID-19 vaccine candidate. Alternatively,
sponsors may submit available data from DART studies with a similar product
using comparable platform technology if, after consultation with the agency, the
agency agrees those data are scientifically sufficient.
Biodistribution studies in an animal species should be considered if the vaccine

construct is novel in nature and there are no existing biodistribution data from the
platform technology. These studies should be conducted if there is a likelihood of
altered infectivity and tissue tropism or if a novel route of administration and
formulation is to be used.
C. Characterization of the Immune Response in Animal Models
Immunogenicity studies in animal models responsive to the selected COVID-19

vaccine antigen should be conducted to evaluate the immunologic properties of
the COVID-19 vaccine candidate and to support FIH clinical trials. The aspects of
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immunogenicity to be measured should be appropriate for the vaccine construct

and its intended mechanism of action.
Studies should include an evaluation of humoral, cellular, and functional immune

responses, as appropriate to each of the included COVID-19 antigens. Use of
antigen-specific enyzme linked immunosorbent assays (ELISA) should be
considered to characterize the humoral response. Evaluation of cellular reponses
should include the examination of CD8+ and CD4+ T cell responses using
sensitive and specific assays. The functional activity of immune responses should
be evaluated in vitro in neutralization assays using either wild-type virus or
pseudovirion virus. The assays used for immunogencity evaluation should be
demonstrated to be suitable for their intended purpose.
D. Studies to Address the Potential for Vaccine-associated Enhanced Respiratory

Disease
Current knowledge and understanding of the potential risk of COVID-19 vaccine

associated ERD is limited, as is understanding of the value of available animal
models in predicting the likelihood of such occurrence in humans. Nevertheless,
studies in animal models (e.g., rodents and non-human primates) are considered
important to address the potential for vaccine-associated ERD.
Post-vaccination animal challenge studies and the characterization of the type of

the nonclinical and clinical immune response induced by the particular COVID-19
vaccine candidate can be used to evaluate the likelihood of the vaccine to induce
vaccine-associated ERD in humans.
To support proceeding to FIH clinical trials, sponsors should conduct studies

characterizing the vaccine-induced immune response in animal models evaluating
immune markers of potential ERD outcomes. These should include assessments
of functional immune responses (e.g., neutralizing antibody) versus total antibody
responses and Th1/Th2 balance in animals vaccinated with clinically relevant
doses of the COVID-19 vaccine candidate.
COVID-19 vaccine candidates with immunogenicity data demonstrating high

neutralizing antibody titers and Th1-type T cell polarization may be allowed to
proceed to FIH trials without first completing postvaccination challenge studies in
appropriate animal models, provided adequate risk mitigation strategies are put in
place in the FIH trials. In these situations, postvaccination challenge studies are
expected to be conducted in parallel with FIH trials to ensure the potential for
vaccine-associated ERD is addressed prior to enrolling large numbers of human
subjects into Phase 2 and 3 clinical trials. For COVID-19 vaccine candidates for
which other data raise increased concerns about ERD, postvaccination animal
challenge data and/or animal immunopathology studies are critical to assess
protection and/or ERD prior to advancing to FIH clinical trials.
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The totality of data for a specific COVID-19 vaccine candidate, including data
from postvaccination challenge studies in small animal models and from FIH
clinical trials characterizing the type of immune responses induced by the vaccine
will be considered in determining whether Phase 3 studies can proceed in the
absence of postvaccination challenge data to address risk of ERD.
V. CLINICAL TRIALS – KEY CONSIDERATIONS
Understanding of SARS-CoV-2 immunology, and specifically vaccine immune

responses that might predict protection against COVID-19, is currently limited
and evolving. Thus, while evaluation of immunogenicity is an important
component of COVID-19 vaccine development, at this time, the goal of
development programs should be to pursue traditional approval via direct evidence
of vaccine efficacy in protecting humans from SARS-CoV-2 infection and/or
disease.
Clinical development programs for COVID-19 vaccines might be expedited by

adaptive and/or seamless clinical trial designs (described below) that allow for
selection between vaccine candidates and dosing regimens and for more rapid
progression through the usual phases of clinical development.
Regardless of whether clinical development programs proceed in discrete phases

with separate studies or via a more seamless approach, an adequate body of data,
including data to inform the risk of vaccine-associated ERD, will be needed as
clinical development progresses to support the safety of vaccinating the proposed
study populations and number of participants and, for later stage development, to
ensure that the study design is adequate to meet its objectives.
FDA can provide early advice, and potentially concurrence in principle, on plans
for expedited/seamless clinical development. However, sponsors should plan to
submit summaries of data available at each development milestone for FDA
review and concurrence prior to advancing to the next phase of development.
Conducting clinical trials in the setting of a public health emergency presents

operational challenges. FDA has issued guidance to provide general
considerations to assist sponsors in assuring the safety of trial participants,
maintaining compliance with good clinical practice (GCP), and minimizing risks
to trial integrity for the duration of the COVID-19 public health emergency. It
should be noted that not all of the recommendations in that guidance may be
applicable to vaccine development, given some of the different considerations for
these products (Ref. 15).
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B. Trial Populations
Once acceptable pre-clinical data are available, FIH and other early phase studies
(which typically expose 10–100 participants to each vaccine candidate being
evaluated) should first enroll healthy adult participants who are at low risk of
severe COVID-19. Exclusion of participants at higher risk of severe COVID-19
from early phase studies is necessary to mitigate potential risk of vaccine-
associated ERD until additional data to inform that potential risk becomes
available through ongoing product development.
o As the understanding of COVID-19 pathogenesis continues to evolve,

exclusion criteria should reflect the current understanding of risk factors for
more severe COVID-19, such as those described by the Centers for Disease
Control and Prevention (Ref. 16).
o Older adult participants (e.g., over 55 years of age) may be enrolled in FIH
and other early phase studies so long as they do not have medical
comorbidities associated with an increased risk of severe COVID-19. Some
preliminary safety data in younger adults (e.g., 7 days after a single
vaccination) should be available prior to enrolling older adult participants,
especially for vaccine platforms without prior clinical experience.
o If possible, early clinical studies should also exclude participants at high risk
of SARS-CoV-2 exposure (e.g., healthcare workers).
Sponsors should collect and evaluate at least preliminary clinical safety and
immunogenicity data for each dose level and age group (e.g., younger versus older
adults) to support progression of clinical development to include larger numbers
(e.g., hundreds) of participants and participants at higher risk of severe COVID-19.
o Preliminary immunogenicity data from early phase development should

include assessments of neutralizing vs. total antibody responses and Th1 vs.
Th2 polarization.
o Additional data to further inform potential risk of vaccine-associated ERD and

to support progression of clinical development, if available, may include
preliminary evaluation of COVID-19 disease outcomes from earlier clinical
development and results of non-clinical studies evaluating protection and/or
histopathological markers of vaccine-associated ERD following SARS-CoV-2
challenge.
To generate sufficient data to meet the BLA approval standard, late phase clinical
trials to demonstrate vaccine efficacy with formal hypothesis testing will likely
need to enroll many thousands of participants, including many with medical
comorbidities for trials seeking to assess protection against severe COVID-19.
o Initiation of late phase trials should be preceded by adequate characterization

of safety and immunogenicity (e.g., in a few hundred participants for each
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vaccine candidate, dose level, and age group to be evaluated) to support

general safety, potential for vaccine efficacy, and low risk of vaccine-
associated ERD.
o Results of non-clinical studies evaluating protection and/or histopathological

markers of vaccine-associated ERD following SARS-CoV-2 challenge and
COVID-19 disease outcomes from earlier clinical development are other
potentially important sources of information to support clinical trials with
thousands of participants.
Although establishing vaccine safety and efficacy in SARS-CoV-2 naïve

individuals is critical, vaccine safety and COVID-19 outcomes in individuals with
prior SARS-CoV-2 infection, which might have been asymptomatic, is also
important to examine because pre-vaccination screening for prior infection is
unlikely to occur in practice with the deployment of licensed COVID-19 vaccines.
Therefore, COVID-19 vaccine trials need not screen for or exclude participants
with history or laboratory evidence of prior SARS-CoV-2 infection. However,
individuals with acute COVID-19 (or other acute infectious illness) should be
excluded from COVID-19 vaccine trials.
FDA encourages the inclusion of diverse populations in all phases of vaccine

clinical development. This inclusion helps to ensure that vaccines are safe and
effective for everyone in the indicated populations.
o FDA strongly encourages the enrollment of populations most affected by

COVID-19, specifically racial and ethnic minorities.
o Evaluation of vaccine safety and efficacy in late phase clinical development in

adults should include adequate representation of elderly individuals and
individuals with medical comorbidities.
o FDA encourages vaccine developers to consider early in their development

programs data that might support inclusion of pregnant women and women of
childbearing potential who are not actively avoiding pregnancy in pre-
licensure clinical trials (Ref. 17).
o It is important for developers of COVID-19 vaccines to plan for pediatric

assessments of safety and effectiveness, given the nature of the COVID-19
public health emergency, and to help ensure compliance with the Pediatric
Research Equity Act (PREA) (section 505B of the FD&C Act (21 U.S.C.
355c)) (Ref. 18). The epidemiology and pathogenesis of COVID-19, and the
safety and effectiveness of COVID-19 vaccines, may be different in children
compared with adults. In order to ensure compliance with 21 CFR Part 50
Subpart D (Additional safeguards for children in clinical investigations),
considerations on the prospect of direct benefit and acceptable risk to support
initiation of pediatric studies, and the appropriate design and endpoints for
pediatric studies, should be discussed in the context of specific vaccine
development programs.
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C. Trial Design
Early phase trials often aim to down-select among multiple vaccine candidates
and/or dosing regimens via randomization of participants to different treatment
groups. While including a placebo control and blinding are not required for early
phase studies, doing so may assist in interpretation of preliminary safety data.
Later phase trials, including efficacy trials, should be randomized, double-blinded,

and placebo controlled.
o An individually randomized controlled trial with 1:1 randomization between

vaccine and placebo groups is usually the most efficient study design for
demonstrating vaccine efficacy. Other types of randomization, such as cluster
randomization, may be acceptable but require careful consideration of
potential biases that are usually avoided with individual randomization.
o An efficacy trial that evaluates multiple vaccine candidates against a single

placebo group may be an acceptable approach to further increase efficiency,
provided that the trial is adequately designed with appropriate statistical
methods to evaluate efficacy.
o If the availability of a COVID-19 vaccine proven to be safe and effective

precludes ethical inclusion of a placebo control group, that vaccine could serve
as the control treatment in a study designed to evaluate efficacy with non-
inferiority hypothesis testing.
Protocols for adaptive trials should include pre-specified criteria for adding or
removing vaccine candidates or dosing regimens, and protocols for seamless trials
should include pre-specified criteria (e.g., safety and immunogenicity data) for
advancing from one phase of the study to the next.
Follow-up of study participants for COVID-19 outcomes (in particular, for severe
COVID-19 disease manifestations) should continue as long as feasible, ideally at
least one to two years, to assess duration of protection and potential for vaccine-
associated ERD as immune responses to the vaccine wane.
Efficacy trials should include contingency plans for continued follow up and
analysis of safety and effectiveness outcomes in the event that a safe and effective
vaccine becomes available (e.g., as demonstrated in a planned interim analysis or
as demonstrated in another clinical trial). In that case, discussion with the agency
may be necessary to address ethical arguments to break the blind and offer vaccine
to placebo recipients.
In cases where statistical equivalency testing of vaccine immune responses in

humans is required to support manufacturing consistency (clinical lot-to-lot
consistency trial), this testing can be incorporated into the design of an efficacy
trial and does not need to be conducted in a separate study.
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D. Efficacy Considerations
Either laboratory-confirmed COVID-19 or laboratory-confirmed SARS-CoV-2

infection is an acceptable primary endpoint for a COVID-19 vaccine efficacy trial.
o Acute cases of COVID-19 should be virologically confirmed (e.g., by RT-

PCR).
o SARS-CoV-2 infection, including asymptomatic infection, can be monitored

for and confirmed either by virologic methods or by serologic methods
evaluating antibodies to SARS-CoV-2 antigens not included in the vaccine.
Standardization of efficacy endpoints across clinical trials may facilitate

comparative evaluation of vaccines for deployment programs, provided that such
comparisons are not confounded by differences in trial design or study
populations. To this end, FDA recommends that either the primary endpoint or a
secondary endpoint (with or without formal hypothesis testing) be defined as
virologically confirmed SARS-CoV-2 infection with one or more of the following
symptoms:
o Fever or chills
o Cough
o Shortness of breath or difficulty breathing
o Fatigue
o Muscle or body aches
o Headache
o New loss of taste or smell
o Sore throat
o Congestion or runny nose
o Nausea or vomiting
o Diarrhea
As it is possible that a COVID-19 vaccine might be much more effective in

preventing severe versus mild COVID-19, sponsors should consider powering
efficacy trials for formal hypothesis testing on a severe COVID-19 endpoint.
Regardless, severe COVID-19 should be evaluated as a secondary endpoint (with
or without formal hypothesis testing) if not evaluated as a primary endpoint. FDA
recommends that severe COVID-19 be defined as virologically confirmed SARS-
CoV-2 infection with any of the following:
or PaO2/FiO2 < 300 mm Hg)

o Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation or ECMO)
o Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring
vasopressors)
o Significant acute renal, hepatic, or neurologic dysfunction
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o Admission to an ICU
o Death
SARS-CoV-2 infection (whether or not symptomatic) should be evaluated as a

secondary or exploratory endpoint, if not evaluated as a primary endpoint.
The above diagnostic criteria may need to be modified in certain populations; for
example, in pediatric patients and those with respiratory comorbidities. Sponsors
should discuss their proposed case definitions with the Agency prior to initiating
enrollment.
E. Statistical Considerations
To ensure that a widely deployed COVID-19 vaccine is effective, the primary

efficacy endpoint point estimate for a placebo-controlled efficacy trial should be at
least 50%, and the statistical success criterion should be that the lower bound of
the appropriately alpha-adjusted confidence interval around the primary efficacy
endpoint point estimate is >30%.
o The same statistical success criterion should be used for any interim analysis
designed for early detection of efficacy.
o A lower bound 30% but >0% may be acceptable as a statistical success

criterion for a secondary efficacy endpoint, provided that secondary endpoint
hypothesis testing is dependent on success on the primary endpoint.
For non-inferiority comparison to a COVID-19 vaccine already proven to be

effective, the statistical success criterion should be that the lower bound of the
appropriately alpha-adjusted confidence interval around the primary relative
efficacy point estimate is >-10%.
For each vaccine candidate, appropriate statistical methods should be used to

control type 1 error for hypothesis testing on multiple endpoints and/or interim
efficacy analyses.
Late phase studies should include interim analyses to assess risk of vaccine-
associated ERD (see section F) and futility.
Study sample sizes and timing of interim analyses should be based on the
statistical success criteria for primary and secondary (if applicable) efficacy
analyses and realistic, data-driven estimates of vaccine efficacy and incidence of
COVID-19 (or SARS-CoV-2 infection) for the populations and locales in which
the trial will be conducted.
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F. Safety Considerations
The general safety evaluation of COVID-19 vaccines, including the size of the
safety database to support vaccine licensure, should be no different than for other
preventive vaccines for infectious diseases. Safety assessments throughout
clinical development should include:
o Solicited local and systemic adverse events for at least 7 days after each study
vaccination in an adequate number of study participants to characterize
reactogenicity (including at least a subset of participants in late phase efficacy
trials).
o Unsolicited adverse events in all study participants for at least 21–28 days
after each study vaccination.
o Serious and other medically attended adverse events in all study participants
for at least 6 months after completion of all study vaccinations. Longer safety
monitoring may be warranted for certain vaccine platforms (e.g., those that
include novel adjuvants).
o All pregnancies in study participants for which the date of conception is prior
to vaccination or within 30 days after vaccination should be followed for
pregnancy outcomes, including pregnancy loss, stillbirth, and congenital
anomalies.
The pre-licensure safety database for preventive vaccines for infectious diseases
typically consists of at least 3,000 study participants vaccinated with the dosing
regimen intended for licensure. FDA anticipates that adequately powered efficacy
trials for COVID-19 vaccines will be of sufficient size to provide an acceptable
safety database for each of younger adult and elderly populations, provided that no
significant safety concerns arise during clinical development that would warrant
further pre-licensure evaluation.
COVID-19 vaccine trials should periodically monitor for unfavorable imbalances

between vaccine and control groups in COVID-19 disease outcomes, in particular
for cases of severe COVID-19 that may be a signal for vaccine-associated ERD.
o Studies should include pre-specified criteria for halting based on signals of

potential vaccine-associated ERD.
o FDA recommends use of an independent data safety monitoring board

(DSMB) (Ref. 18) for vaccine-associated ERD and other safety signal
monitoring, especially during later stage development.
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VI. POST-LICENSURE SAFETY EVALUATION – KEY CONSIDERATIONS
As with all licensed vaccines, there can be limitations in the safety database accrued
from the pre-licensure clinical studies of a COVID-19 vaccine. For example:
o The number of subjects receiving a COVID-19 vaccine in pre-licensure
clinical studies may not be adequate to detect some adverse reactions that may
occur infrequently.
o Pre-licensure safety data in some subpopulations likely to receive a COVID-19
vaccine (e.g., pregnant individuals, or individuals with medical comorbidities)
may be limited at the time of licensure.
o For some COVID-19 vaccines, the safety follow-up period to monitor for
possible vaccine-associated ERD and other adverse reactions may not have
been completed for all subjects enrolled in pre-licensure clinical studies before
the vaccine is licensed.
For COVID-19 vaccines, it is likely that during the early postmarketing period, a
large population might be vaccinated in a relatively short timeframe. Thus, FDA
recommends early planning of pharmacovigilance activities before licensure.
To facilitate accurate recording and identification of vaccines in health records,

manufacturers should consider establishment of individual Current Procedural
Terminology (CPT) codes and the use of bar codes to label the immediate
container.
B. Pharmacovigilance Activities for COVID-19 Vaccines
Routine pharmacovigilance for licensed biological products includes expedited

reporting of serious and unexpected adverse events as well as periodic safety
reports in accordance with 21 CFR 600.80 (Postmarketing reporting of adverse
experiences).
FDA recommends that at the time of a BLA submission for a COVID-19 vaccine,
applicants submit a Pharmacovigilance Plan (PVP) as described in the FDA
Guidance for Industry; E2E Pharmacovigilance Planning (Ref. 20). The contents
of a PVP for a COVID-19 vaccine will depend on its safety profile and will be
based on data, which includes the pre-licensure clinical safety database, preclinical
data, and available safety information for related vaccines, among other
considerations.
The PVP should include actions designed to address all important identified risks,
important potential risks or important missing information.
Pharmacoepidemiologic studies or other actions to evaluate notable potential risks,
such as vaccine-associated ERD, should be considered. FDA may recommend
one or more of the following as components of a PVP for a COVID-19 vaccine:
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o Submission of reports of specific adverse events of interest in an expedited

manner beyond routine required reporting;
o Submission of adverse event report summaries at more frequent intervals than
specified for routine required reporting;
o Ongoing and/or extended safety follow-up (under an IND) for vaccine-
associated ERD of subjects enrolled in pre-licensure clinical studies;
o A pharmacoepidemiologic study to further evaluate (an) important identified
or potential risk(s) from the clinical development program, such as vaccine-
associated ERD or other uncommon or delayed-onset adverse events of special
interest;
o A pregnancy exposure registry that actively collects information on
vaccination during pregnancy and associated pregnancy and infant outcomes
(Ref. 21).
C. Required Postmarketing Safety Studies
Section 505(o)(3) of the FD&C Act (21 U.S.C. 355(o)(3)) authorizes FDA to
require certain postmarketing studies or clinical trials for prescription drugs
approved under section 505(b) of the FD&C Act (21 U.S.C. 355(b)) and
biological products approved under section 351 of the PHS Act (42 U.S.C. 262)
(Ref. 22). Under section 505(o)(3), FDA can require such studies or trials at the
time of approval to assess a known serious risk related to the use of the drug, to
assess signals of serious risk related to the use of the drug, or to identify an
unexpected serious risk when available data indicate the potential for a serious
risk. Under section 505(o)(3), FDA can also require such studies or trials after
approval if FDA becomes aware of new safety information, which is defined at
section 505-1(b)(3) of the FD&C Act (21 U.S.C. 355-1(b)(3)).
For COVID-19 vaccines, FDA may require postmarketing studies or trials to

assess known or potential serious risks when such studies or trials are warranted.
VII. DIAGNOSTIC AND SEROLOGICAL ASSAYS – KEY CONSIDERATIONS
Diagnostic assays used to support the pivotal efficacy analysis (e.g., RT-PCR)
should be sensitive and accurate for the purpose of confirming infection and
should be validated before use.
Assays used for immunogenicity evaluation should be suitable for their intended
purpose of assessing relevant immune responses to vaccination and be validated
before use in pivotal clinical trials.
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VIII. ADDITIONAL CONSIDERATIONS
A. Additional Considerations in Demonstrating Vaccine Effectiveness
Given the current state of knowledge about COVID-19, the most direct approach
to demonstrate effectiveness for a COVID-19 vaccine candidate is based on
clinical endpoint efficacy trials showing protection against disease (see section V.
D. above).
Once additional understanding of SARS-CoV-2 immunology, and specifically

vaccine immune responses that might be reasonably likely to predict protection
against COVID-19, is acquired, accelerated approval of a COVID-19 vaccine
pursuant to section 506 of the FD&C Act (21 U.S.C. 356) and 21 CFR 601.40
may be considered if an applicant provides sufficient data and information to meet
the applicable legal requirements. For a COVID-19 vaccine, it may be possible to
approve a product under these provisions based on adequate and well-controlled
clinical trials establishing an effect of the product on a surrogate endpoint (e.g.,
immune response) that is reasonably likely to predict clinical benefit.
A potential surrogate endpoint likely would depend on the characteristics of the

vaccine, such as antigen structure, mode of delivery, and antigen processing and
presentation in the individual vaccinated. For example, an immune marker
established for an adenovirus-based vaccine cannot be presumed applicable to a
VSV-based vaccine, given that the two vaccines present antigen in different ways
and engender different types of protective immune responses.
Since SARS-CoV-2 represents a novel pathogen, a surrogate endpoint reasonably

likely to predict protection from COVID-19 should ideally be derived from human
efficacy studies examining clinical disease endpoints. If the surrogate endpoint is
derived from other data sources, sponsors should consult the FDA to reach
agreement on the use of the surrogate endpoint.
An adequate dataset evaluating the safety of the vaccine in humans would need to
be provided for consideration of licensure.
For drugs granted accelerated approval, postmarketing confirmatory trials have

been required to verify and describe the predicted effect on clinical benefit. These
studies should usually be underway at the time of the accelerated approval, 21
CFR Part 601, Subpart E, and must be completed with due diligence (section
506(c)(3)(A) of the FD&C Act (21 U.S.C. 356(c)(3)(A)) and 21 CFR 601.41).
If it is no longer possible to demonstrate vaccine effectiveness by way of

conducting clinical disease endpoint efficacy studies, the use of a controlled
human infection model to obtain evidence to support vaccine efficacy may be
considered. However, many issues, including logistical, human subject protection,
ethical, and scientific issues, would need to be satisfactorily addressed. At this
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time no controlled human infection models for SARS-CoV-2 have been

established or characterized.
B. Emergency Use Authorization
An Emergency Use Authorization (EUA) may be issued only after several

statutory requirements are met (section 564 of the FD&C Act (21 U.S.C. 360bbb-
2)) (Ref. 23). Among these requirements is a determination by FDA that the
known and potential benefits of a product, when used to diagnose, prevent, or treat
serious or life-threatening diseases, outweigh the known and potential risks of the
product.
Issuance of an EUA (Ref. 23) may be appropriate for a COVID-19 vaccine

provided the standard for issuing an EUA is met. Issuance of an EUA for a
COVID-19 vaccine prior to the completion of large randomized clinical efficacy
trials could reduce the ability to demonstrate effectiveness of the investigational
vaccine in a clinical disease endpoint efficacy trial to support licensure, and such
clinical disease endpoint efficacy trials may be needed to investigate the potential
for vaccine-associated ERD. Thus, for a vaccine for which there is adequate
manufacturing information, issuance of an EUA may be appropriate once studies
have demonstrated the safety and effectiveness of the vaccine but before the
manufacturer has submitted and/or FDA has completed its formal review of the
biologics license application.
In the case of investigational vaccines being developed for the prevention of

COVID-19, any assessment regarding an EUA would be made on a case by case
basis considering the target population, the characteristics of the product, the
preclinical and human clinical study data on the product, and the totality of the
available scientific evidence relevant to the product.
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IX. REFERENCES
1. COVID-19 Public Health Emergency: General Considerations for Pre-IND Meeting Requests
for COVID-19 Related Drugs and Biological Products; Guidance for Industry, May 2020,
2. Guidance for Industry: Process Validation: General Principles and Practices, January 2011,
3. Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls
Information and Establishment Description Information for a Vaccine or Related Product,
January 1999, https://www.fda.gov/media/73614/download.
4. Perlman S and Dandekar AA, 2005, Immunopathogenesis of Coronavirus Infections:

Implications for SARS, Nat Rev Immunol 5: 917-927, https://doi.org/10.1038/nri1732.
5. Haagmans BL, Boudet F, Kuiken T, deLang A, et al., 2005, Protective immunity induced by
the inactivated SARS coronavirus vaccine, Abstract S 12-1 Presented at the X International
Nidovirus Symposium, Colorado, Springs, CO.
6. Tseng C-T, Sbrana E, Iwata-Yoshikawa N, Newman P, et al., 2012, Immunization with SARS
Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS
Virus, PloS One, 7(4): e35421,
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035421.
7. Yasui F, Kai C, Kitabatake M, Inoue S, et al., 2008, Prior Immunization With Severe Acute
Respiratory Syndrome (SARS) – associated Coronavirus (SARS-CoV) Nucleocapsid Protein
Causes Severe Pneumonia in Mice Infected with SARS-CoV, J Immunol, 181(9): 6337-6348,
https://www.jimmunol.org/content/181/9/6337.long.
8. Bolles M, Deming D, Long K, Agnihothram S, et al., 2011, A Double-Inactivated Severe

Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection In Mice
And Induces Increased Eosinophilic Proinflammatory Pulmonary Response Upon Challenge,
J Virol 85(23) 12201-12215, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209347/.
9. Agrawal AS, Tao X, Algaissi A, Garron T, et al., 2016, Immunization With Inactivated
Middle East Respiratory Syndrome Coronavirus Vaccine Leads To Lung Immunopathology
On Challenge With Live Virus, Hum Vaccin Immunother, 12(9): 2351-2356,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027702/.
10. Guidance for Industry: Considerations For Plasmid DNA Vaccines For Infectious Disease
Indications, November 2007, https://www.fda.gov/media/73667/download.
11. [Intentionally left blank.]
12. Guidance for Industry: Considerations For Developmental Toxicity Studies For Preventive
And Therapeutic Vaccines For Infectious Disease Indications, February 2006,
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13. World Health Organization, WHO Guidelines On Nonclinical Evaluation Of Vaccines,

Annex 1, WHO Technical Report Series, 2005; 927:31-63,
https://www.who.int/biologicals/publications/trs/areas/vaccines/nonclinical_evaluation/ANN
EX%201Nonclinical.P31-63.pdf?ua=1.
14. World Health Organization, Guidelines On The Nonclinical Evaluation Of Vaccine

Adjuvants And Adjuvanted Vaccines, Annex 2, WHO Technical Report Series, TRS 987:59-
100, https://www.who.int/biologicals/areas/vaccines/TRS_987_Annex2.pdf?ua=1.
15. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public
Health Emergency; Guidance for Industry, Investigators, and Institutional Review Boards,
March 2020 and updated June 2020, https://www.fda.gov/media/136238/download.
16. Centers for Disease Control and Prevention, Coronavirus Disease 2019 (COVID-19) At Risk
for Severe Illness, last reviewed May 14, 2020, https://www.cdc.gov/coronavirus/2019-
ncov/need-extra-precautions/groups-at-higher-risk.html.
17. Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials; Draft
Guidance for Industry, April 2018, https://www.fda.gov/media/112195/download.*
18. Draft Guidance for Industry: How to Comply with the Pediatric Research Equity Act,
September 2005, https://www.fda.gov/media/72274/download.*
19. Guidance for Industry: Establishment and Operation of Clinical Trial Data Monitoring
Committees, March 2006, https://www.fda.gov/media/75398/download.
20. Guidance for Industry: E2E Pharmacovigilance Planning, April 2005,

21. Postapproval Pregnancy Safety Studies; Draft Guidance for Industry, May 2019,
https://www.fda.gov/media/124746/download.*
22. Guidance for Industry: Postmarketing Studies and Clinical Trials — Implementation of
Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act, April 2011,
23. Emergency Use Authorization of Medical Products and Related Authorities; Guidance for
Industry and Other Stakeholders, January 2017, https://www.fda.gov/media/97321/download.
* When finalized, this guidance will represent FDA’s current thinking on this topic.
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Marks Decl.
Exhibit F
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July 23, 2021
Electronic Submission
Division of Dockets Management

Department of Health and Human Services
5630 Fishers Lane, Room 1061
Rockville, MD 20852
CITIZEN PETITION
This petition for administrative action is submitted on behalf of CAALM, the Coalition
related relevant provisions of the Federal Food, Drug, and Cosmetic Act or the Public Health
Service Act to request th
-19 vaccine.
The Food and Drug Administration (FDA) has granted Emergency Use Authorizations (EUAs) to
three COVID-19 vaccines, enabling rapid, and widespread vaccine rollout across the United
States. These EUAs do not have any built-in expiration date, and therefore vaccines can
continue to be lawfully distributed under EUA even after a future date when a public health
emergency no longer exists.
Approximately seven months have passed since the first EUAs were granted, and two vaccine
manufacturers now seek licensure (approval) and have submitted Biologics License Applications
(BLAs). Other manufacturers have indicated similar intentions, as well as intentions for EUAs for
additional pediatric populations.
We believe the FDA should not prematurely grant a license to any COVID-19 vaccine until all
necessary efficacy and safety studies are completed and substantial evidence demonstrates the
benefits of an individual COVID-19 vaccine product outweigh the harms for the indicated,
recipient population. We are concerned that the premature licensure of a COVID-19 vaccine
can seriously undermine public confidence in regulatory authorities, particularly if long-term
safety issues were to emerge following licensure.
In this petition, we outline efficacy and safety measures that must be met before serious
consideration is given to granting a BLA of any COVID-19 vaccine. These measures include:
1. Completing at least 2 years of follow-up of participants originally enrolled in pivotal

clinical trials, even if the trials were unblinded and now lack a placebo control. All
vaccine manufacturer phase 3 trials were already designed with this planned duration.
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2. Ensuring, prior to including in the list of populations for which a vaccine is approved,
that there is substantial evidence of clinical effectiveness that outweighs harms in
special populations such as: infants, children, and adolescents; those with past SARS-
CoV-2 infection; immunocompromised; pregnant women; nursing women; frail older
adults; and individuals with cancer, autoimmune disorders, and hematological
conditions.
3. Requiring thorough safety assessment of spike proteins being produced in-situ by the
pharmacokinetics, and tissue specific toxicity.

4. Completion of vaccine biodistribution studies from administration site and safety
implications of mRNA translation in distant tissues.
5. Thorough investigation of all severe adverse reactions reported following COVID-19
vaccination, such as deaths, reported in the United States and global pharmacovigilance
systems.
6. Assessment of safety in individuals receiving more than two doses.
7. Inclusion of gene delivery and therapy experts in the Vaccines and Related Biological
Products Advisory Committee (VRBPAC), in recognition of the fact that the novel COVID
vaccines work on the premise of gene delivery, in contrast to conventional vaccines.
8. Enforcing stringent conflict of interest requirements to ensure individuals involved in
data analysis and BLA-related decision making processes have no conflict of interests
with vaccine manufacturers.
A COVID-19 vaccine BLA should be approved when and only when substantial evidence
demonstrates the benefits of a specific product outweigh the harms for the indicated, recipient
population.
This means that the following are invalid reasons to approve a COVID-19 vaccine:
To ensure vaccines are accessible after the public health emergency has ended. COVID-
19 vaccines granted an emergency use authorization (EUA) can be lawfully used after
the expiry of the SARS-CoV-2 public health emergency declaration. (This is made clear
by the many products for Ebola and Zika viruses which still have active EUAs. 1)
To ensure adequate access to vaccines across the population. A BLA is not necessary to
assure access to COVID-19 vaccines. Unlike normal licensing, in which widespread use
of a drug or vaccine follows approval, EUAs for COVID-19 vaccines have enabled, and
continue to enable, their widespread use. Ensuring access to vaccines is irrelevant to
the considerations for issuance of a BLA because broad access to COVID-19 vaccines has
already been accomplished.
To enable vaccine mandates.

purview. Furthermore, a mandate should only be considered once the evidentiary
conditions are met for a BLA (demonstrating that benefits outweigh harms).
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To bolster public confidence. Like mandates, approving a medical product in order to

bolster public confidence is backward logic a
before substantial evidence that population-based evidence of clinical effectiveness is
superior to harms may contribute to public wariness and hesitancy, not only about
COVID-19 vaccines, but other vaccines and public health authorities more broadly. An
approval may bolster public confidence, but it is not a valid reason to approve.
Regardless of any legitimacy of each of the above reasons, none provides grounds to approve a
COVID-19 vaccine.
The widespread use of a COVID-19 vaccine under EUA, particularly for a limited amount of time,
also is not a valid reason to approve a product. Even if vaccine recipients are followed up within
observational studies, such studies may have important design biases and flaws, and their
conclusions, especially concerning clinical effectiveness outcomes, may not be reliable.
Premature FDA approval of any COVID-19 vaccine could negatively impact the health and safety
of US residents, with global ramifications considering the international importance of FDA
decisions. It also could set a precedent of lowered standards for future vaccine approvals. For
these reasons and due to the compelling need to ensure the safety and efficacy of any COVID-
19 vaccine licensed by the FDA and to allow Petitioner the opportunity to seek emergency
judicial relief should the instant Petition be denied, it is respectfully requested that FDA act on
the instant Amended Petition by July 30, 2021.
I. ACTIONS REQUESTED
Petitioner request that the FDA, prior to granting any license for a COVID-19 vaccine:
1. Confirm, in revised Guidance, that the FDA expects a minimum of 2 years of follow-up of
participants enrolled in pivotal clinical trials, even if trials are unblinded and lack a
placebo control.
2. Require data demonstrating substantial evidence of clinical effectiveness that outweighs

harms, in all special populations, as a condition of consideration of including these
populations among the indicated populations. Special populations include: infants,
children, and adolescents; those with past SARS-CoV-2 infection; immunosuppressed
individuals; those with history of or current cancer; individuals with hematological
disorders or autoimmune diseases; pregnant or nursing women; and frail older adults.
3. Require data on the safety and pharmacokinetic profiles of the spike protein.
4. Require data from biodistribution studies investigating the actual COVID-19 vaccines.
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5. Require data from pharmacovigilance systems in the US and globally documenting a

thorough investigation of serious adverse events, carried out by independent, impartial
individuals.
6. Clarify in revised Guidance that safety data from individuals receiving more than 2
vaccine doses must be submitted.
7. Ensure the inclusion of experts in gene therapy in the VRBPAC.
8. Ensure that the analysis of data and decisions regarding any COVID-19 vaccine BLA
application are informed by experts with no financial or research relationships with any
vaccine manufacturers within the last 36 months, both within FDA and amongst the
composition of the VRBPAC.
II. STATEMENT OF GROUNDS
Here, in the order as above, we set out the rationale for each requested action.
1. Confirm, in revised Guidance, that the FDA expects a minimum of 2 years of follow-up
of participants enrolled in pivotal clinical trials, even if trials are unblinded and lack a
placebo control. Rationale:
a. Requiring at least 2 years is consistent with the 2 year follow-up duration
prospectively proposed by the manufacturers when they registered their
ongoing phase 3 trials of COVID-19 vaccines (Moderna: NCT04470427, Pfizer:
NCT04368728, Janssen: NCT04505722) and consistent with the June 2020 FDA
guidance on COVID-19 vaccines which stated participants should be followed for
COVID- 2
b. Important adverse event signals can be detected in clinical trials. This is true
despite enrolling tens of thousands of participants, which is still too few to
assess rare adverse events. For example, a serious blood clot occurring in the
phase 3 Janssen clinical trial led to an initial trial pause in October 2020. 3
c. Two year follow-up from trials allows the detection of commonly experienced
longer-term adverse effects that may not manifest until many months following
vaccination.
d. Two year follow-up from trials would also allow for more detailed assessment of
infection, re-infection, infectiousness, and the monitoring of immune response
over time, among all vaccinated participants.
e. The quality of data collection in clinical trials can be expected to be superior to
passive data collection systems like the Vaccine Adverse Event Reporting System
(VAERS). Therefore, trials of at least 2 years duration provide a valuable chance
to develop a more complete understanding of the adverse event profile in the
general population as well as in specific groups, such as individuals of
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reproductive age, immunocompromised individuals, and different age groups,

including adolescents and young children.
f. The quality of data on adverse events during an ongoing trial can be improved
while the trial is ongoing (e.g., improving the range of types of adverse events
that are systematically assessed), as and when evidence from other data sources
(e.g., pre-clinical or pharmacovigilance) show any trends or indicate specific
types of adverse events of special interest.
g. Finally, the expectation of at least 2 years of follow-up prior to BLA also carries
the advantage of longer-term data collection from other available sources (e.g.,
MedWatch/VAERS, V-safe, Vaccine Safety Datalink, FDA-CMS, BEST & PRISM, VA
Electronic Health Records & data warehouse, Department of Defense DMSS, and
Genesis HealthCare (Brown University & NIH-National Institute of Aging), as well
as other medical claims databases).
2. Require data demonstrating substantial evidence of clinical effectiveness that

outweighs harms, in all special populations, as a condition of consideration of
including these populations among the indicated populations. Special populations
include: infants, children, and adolescents; those with past SARS-CoV-2 infection;
immunosuppressed individuals; those with history of or current cancer; individuals
with hematological disorders or autoimmune diseases; pregnant or nursing women;
and frail older adults. Rationale:
a. The efficacy and safety of medicines often differs amongst populations such as
healthy young adults vs. older adults, men vs. women, or SARS-CoV-2 survivors
vs. never-exposed individuals.
b. For example, the relative risks of SARS-CoV-2 infection, hospitalization, and
death are considerably lower in infants, children, and adolescents in comparison
to adults.4,5
c. For example, individuals who experienced past SARS-CoV-2 infection (which are
now believed to be a significant minority of many subpopulations 6) are likely to
have immunity to subsequent infections for as long or longer than immunity
conferred by vaccine,7 10 and may also be at heightened risk for adverse
effects.11 14
d. The ongoing phase 3 trials of COVID-19 vaccines (Moderna: NCT04470427,
Pfizer: NCT04368728, Janssen: NCT04505722) largely (or wholly) excluded the
following important populations in which there is reason to believe the effects of
the product may differ from the populations enrolled in the trial:
i. Infants, children, and adolescents
ii. Those with past SARS-CoV-2 infection
iii. Those who are immunosuppressed
iv. Those with history of or current cancer
v. Those with hematological disorders
vi. Those with autoimmune diseases
vii. Those who are pregnant or nursing
viii. Frail older adults (including those living in nursing homes)
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e. The question is not simply whether there is efficacy, but how much efficacy
exists in these populations, what kind of efficacy (e.g. reduction in risk of
symptomatic COVID-19 vs. reduction in risk of hospitalization or death), and do
efficacy advantages outweigh potential harms in these populations.
f. Before these special populations can be considered for inclusion amongst the
approved indicated populations, data demonstrating substantial evidence of
clinical effectiveness that outweighs harms in these specific populations, are
needed.
3. Require data on the safety and pharmacokinetic profiles of the spike protein.
Rationale:
a. In-situ production of SARS-CoV-2 spike protein is the target mechanism of action
of all COVID-19 vaccines with an EUA at present. Therefore, the safety profile of
spike protein itself (i.e., in the absence of virus) must be thoroughly understood
in the range of populations on the indications list.
b. Recently, evidence of systemic circulation of spike protein or its components in
subjects post-immunization was reported.15 All studies we are aware of to date
raise concerns about the safety of spike protein, 16 28 and the concentration of
circulatory spikes was correlated to the disease severity in COVID-19 patients. 29
c. Required studies must, at a minimum, address these concerns:
i. Coagulopathy issues, including blood clots, hemorrhage,
thrombocytopenia, heart attack, and strokes. According to the VAERS, as
of May 21, 2021, there have been a total of 1,222 reports of
thrombocytopenia/low platelets; and 6,494 (112 in 0-24 year-olds)
reports of blood clots/strokes.
ii. Reproductive issues, including menstrual irregularities, reduced fertility,
miscarriages, and preterm births. According to VAERS, as of May 21,
2021, there were 511 reports of miscarriage and 522 reports of uterine
hemorrhage (including 88 in women older than 50 years). The vaccines
induce the generation of antibodies to attack spike protein, which are
genetically similar to proteins produced by the placenta. 30 To date, no
vaccine sponsors have conducted immunologic studies of spike protein
involvement with proteins involved in placental development.
iii. Carcinogenesis. There is preliminary and theoretical evidence that the
spike protein may promote cancer.31,32 Considering the potential for
annual booster vaccinations, COVID-19 vaccines should be treated
similarly to medication taken for chronic conditions on a long term basis.
Carcinogenic potential is important to characterize.
iv. Transmission of spike protein (or its fragments) from vaccinated
individuals, such as through breast milk and associated risk in neonates
and infants. According to the UK Medicines & Healthcare products
Regulatory Agency, there are 921 reports of exposure via breast milk
following AstraZ
vaccine.
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v. Neurological disorders, including Guillain-Barré syndrome, acute

disseminated encephalomyelitis, transverse myelitis, encephalitis,
myelitis, encephalomyelitis, meningoencephalitis, meningitis,
encephalopathy, demyelinating diseases, and multiple sclerosis.
vi. Cardiac issues, including myocardial infarction, myocarditis and
pericarditis, among others. According to the VAERS, as of May 21, 2021,
there have been a total of 1,598 reports of heart attacks (24 reported in
0-24 year-olds; 501 resulted in death).
vii. Autoimmune diseases, including thyroiditis and diabetes mellitus,
immune thrombocytopenia, autoimmune hepatitis, primary biliary
cholangitis, systemic sclerosis, autoimmune disease for skeletal muscles
(myasthenia gravis, myositis such as polymyositis, dermatomyositis, or
other inflammatory myopathies)
viii. Studies should be conducted in individuals of both sexes 33 and all ages.
We cannot assume that the effects of spike protein are the same across
populations of all ages, sex, and across pre-existing conditions.
4. Require data from biodistribution studies investigating the actual COVID-19 vaccines.
Rationale:
a. Data from the biodistribution studies submitted by Moderna and Pfizer suggests
that the vaccines distribute widely in the body, including to the liver, brain,
heart, lung, adrenals, ovaries, and testes, among many other tissues. 34,35 (See
Tables 1a, 1b, and 2 below for studies R-[?]-0072 and 185350 submitted by
Pfizer and study 5002121 submitted by Moderna.)
b.
- 34 36
c. Instead of presenting novel biodistribution studies of the COVID-19 vaccine

formulations, sponsors presented substitute studies to FDA for an EUA during
the pandemic. 34 36
d. Therefore, novel biodistribution studies investigating the actual COVID-19
vaccines are necessary.
e. Biodistribution studies would be required for any small molecule pharmaceutical
drug submitted for approval (i.e. New Drug Application), and should be
conducted on the COVID-19 vaccines as well as these novel vaccines which work
on the premise of gene delivery--very different to conventional vaccines.
f. Biodistribution studies help inform an understanding of vaccine transfection to
various tissues (away from injection site) spurring various distant tissues to
produce spike proteins and consequent autoimmune response against the
of the
nature of potential short and long term adverse events. At this point in time, in
which other data sources exist to characterize short term harms of COVID-19
vaccines with an EUA, the utility of biodistribution studies to characterize long
term adverse effects and better understand potential mechanism(s) of action of
short and long term harms, remains critically important.
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g. Necessary studies must, at a minimum, address these concerns related to

biodistribution, as well as the effects of vaccines in the body:
i. The need to know basic pharmacokinetic parameters, including
absorption, distribution, metabolism, and excretion (ADME).
ii. Effects of multiple doses. ADME may change depending on dose and
cumulative dose and should be investigated. This is more important
than usual as the whole purpose of all COVID-19 vaccines with an EUA
therefore repeated injections should result in different rates of

clearance of spike protein from the blood, and different rates of
immune attack on spike protein producing cells.
iii. The impact of body mass index (size of deltoid muscle) and vaccine
distribution away from injection site, implications for dose estimation
for lean or younger age groups or frail older adults.
iv. The duration of the studies must be sufficient to fully understand the
complete distribution and elimination of the injected vaccine and its
carrier and other constituents. For example, data from the substitute
(see Tables 1a, 1b, and 2 below for
studies R-[?]-0072 and 185350 submitted by Pfizer and study 5002121
submitted by Moderna) showed levels of drug product increasing at
the 48 hour mark, but it is unknown what occurred after 48 hours as
this was apparently the study cut off.37
v. Potential side effects (safety review) in those organs/tissues with a
detectable proportion of injected vaccine (antigen or novel excipients)
from the circulatory system.
5. Require data from pharmacovigilance systems in the US and globally documenting a

thorough investigation of serious adverse events, carried out by independent,
impartial individuals. Rationale:
a. A major testament to the overall short-term safety of a medical product is the
absence of serious adverse events (SAEs) when administered to millions. COVID-
19 vaccines have now been administered to hundreds of millions of individuals,
and it is vital that all reports of SAEs are thoroughly investigated to determine
whether the vaccine played any role in the SAE.
b. The most serious of all SAEs is death, and a CDC webpage on VAERS discusses
4,863 reports of death after COVID-19 vaccination reported between December
14, 2020 and May 24, 2021. 38 CDC states that:
i. al
information to learn more about what occurred and to determine
ii.
notified and CDC requests medical records to further asse
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iii.
autopsy, and medical records has not established a causal link to
COVID- 38
c. However, the FDA has stated that VAERS staff do not contact family members to
designed to determine causality of adverse events, there is not a mechanism to

follow-up with families for additional details. The determination of the cause of
death is done by the certifying official who completes the death certificate or the
39
d. Regulators in other countries have conducted detailed case investigations (e.g.

lowing COVID-19
vaccination 40,41).
e. FDA must require evidence of a thorough investigation into deaths and other
SAEs investigations that include contacting families to obtain a full medical
history and personal accounts (in the case of deaths) and those who experienced
the adverse event (in the case of other SAEs). Event adjudication, as done on
data safety monitoring boards, must be in place in order to carry out detailed
case investigations, and must be carried out by independent, impartial
individuals.
6. Clarify in revised Guidance that safety data from individuals receiving more than 2
vaccine doses must be submitted by vaccine manufacturers. Rationale:
a. There is wide speculation that COVID-19 vaccines may become offered as annual
vaccines, much like influenza vaccines, and regulators have already released
guidance to this effect.42
b. Some manufacturers, such as Pfizer and Moderna, have indicated that a third
dose may be necessary within the first 12 months. Other manufacturers may
present similar claims in the future.43
c. The safety profile of multiple doses, possibly more than 70 doses across an
average lifetime, must be considered at the time of licensure. Phase 3 trial data
make clear that the safety profile differs by dose (e.g. dose 2 of the Pfizer and
Moderna vaccines induce more severe systemic adverse events than dose 1). 44,45
d. Information on the types and severity of adverse events that emerge following
the administration of additional doses is necessary to better characterize long
term safety.
7. Ensure the inclusion of experts in gene therapy in the VRBPAC. Rationale:

a. The COVID-19 vaccines produced by Pfizer, Moderna, and Janssen (as well as
AstraZeneca, CanSinoBio (China) and Gamaleya Research Institute (Russia)) are
gene based vaccines. Their mechanism of action differs substantially from all
other vaccines that have been used on populations globally, as these novel
vaccines work on the premise of gene delivery, and may therefore be considered
a type of gene therapy. These gene based vaccines involve entering the cell,
where the overwhelming majority of critical body activities occur, and utilizing
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Angela Spelsberg, MD, SM Linda Wastila, BSPharm, Patrick Whelan, MD PhD

Comprehensive Cancer Center MSPH, PhD Associate Clinical Professor of
Aachen Professor, Pharmaceutical Pediatrics
Aachen, Germany Health Services Research David Geffen School of
University of Maryland School Medicine at UCLA
affiliation is included for of Pharmacy Los Angeles, California, U.S.A.
identification purposes only. 220 Arch Street, Baltimore,
Maryland 21201, U.S.A. affiliation is included for
Erick Turner, MD *
Dr. Wastila is serving as the identification purposes only.
Associate Professor of Representative of CAALM
Psychiatry Kim Witczak
Oregon Health & Science affiliation is included for President/Co-Founder
University identification purposes only. Woodymatters
Portland, Oregon, U.S.A. Minneapolis, Minnesota, U.S.A.
affiliation is included for

identification purposes only.
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http://dx.doi.org/10.1056/NEJMoa2035389
46. Thacker PD. Covid-19: How independent were the US and British vaccine advisory committees?
BMJ [Internet]. 2021 May 26;373:n1283. Available from: http://dx.doi.org/10.1136/bmj.n1283
47. Moderna. SARS-CoV-

[summary of pharmacokinetic studies] [Internet]. 2021 [cited 2021 May 29]. Available from:
https://www.pmda.go.jp/drugs/2021/P20210519003/400256000 30300AMX00266 I100 1.pdf#pa
ge=7
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Marks Decl.
Exhibit G
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August 23, 2021
Linda Wastila, BSPharm, MSPH, PhD

Representative
Coalition Advocating for Adequately Licensed Medicines (CAALM)
Re: Citizen Petition (Docket Number FDA-2021-P-0786)
Dear Petitioner,
This letter responds to the citizen petition that the Coalition Advocating for Adequately Licensed
Medicines (CAALM) (the Petitioner, you) submitted to the Food and Drug Administration
(FDA, the Agency, we) relating to licensure of vaccines to prevent Coronavirus Disease 2019
(COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (the
CP).
In the CP, Petitioner requests that FDA:
that the FDA expects a minimum of 2 years of follow-up of

participants enrolled in pivotal clinical trials, even if trials are unblinded and lack a placebo
substantial evidence of clinical effectiveness that outweighs

harms, in all special populations, as a condition of consideration of including these
populations among the indicated
children, and adolescents; those with past SARS-CoV-2 infection; immunosuppressed
individuals; those with history of or current cancer; individuals with hematological disorders
or autoimmune diseases; pregnant or
and pharmacokinetic profil
ribution studies investigating
stems in the US and globally documenting a
thorough investigation of serious adverse events, carried out by independent, impartial
ta from individuals receiving more than 2
decisions regarding any COVID-19 vaccine BLA

application are informed by experts with no financial or research relationships with any
vaccine manufacturers within the last 36 months, both within FDA and amongst the
CP at 3-4.
U.S. Food and Drug Administration

10903 New Hampshire Avenue
Silver Spring, MD 20993
www.fda.gov
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This letter responds to the CP in full. FDA has carefully reviewed the CP and other relevant
information available to the Agency. Based on our review of these materials and for the reasons
described below, we conclude that the CP does not contain facts demonstrating any reasonable
grounds for the requested action. In accordance with 21 CFR § 10.30(e)(3), and for the reasons
stated below, FDA is denying the CP.
In this letter, we discuss the requirements for licensed vaccines. We then turn to the requests
contained in the CP. We consider each of your requests in light of the legal standards for FDA
action, and provide our conclusions based on the facts, the science, and the law.
I. Background
There is currently a pandemic of respiratory disease, COVID-19, caused by a novel coronavirus,
SARS-CoV-2. The COVID-19 pandemic presents an extraordinary challenge to global health.
On January 31, 2020, the Department of Health and Human Services (HHS) issued a declaration
of a public health emergency related to COVID-19.1 On February 4, 2020, pursuant to section
564 of the FD&C Act, the Secretary of HHS determined that there is a public health emergency
that has a significant potential to affect national security or the health and security of U.S.
citizens living abroad, and that involves the virus that causes COVID-19. 2 On the basis of such
determination, on March 27, 2020, the Secretary then declared that circumstances exist justifying
the authorization of emergency use of drugs and biological products during the COVID-19
3
In
addition, on March 13, 2020, the Presidential declared a national emergency in response to
COVID-19.4
Commercial vaccine manufacturers and other entities are developing COVID-19 vaccine
candidates, and clinical studies of these vaccines are underway and/or have been
completed. Between December 11, 2020 and February 27, 2021, FDA issued emergency use
authorizations for three vaccines to prevent COVID-19, including vaccines sponsored by Pfizer
Inc. (Pfizer); ModernaTX, Inc. (Moderna); and Janssen Biotech, Inc. (Janssen), a pharmaceutical
company of Johnson & Johnson. FDA received a Biologics License Application (BLA) for the
COVID-19 vaccine, BNT162b2, intended to prevent COVID-19 in individuals 16 years of age
and older. As announced by FDA on August 23, 2021, the Agency is issuing a biologics license
1
Secretary of Health and Human Services Alex M. Azar, Determination that a Public Health Emergency Exists
(Originally issued Jan. 31, 2020, and subsequently
renewed), https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.
2
HHS, Determination of Public Health Emergency, 85 FR 7316, February 7, 2020,
https://www.federalregister.gov/documents/2020/02/07/2020-02496/determination-of-public-health-emergency.
3
HHS, Emergency Use Authorization Declaration, 85 FR 18250, April 1, 2020,
https://www.federalregister.gov/documents/2020/04/01/2020-06905/emergency-use-authorization-declaration.
4
Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19)
Outbreak, issued March 13, 2020, https://trumpwhitehouse.archives.gov/presidential-actions/proclamation-
declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/.
2
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for this COVID-19 vaccine (COVID-19 Vaccine, mRNA; Comirnaty) to BioNTech

Manufacturing GmbH.5,6
II. Vaccines That Are FDA-Licensed Meet Relevant Statutory Requirements
1. Vaccines Are Shown to Be Safe, Pure, and Potent at the Time of Licensure
FDA has a stringent regulatory process for licensing vaccines. 7,8 The Public Health Service
Act (PHS Act) authorizes FDA to license biological products, including vaccines, if they have
9
Prior to approval by FDA, vaccines are
extensively tested in non-clinical gulations describe some of the
extensive data and information that each sponsor of a vaccine must submit to FDA in order to
consider licensing the vaccine. FDA requires
gs, data derived from nonclinical and clinical
safety, purity, and potency; a full description of manufacturing
methods for the product; data esta through the dating period; and a
representative sample of the product and summaries of results of tests performed on the lot(s)
represented by the sample.10
As is evident from the gulations, the licensure process for
a vaccine requires the sponsor to establish, through carefully controlled laboratory and clinical
studies, as well as through other data, that the product is safe and effective for its approved
data, as well as other information, to help assess whether the

safety, purity, and potency of a vaccine has been demonstrated. 11
are met is a vaccine licensed.
FDA regulations explicitly state that se application or issuance of
a biologics license shall constitute a determination that the establishment(s) and the product meet
12
applicable requirements to ensure the continued safety, purit
Therefore, the manufacturers of vaccines that have been licensed in the U.S. have necessarily
demonstrated the safety of the vaccines within the meaning of the applicable statutory and
regulatory provisions before the vaccines were licensed and allowed to be marketed.
thorough process for evaluating the safety of vaccines, see
Appendix I of this letter, Aspects of Vaccine Development and Process for Licensure.
5
BioNTech Manufacturing GmbH is the biologics license holder for this vaccine, which is manufactured by Pfizer
Inc. for BioNTech Manufacturing Gm
6
The basis for FDA's licensure decision is set forth in FDA's Summary Basis for Regulatory Action for the
BioNTech application. This memorandum will be posted on fda.gov. We incorporate by reference the SBRA for the
BLA.
7
CDC, Ensuring the Safety of Vaccines in the United States, February 2013,
https://www.cdc.gov/vaccines/hcp/patient-ed/conversations/downloads/vacsafe-ensuring-bw-office.pdf.
8
Vaccine Safety Questions and Answers, last updated March 2018, https://www.fda.gov/vaccines-blood-
biologics/safety-availability-biologics/vaccine-safety-questions-and-answers.
9
42 U.S.C. § 262(a)(2)(C)(i)(I).
10
21 CFR § 601.2(a).
11
Vaccines, last updated January 2021, https://www.fda.gov/vaccines-blood-biologics/vaccines.
12
21 CFR § 601.2(d) (emphasis added).
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2. Vaccine Safety Continues to Be Monitored Post-Licensure

continues after licensure of the product. Once the licensed
vaccine is on the market, post-marketing surveillance of vaccine safety is conducted in order to
detect any rare, serious, or unexpected adverse events, as well as to monitor vaccine lots. FDA
employs multiple surveillance systems and databases to continue to evaluate the safety of these
vaccines. In certain cases, FDA may require the manufacturer to conduct post-marketing studies
to further assess known or potential serious risks.
For more information on post-licensure safety monitoring of vaccines, see Appendix II of this
letter, Aspects of Vaccine Postmarketing Safety Monitoring.
III. Discussion
The CP makes a series of requests regarding the data to be submitted in support of licensure of
vaccines to prevent COVID-19. Much of the key data supporting licensure applications is
developed during the clinical trial process, whic investigational new drug
process.13
A. Investigational New Drugs
Before a vaccine is licensed (approved) by FDA for use by the public, FDA requires that it
undergo a rigorous and extensive development progr
effectiveness. This development program encompasses preclinical research (laboratory research,
animal studies14) and clinical studies. At the preclinical stage, the sponsor focuses on collecting
the data and information necessary to establish that the product will not expose humans to
unreasonable risks when used in limited, early-stage clinical studies. Clinical studies, in humans,
are conducted under well-defined conditions and with careful safety monitoring through all the
phases of the investigational new drug process. erning the conduct of
clinical investigations are set out at 21 CFR Part 312.
Before conducting a clinical investigation in the U.S. in which a new drug or biological product
is administered to humans, a sponsor must submit an investigational new drug application (IND)
to FDA.15 The IND describes the proposed clinical study in detail and, among other things,
helps protect the safety and rights of human subjects.16 In addition to other information, an IND
must contain information on clinical protocols and clinical investigators. Detailed protocols for
proposed clinical studies permit FDA to assess whether the initial-phase trials will expose
subjects to unnecessary risks. Information on the qualifications of clinical investigators
(professionals, generally physicians, who oversee the administration of the experimental drug)
permits FDA to assess whether they are qualified to fulfill their clinical trial duties. The IND
13
See 21 CFR § 312.2 (explaining that the IND regulations apply to clinical investigations of both drugs and
biologics).
14
We support the principles of
encourage sponsors to consult with us if they wish to use a non-animal testing method they believe is suitable,
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency
to an animal test method.
15
See 21 CFR § 312.20(a).
16
For additional information regarding the IND review process and general responsibilities of sponsor-investigators
related to clinical investigations see Investigational New Drug Applications Prepared and Submitted by Sponsor-
Investigators; Draft Guidance for Industry, May 2015, https://www fda.gov/media/92604/download.
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includes commitments to obtain informed consent from the research subjects, to obtain review of
the study by an institutional review board (IRB),17 and to adhere to the investigational new drug
regulations.
Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical
trials, unless FDA informs the sponsor that the trial may begin earlier. During this time,
reviewing an IND are, in all phases of the
investigation, to assure the safety and rights of subjects, and, in Phase 2 and Phase 3, to help
assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of
eness and safety.18
in effect, the sponsor may conduct a clinical
investigation of the product, with the investigation generally being divided into three phases.
With respect to vaccines, the initial human studies, referred to as Phase 1 studies, are generally
safety and immunogenicity studies performed in a small number of closely monitored subjects.
Phase 2 studies may include up to several hundred individuals and are designed to provide
information regarding the incidence of common short-term side effects such as redness and
swelling at the injection site or fever and to further describe the immune response to the
investigational vaccine. If an investigational new vaccine progresses past Phase 1 and Phase 2
studies, it may progress to Phase 3 studies. For Phase 3 studies, the sample size is often
determined by the number of subjects required to establish the effectiveness of the new vaccine,
which may be in the thousands or tens of thousands of subjects. Phase 3 studies provide the
critical documentation of effectiveness and important additional safety data required for
licensing.
At any stage of development, if data raise significant concerns about either safety or
effectiveness, FDA may request additional information or studies; FDA may also halt ongoing
clinical studies. The FD&C Act provides a sp
prohibiting sponsors of clinical investigations from conducting the investigation (section
505(i)(3) of the FD&C Act; 21 U.S.C. § 355(i)(3
312.42 identify the circumstances that may justify a clinical hold. Generally, a clinical hold is an
order issued by FDA to the sponsor of an IND to delay a proposed clinical investigation or to
suspend an ongoing investigation.19
B. The Citizen Petition
In the CP, Petitioner requests that before FDA licenses any vaccine20 for COVID-19, the agency
require certain data be submitted. Because much of the relevant data is the kind that would be
17
The IRB is a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical
research. IRBs approve clinical study protocols, which describe the type of people who may participate in the
clinical study; the schedule of tests and procedures; the medications and dosages to be studied; the length of the
study; the study's objectives; and other details. IRBs make sure that the study is acceptable, that participants have
given consent and are fully informed of the risks, and that researchers take appropriate steps to protect patients from
harm. See The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective web page, last updated
November 2017, https://www.fda.gov/drugs/drug-information-consumers/fdas-drug-review-process-ensuring-drugs-
are-safe-and-effective.
18
21 CFR § 312.22(a).
19
21 CFR § 312.42(a).
20
issuing licenses, or approving a
BLA. See 21 CFR § 601.2(d); 21 CFR § 601.4(a).
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gathered during clinical trials, we interpret the CP as asking that FDA require the sponsors to
make the requested changes to their investigations, as well as, in some cases, to submit certain
other data. As explained above, with certain exceptions, clinical investigations in which a drug
is administered to human subjects must be conducted under an IND submitted to FDA by the
view of the study protocol which describes,
among other things, the design of the clinical study, including the identified endpoints and
methods for assessing the safety and effectiveness of the investigational product.
Below, we discuss the requested changes to the study design and other data submissions.
1.
evidence of clinical effectivenes
Petitioner asks that, prior to issuing a license for a COVID-19 vaccine, FDA require certain types
of clinical data, specifically:
data demonstrating substantial evidence of clinical effectiveness that outweighs harms, in all
special populations, as a condition of consideration of including these populations among the
indicated populations. Special populations include: infants, children, and adolescents; those with
past SARS-CoV-2 infection; immunosuppressed individuals; those with history of or current
cancer; individuals with hematological disorders or autoimmune diseases; pregnant or nursing
women; and frail older adults.
CP at 3.
Petitioner refers to the ongoing phase 3 trials of COVID-19 vaccines for the Moderna, Pfizer,
and Janssen products, and states th
populations. CP at 5. Petitioner states that there should be in
vs. reduction in risk of hospitalization or d .

Thus, Petitioner appears to request that FDA require evidence derived from clinical trials to
provide evidence of effectiveness for each of the identified populations, and also that clinical
trials be designed and conducted in each population to assess the effectiveness of these vaccines
to prevent COVID-19 disease of varying severity in the specified populations.
Petitioner asserts that
lower in infants, children, and adolescents

FDA addressed trial populations in the guidance.21 In the June 2020 guidance, FDA noted that
while certain exclusions were sion of participants at higher
associated [enhanced respiratory disease] until additional data to inform that potential risk
22
becomes available through
21
Development and Licensure of Vaccines to Prevent COVID-19; Guidance for Industry, June 2020 (June 2020
Guidance), https://www.fda.gov/media/139638/download.
22
June 2020 Guidance at 10.
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23
inclusion of diverse populations in all FDA also
safety and COVID-19 outcomes in individuals
with prior SARS-CoV-2 infection, which might have been asymptomatic, is also important to
examine because pre-vaccination screening for prior infection is unlikely to occur in practice
24
With respect to the pediatric population, the J

25
and effectiveness of COVID-19 vaccines, may be
pect of direct benefit and acceptable risk to
support initiation of pediatric studies, and the appropriate design and endpoints for pediatric
26
studies, should be discussed in the contex
Although the June 2020 Guidance includes various recommendations, ultimately FDA licensure
decisions are based on an evaluation of the entirety of the data contained in a BLA and a finding
outweigh its potential risks.
In assessing benefits and risks, FDA takes into account a number of factors including, but not
limited to, the evidence for benefit, the requested indication, severity of the disease or condition,
treatment alternatives, and the type and severity of adverse events. In general, the evidence for
benefit is based on the results of clinical trials. In some cases, vaccine clinical trials assess
clinical disease endpoints. In other cases, it may be scientifically acceptable to utilize
immunogenicity endpoints.
In assessing benefits for particular populations, FDA is not limited to considering evidence of
effectiveness based on clinical trial studies with disease endpoints. In some cases, FDA may
conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled
studies in adults.27 Furthermore, a study may not be needed in each pediatric age group if data
from one age group can be extrapolated to another age group.28 There are times where it is
scientifically appropriate to demonstrate effectiveness using scientifically accepted immune
marker(s) of protection or to infer effectiveness for a population through immunobridging.
In assessing risks, FDA takes into account the type, frequency, and severity of any adverse
events.
The benefit-risk assessment will be informed by the body of evidence about
and effectiveness submitted by an applicant in the BLA, the severity of the target disease, and the
target population. Thus, in approving or authorizing a vaccine for use in a particular population
(such as children), FDA will take into account the severity of the disease in the population as
well as the benefits of the vaccine.
23
Id. at 11.
24
Id.
25
Id.
26
Id.
27
See
disease and the effects of the drug are sufficiently similar in adults and pediatric patients, the Secretary may
conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults, usually
28
See
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.e., of requiring effectiveness

data from clinical trials specific to each population group and specifically designed to evaluate
disease endpoints of varying severity (e.g., hospitalization and death) in all of the specified
e scientifically valid methods of assessing safety and
effectiveness described above. Petitioner has not provided a scientific justification for why such
tools as immunobridging or extrapolation across population groups cannot be used. Therefore,
29
to require effectiveness data from clinical trials specifically
designed to assess disease endpoints of varying severity (e.g., hospitalization and death) for each
of the identified populations as a condition of licensing a COVID-19 vaccine. 30,31
29
can differ across population groups. That has been a featur

adolescents generally experiencing a milder disease course compared to older adults. But as with adults, children
and adolescents with underlying conditions such as asthma, chronic lung disease, and cancer are at higher risk than
their healthier counterparts for COVID-19-related hospitalization and death. See generally Emergency Use
Authorization (EUA) Amendment for an Unapproved
authorization of the Pfizer-BioNTech COVID-19 Vaccine for individuals 12 years and older),
https://www.fda.gov/media/148542/download. These are features of COVID-19 that FDA may consider in weighing
the risks and benefits of COVID-19 vaccines for different populations.
30
different populations, with the example of reduction of risk of hospitalization or death vs. reduction of risk of
symptomatic COVID-19, we agree that severity of disease experienced by different groups is an important
consideration that may be accounted for in a risk-benefit
request that FDA only accept the results of clinical trials that have different endpoints for different populations (e.g.,
hospitalization or death for a younger population and symptomatic COVID-19 for older populations). A clinical
trial endpoint of symptomatic disease for all populations included in the trial may provide sufficient information for
FDA to adequately assess the risks and benefits of the vaccine, and FDA may evaluate the effectiveness of the
vaccine in different populations by considering subgroup analyses of the data including analyses of vaccine
effectiveness against disease of varying severity using pre-specified case definitions.
31
we note that there is scientific uncertainty about the

duration of protection provided by previous natural infection, but that the scientific community believes that
vaccines may provide a longer duration of protection than that provided by natural infection. See CDC, COVID-19
Frequently Asked Questions, last updated August 2021, https://www.cdc.gov/coronavirus/2019-
ncov/vaccines/faq.html; Boyton, R. and D Altmann, 2021, Risk of SARS-CoV-2 reinfection after natural infection,
Lancet, 397(10280):1161-1163, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00662-
0/fulltext
In addition, you state that individuals with previous infectio

CP at 5. The sources that you cite for this proposition are unavailing. First, the Krammer et al. publication
(http://medrxiv.org/lookup/doi/10.1101/2021.01.29.21250653) does not assert safety problems with this population
receiving COVID-19 vaccines; rather, the publication asserts that these individuals could receive only one dose of
vaccine without negatively impacting their antibody titers and sparing them from unnecessary local and systemic
adverse reactions (e.g., pain, swelling, fatigue, headache, chills, fever, muscle or joint pains) while also freeing up
many urgently needed vaccine doses. The Samanovic et al. publication
(http://dx.doi.org/10.1101/2021.02.07.21251311) similarly does not identify safety concerns, but rather concludes
that prior history of COVID-19 affects adaptive immune responses to mRNA vaccination. The Camara et al.
publication (https://www.biorxiv.org/content/10.1101/2021.03.22.436441v1) asserts only that the second dose may
detailed analysis of the phenotype of the spike-specific T cells induced by COVID-19 vaccines both in naïve and
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2.
pharmacokinetic profiles of the spike protein
fety and pharmacokinetic profiles of the spike
CP at 6. In support of this request, Petitioner
on of SARS-CoV-2 spike protein is the target mechanism of action
of all COVID-19 vaccines with an EUA at present. Therefore, the safety profile of the spike
protein itself (i.e., in the absence of virus) must be thoroughly understood in the range of
populations on the indicati
This request relates to the technology used to make the COVID-19 vaccines that have been
authorized by FDA for emergency use. The Pfizer-BioNTech and Moderna vaccines contain a
piece of mRNA that instructs cells in the body to
SARS-COV-2 virus. The Janssen COVID-19 vaccine is manufactured using a specific type of
virus called adenovirus type 26 (Ad26) that delivers a piece of the DNA that is used to make the
of the SARS-CoV-2 virus.
Your request appears to be premised on the notion that licensure should be contingent on
ic protein produced by the COVID-19 vaccines
that is designed to elicit an immune response. Contrary to the assumption underlying your
request, it is not scientifically necessary to require toxicological or pharmacokinetic studies in
individuals to evaluate specific features of a vaccine outside the context of evaluating the vaccine
as a whole. In making a licensure decision, FDA determines whether the data and information
provided by a manufacturer have demonstrated that a vaccine is safe, pure, and potent. In
making a determination about the safety of a vaccine, the agency evaluates the complete
manufacturing process and whether specific features of a vaccine are such that the finished
product itself, when used at the recommended dose, is safe for the recipient. FDA applies its
Petitioner also references a preprint by Levi et al.

(https://www medrxiv.org/content/10.1101/2021.02.01.21250923v2). In the published version of that study, the
dose is sufficient in symptomatic SARS-CoV-2-exposed subjects to reach a
high titer of antibodies, suggesting no need for a second dose, partic
Levi et al. One Dose of SARS-CoV-2 Vaccine Exponentially Increases Antibodies in Individuals Who Have
Recovered from Symptomatic COVID-19, J Clin Invest. 2021;131(12):e149154:
https://www.jci.org/articles/view/149154). Levi et al. does not identify safety concerns with COVID-19 vaccines.
We note that history of infection prior to vaccination is not usually known in adverse event reports (either because it
asymptomatic and the patient never knew they had
infection). Likewise, there could be a reporting bias for a reporting system like VAERS, which relies on vaccine
recipients, healthcare providers, or others to initiate reports to the system, because individuals who were infected
previously might be more likely to report adverse events. However, FDA, together with CDC, has not become
aware of data from VAERS to suggest an increased frequency of adverse events in vaccinees who were infected
with SARS-CoV-2 prior to vaccination. FDA and CDC Medical Officers conduct on-going review of certain,
serious adverse events of special interest for the COVID vaccines. These reviews often include examination of the
narrative and other fields which would contain information about past infection, if provided. Additionally, CDC and
the VAERS Program contractor collect follow-up medical records for certain serious reports. Teams of physicians,
nurses, and other reviewers abstract key clinical details, including medical history, from these records. The
reviewers conducting these on-going surveillance efforts have not identified patterns of adverse events associated
with prior infection.
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Petitioner further states that the studies are

ong term adverse effects and better understand potential
mechanism(s) of action of short and
FDA addressed biodistribution studies in the June 2020 Guidance in the section regarding
toxicity studies. FDA recommended biodistribution studies
construct is novel in nature and there are no existing biodistribution data from the
35
FDA specified that biodistribution studies may not be necessary in
didate is made using a platform technology
utilized to manufacture a licensed vaccine or other previously studied investigational vaccines
36
Petitioner has not demonstrated the need for biodistribution studies of

ically inappropriate to support a BLA with
biodistribution data for a surrogate protein produced using the platform technology, for example
if imaging on such protein can be performed to visualize the location of the protein expression.
Because Petitioner has not explained why such alternative approaches cannot be used, we deny
4.
Systems Documenting an Investigation into Serious Adverse Events
Petitioner asks FDA to require stems in the US and globally
documenting a thorough investigation serious adverse events, carried out by independent,
administered to hundreds of millions of individuals, and it is vital that all reports of SAEs
[significant adverse events] are thoroughly investigated to determine whether the vaccine played
states that the investigat
9. Thus, Petitioner appears to be asking for
It is unclear whether Petitioner is requesting that individual manufacturers perform the

pharmacovigilance, or if Petitioner asks that FDA do so. Given that post-marketing surveillance
systems are conducted both by sponsors and FDA, we interpret the request as asking that FDA
ensure that both the agency and sponsors conduct the requested investigations.
Petitioner has not demonstrated any failures
marketing serious adverse events, so it is unclear what additional action FDA could take in
response to the CP. Therefore, we deny this request.
FDA agrees that post-marketing surveillance plays an important role. FDA is monitoring the
safety of the Authorized COVID-19 Vaccines through both passive and active safety surveillance
systems. FDA is doing so in collaboration with the Centers for Disease Control and Prevention
(CDC), the Centers for Medicare and Medicaid Services (CMS), the Department of Veterans
Affairs (VA), and other academic and large non-government healthcare data systems.
35
June 2020 Guidance, at 7.
36
Id.
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In addition, FDA participates actively in ongoing international pharmacovigilance efforts,

including those organized by the International Coalition of Medicines Regulatory Authorities
(ICMRA) and the World Health Organization (WHO). These efforts are in addition to the
pharmacovigilance efforts being undertaken by the individual manufacturers for authorized
vaccines. A coordinated and overlapping approach using state-of the art technologies has been
implemented. As part of our efforts to be transparent about our COVID-19 vaccine safety
monitoring activities, FDA is posting summaries of the key safety monitoring findings on the
FDA website.37
Passive Surveillance
VAERS is a national passive surveillance vaccine safety database that receives unconfirmed
reports of possible adverse events following the use of a vaccine licensed or authorized in the
United States. Passive surveillance is defined as unsolicited reports of adverse events that are
sent to a central database or health authority. In the United States, these are received and entered
into VAERS, which is co-managed by FDA and CDC. In the current pandemic, these reports are
being used to monitor the occurrence of both known and unknown adverse events, as providers
of COVID-19 vaccines are required to report serious adverse events to VAERS.
As part of FDA and CDC's multi-system approach to post-licensure and post-authorization

vaccine safety monitoring, VAERS is designed to rapidly detect unusual or unexpected patterns
determine if a vaccine caused or contributed to an adverse event or illness. If the VAERS data
suggest a possible link between an adverse event and vaccination, the relationship may be further
studied in a controlled fashion.38
Anyone can make a report to VAERS, including vaccine manufacturers, private practitioners,
state and local public health clinics, vaccine recipients, and their parents or caregivers.
Surveillance programs like VAERS perform a critical function by generating signals of potential
problems that may warrant further investigation.
Active Surveillance
Active surveillance involves proactively obtaining and rapidly analyzing information related to
millions of individuals and recorded in large healthcare data systems to verify safety signals
identified through passive surveillance or to detect additional safety signals that may not have
been reported as adverse events to passive surveillance systems. FDA is conducting active
surveillance using the Sentinel BEST (Biologics Effectiveness and Safety) System and the CMS
system, and is also collaborating with other federal and non-federal partners.
BEST
37
https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-
vaccines?
38
FDA, VAERS Overview, available at https://www.fda.gov/vaccines-blood-biologics/vaccine-adverse-
events/vaers-overview
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To elaborate further, the BEST system,39 which is part of the Sentinel initiative,40 comprises
large-scale claims data, electronic health records (EHR), and linked claims-EHR databases with
a data lag of approximately three months. The system makes use of multiple data sources and
enables rapid queries to detect or evaluate adverse events as well as studies to answer specific
safety questions for vaccines. The linked claims-EHR database makes it possible to study the
safety of vaccines in sub-populations with pre-existing conditions or in pregnant women. The
major partners for BEST currently are Acumen, IBM Federal HealthCare, IQVIA, and Columbia
University and many affiliated partners such as MedStar Health, BlueCross BlueShield of
America, the Observational Health Data Sciences and Informatics (OHDSI), OneFlorida,
University of California and several others.41
Using BEST, CBER plans to monitor about 15 adverse events42 that have been seen with the
deployment of previous vaccines but have yet to be associated with a safety concern for an
authorized COVID-19 vaccine at this time. CBER further plans to use the BEST system to
conduct more in-depth analyses should a safety concern be identified from sources such as
VAERS.
CMS
FDA has worked over the past several years with CMS to develop capabilities for routine and
time-sensitive assessments of the safety of vaccines for people 65 years of age and older using
the Medicare Claims database.43 Because it was already in place, this system was immediately
put into use for COVID-19 vaccine surveillance to monitor for adverse events.44
39
Biologics Effectiveness and Safety (BEST) System, https://www fda.gov/vaccines-blood-biologics/safety-
availability-biologics/cber-biologics-effectiveness-and-safety-best-system
40
https://www fda.gov/safety/fdas-sentinel-initiative
41
To confirm the utility of the BEST system for situations such as COVID-19 vaccine surveillance, a test case was
conducted. This study aimed to repli Vaccine Safety Datalink (VSD) (Klein et al.
Pediatrics 2010) that examined the databases and analytic capabilities of the new system. The objective of this study
reproduce the increased risk of febrile seizures in children receiving the first
dose of measles-mumps-rubella-varicella (MMRV) vaccine, compared to that of MMR and varicella vaccines
separately but on the same day. The results of the study met the objectives and demonstrated the ability of the BEST
Initiative data network to run a complex study protocol at multiple sites using a distributed data network and the
Observational Medical Outcomes Partnership Common Data Model (organizing disparate data sources into the same
database design using a common format).
42
CBER, Background Rates of Adverse Events of Special Interest for COVID-19 Vaccine Safety Monitoring, Draft
Protocol (December 31, 2020), https://www.bestinitiative.org/wp-content/uploads/2021/01/C19-Vaccine-Safety-
AESI-Background-Rate-Protocol-2020.pdf
43
CMS, Standard Analytical F https://www.cms.gov/Research-Statistics-Data-and-
Systems/Files-for-Order/LimitedDataSets/StandardAnalyticalFiles
44
As one example of the capabilities of this system, FDA, CMS, and CDC evaluated the risk of Guillain-Barré
syndrome (GBS) following infl Vaccine Safety Datalink, identified safety signals
suggesting an increased risk of GBS following high-dose influenza vaccinations and Shingrix vaccinations during
the 2018-2019 influenza season. CBER, CDC, and CMS formed working groups in February 2019 to refine these
safety signals in the CMS data.
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During the current pandemic, FDA, CMS, and CDC have already used the Medicare data to
publish a study showing that frailty, comorbidities, and race/ethnicity were strong risk factors of
COVID-19 hospitalization and death among the U.S. elderly.45
In summary, in collaboration and coordination with several different partners, FDA has
surveillance systems
that can detect and refine safety findings with the Authorized COVID-19 Vaccines in a relatively
rapid manner. These systems can also potentially be leveraged to assess safety in specific
subpopulations and to assess vaccine effectiveness.
Petitioner points to a CDC webpage on COVID-19 vaccines that discusses 4,863 reports to
VAERS of death after COVID-19 vaccination that describes the monitoring that is conducted in
connection with such reports.46 Petitioner suggests that this is inadequate because of an FDA
response to a question posed by one of the CP signatories on the proportion of VAERS death
reports for which FDA/CDC staff had reached out to families to collect follow-up information.
system is not designed to determine causality of
anism to follow-up with families for additional
47
However, there are indeed procedures in place to conduct continuous monitoring of
VAERS data, including deaths (though the procedures do not involve following up with
families). When FDA and CDC receive reports of deaths in VAERS, there is a mechanism for
requesting and evaluating other types of follow-up information, including associated health
records, such as hospital discharge summaries, and medical and laboratory results, death
certificates, and autopsy reports.48
5.
Vaccines and Related Biological Products Advisory Committee
(VRBPAC)
Petitioner requests that FDA ensure the inclusion of gene therapy experts on the VRBPAC
the informed perspectives of those with expertise
10. In support of this request, Petitioner states that the vaccines
produced by several manufacturers are gene based
substantially from all other vaccines that have been used on populations globally, as these novel
45
Hector S Izurieta, David J Graham, Yixin Jiao, Mao Hu, Yun Lu, Yue Wu, Yoganand Chillarige, Michael
Wernecke, Mikhail Menis, Douglas Pratt, Jeffrey Kelman, Richard Forshee, Natural History of Coronavirus Disease
2019: Risk Factors for Hospitalizations and Deaths Among >26 Million US Medicare Beneficiaries, The Journal of
Infectious Diseases https://doi.org/10.1093/infdis/jiaa767
https://academic.oup.com/jid/article/223/6/945/6039057
46
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events html.
47
Petitioner refers to a Letter to the Editor authored by one of the CP signatories that includes questions the
https://www.bmj.com/content/372/bmj.n149/rr-25.
48
See Shimabukuro et al., Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS),
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632204/ classified as serious, the
VAERS contractor requests associated health records, including hospital discharge summaries, medical and
laboratory results, and death certificates and autopsy reports for deaths. Additional MedDRA terms might be added
based on information obtained through follow-up. Also, for serious reports where the patient has not recovered from
the adverse event by the time the report was filed or recovery status was unknown, a follow-up letter is sent to the
reporter at one year requesting information on recovery
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vaccines work on the premise of gene delivery, and may therefore be considered a type of gene
es knowledgeable in the fields of

immunology, molecular biology, rDNA, virology; bacteriology, epidemiology or biostatistics,
vaccine policy, vaccine safety science, federal immunization activities, vaccine development
including translational and clinical evaluation programs, allergy, preventive medicine, infectious
49
diseases, pediatrics, mic Additionally, an advisory committee
50
may consult with experts. FDA may also add temporary voting members to the VRBPAC, for
example to provide relevant expertise.51
does not make regulatory decisions.
The premise of the CP is that certain actions n serious consideration is

CP at 1. But it is FDA, not VRBPAC, that
is authorized to determine whether to approve a BLA. Indeed, the Public Health Service Act
confers this authority to the Secretary of the Department of Health and Human Services, and this
authority has been delegated to the Commissioner of FDA. Because FDA is authorized to
approve a BLA, we do not agree that the composition of an advisory committee is determinative
of whether to approve or seriously consider approving a BLA. Accordingly, we deny your
request.
6.
and Amongst VRBPAC Have No Financial or Research
analysis of data and decisions regarding any

COVID-19 vaccine BLA application are informed by experts with no financial or research
relationships52 with any vaccine manufacturers within the last 36 months, both within FDA and
53
CP at 10. In support of this request, Petitioner
states disclosure and transparency would demonstrate the independence of FDA decision making
and that an evaluation of da th independence from vaccine
54
in the public interest. CP at 10.
49
https://www fda.gov/advisory-committees/blood-vaccines-and-other-biologics/vaccines-and-related-biological-
products-advisory-committee.
50
21 CFR § 14.31.
51
See https://www.fda.gov/advisory-committees/vaccines-and-related-biological-products-advisory-
committee/charter-vaccines-and-related-biological-products-advisory-committee.
52
You do not describe what you mean for there to be a confli
disclosure requirements established by the International Committee of Medical Journal Editors (ICMJE)
interests that could influence how they receive scientific work), but an online form we found for ICMJE does not
https://cdn-
links.lww.com/permalink/jbjs/d/jbjs 2017 03 30 tashjian e15 sdc1.pdf. That form does describe financial
conflicts of interests, see id., and gi
53
CP at 10.
54
CP at 10.
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attorney, consultant, contractor or employee apply when the employee has served within the last
year--but not longer.
In evaluating your request, we are guided by these laws and regulations, which do not contain a
36-month prohibition. We also note that you have not demonstrated that any FDA employees or
members of the VRBPAC have been improperly review of COVID-19
vaccines. We are also guided by our consideration of one of the purposes served by an FDA
advisory committee, which is that it permits the agency access to a range of perspectives from
experts with the most current knowledge. We believe that applying our existing standards for
conflict of interest will address the perception concern that the CP articulates, while
appropriately balancing the agency xpertise. Accordingly, we deny
your request.
7.
Years of Follow-Up
onfirm, in revised Guidance, that the FDA expects a minimum
of 2 years of follow-up of participants enrolled in pivotal clinical trials, even if trials are
follow-up from trials
allows the detection of commonly experienced longer-term adverse effects that may not manifest
dd to the data collection in clinical trials
in certain ways that you identify. CP at 4.
tions for follow-up of participants enrolled
in clinical trials.63 FDA does not at this time see a need to revise its guidance documents,
because FDA may communicate to individual sponsors whether there is a need to support a BLA
with a particular duration of follow-up for a clinical trial. While guidance documents allow the
agency to articulate its interpretation of or policy on a regulatory matter (21 CFR § 10.115(b)),
be specific to an individual manufacturer.
In addition, we note that there are many reasons why it may be appropriate to license some
vaccines based on follow-up of participants for less than two years. For example, if a clinical
trial enrolls subjects rapidly and the primary endpoint is the incidence of a disease such as
COVID-19 which occurs frequently, cases may accumulate quickly and may allow FDA to
assess the benefit-risk profile of the vaccine based on a shorter clinical trial duration and
participant follow-up. By contrast, if a clinical trial enrolls subjects more slowly and assesses a
disease with lower incidence, more time may be needed to accumulate a database that allows
statistically meaningful comparisons to be drawn between the vaccine and control groups.
e historical experience with
vaccines, and the fact that most adverse events that are plausibly linked to vaccination occur
within two months of vaccination.64 Furthermore, vaccine trials involve different types of
endpoints, with some trials focusing on immunogenicity endpoints and some focusing on disease
endpoints. All of these features impact the type and duration of data needed to evaluate the
benefits and risks of a vaccine.
63
See, e.g., June 2020 Guidance at 12.
64
Table VI. National Vaccine Injury Compensation Program. Rockville, MD: Health Resources and Services
Administration, 2017 (https://www hrsa.gov/sites/default/files/hrsa/vaccine-compensation/vaccine-injury-table.pdf.
opens in new tab).
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Appendix I: Aspects of Vaccine Development and Process for Licensure
A. Vaccines are Biologics and Drugs

Vaccines are both biological products under the Public Health Service Act (PHS Act) (42 U.S.C.
§ 262) and drugs under the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. §
or cure of a disease or condition of human
use in the diagnosis, cure, mitigation, treatment, or prevention of

321(g)(1)(B).
Under the PHS Act, a biological product may not be introduced or delivered for introduction into
interstate commerce unless a biologics license is in effect for the product. 42 U.S.C. §
262(a)(1)(A).
B. Clinical Investigations of Vaccines
Before a vaccine is licensed (approved) by FDA and can be used by the public, FDA requires
that it undergo a rigorous and extensive development program that includes laboratory research,
animal studies, and human clinical safety and effectiveness.
The PHS Act and the FD&C Act provide FDA with the authority to promulgate regulations that
provide a pathway for the study of unapproved new drugs and biologics. 42 U.S.C. §
262(a)(2)(A) and 21 U.S.C. § 355(i). The regulations on clinical investigations require the
submission of an Investigational New Drug application (IND), which describes the protocol, and,
among other things, assures the safety and rights of human subjects. These regulations are set
out at 21 CFR Part 312. See 21 CFR § 312.2 (explaining that the IND regulations apply to
clinical investigations of both drugs and biologics).
The regulations provide that, once an IND is in effect, the sponsor may conduct a clinical
investigation of the product, with the investigation generally being divided into three phases.
With respect to vaccines, Phase 1 studies typically enroll fewer than 100 participants and are
designed to look for very common side effects and preliminary evidence of an immune response
to the candidate vaccine. Phase 2 studies may include up to several hundred individuals and are
designed to provide information regarding the incidence of common short-term side effects, such
as redness and swelling at the injection site or fever, and to further describe the immune response
to the investigational vaccine. If an investigational new vaccine progresses past Phase 1 and
Phase 2 studies, it may progress to Phase 3 studies. For Phase 3 studies, the sample size is often
determined by the number of subjects required to establish the effectiveness of the new vaccine,
which may be in the thousands or tens of thousands of subjects. Phase 3 studies are usually of
sufficient size to detect less common adverse events.
If product development is successful and the clinical data are supportive of the proposed
indication, the completion of all three phases of clinical development can be followed by
submission of a Biologics License Application (BLA) pursuant to the PHS Act (42 U.S.C. §
262(a)), as specified in 21 CFR § 601.2.
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C. Biologics License Applications

A BLA must include data demonstrating that the product is safe, pure, and potent and that the
facility in which the product is manufactured
biological product continues to be safe, pure, a
does not consider an application to be filed until FDA determines that all pertinent information
s filing of an application indicates that the
application is complete and ready for review but is not an approval of the application.
Under § 601.2(a), FDA may approve a manufacturer
after the manufacturer submits an
from nonclinical laboratory and clinical studies which demonstrate that the manufactured
product meets prescribed requirements of safety, purity, and pote
the multidisciplinary FDA reviewer team (medical officers, microbiologists, chemists,
biostatisticians, etc.) with the Chemistry, Manufacturing, and Controls (CMC) 65 and clinical
information necessary to make a benefit-risk assessment, a
establishment(s) and the product meet the applicable require
FDA generally conducts a pre-license inspection of the proposed manufacturing facility, during
which production of the vaccine is examined in detail. 42 U.S.C. § 262(c). In addition, FDA
carefully reviews information on the manufacturing process of new vaccines, including the
results of testing performed on individual vaccine lots.
FDA scientists and physicians evaluate all the information contained in a BLA, including the
safety and effectiveness data and the manufacturing information, to determine whether the
application meets the statutory and regulatory requirements. FDA may also convene a meeting
of its advisory committee to seek input from outside, independent, technical experts from various
scientific and public health disciplines that provide input on scientific data and its public health
significance.
into account (including preservatives and adjuvants). FDA licenses a vaccine only after the
Agency has determined that the vaccine is safe and effective for its intended use, in that its
benefits outweigh its potential risks.
65
Also referred to as Pharmaceutical Quality/CMC.
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Appendix II: Aspects of Vaccine Postmarketing Safety Monitoring

Post-marketing surveillance of vaccine safety is crucial to detect any rare, serious, or unexpected
adverse events, as well as to monitor vaccine lots. Manufacturers often conduct post-marketing
observational studies. However, FDA also uses multiple tools and databases to evaluate the
safety of vaccines after they have been licensed and used in the general population.
The Vaccine Adverse Event Reporting System (VAERS) is a national passive surveillance
vaccine safety database that receives unconfirmed reports of possible adverse events following
the use of a vaccine licensed in the United States. VAERS is co-administered by FDA and the
Centers for Disease Control and Prevention (CDC). Anyone can make a report to VAERS,
including vaccine manufacturers, private practitioners, State and local public health clinics,
vaccine recipients, and their parents or caregivers. Surveillance programs like VAERS perform
a critical function by generating signals of potential problems that may warrant further
investigation.
It is often difficult to determine with certainty if a vaccine caused an adverse event reported to
VAERS. Many events that occur after vaccination can happen by chance alone. Some adverse
events are so rare that their association with a vaccine is difficult to evaluate. In addition,
VAERS often receives reports where there is no clear clinical diagnosis. FDA draws upon
multiple sources of data and medical and scientific expertise to assess the potential strength of
association between a vaccine and a possible adverse event.
Monitoring and analysis of VAERS reports typically includes daily in-depth medical review of
all serious reports, statistical data mining techniques, and epidemiological analysis. We look for
patterns and similarities in the onset timing and clinical description. We review published
literature to understand possible biologic hypotheses that could plausibly link the reported
adverse event to the vaccine. We review the pre-licensure data and any other post-marketing
studies that have been conducte
which a type of adverse event occurs in the unvaccinated general population. When necessary,
we discuss the potential adverse event with our federal and international safety surveillance
partners. We also carefully evaluate unusual or unexpected reports, as well as reports of
in the same patient after each dose received).
When there is sufficient evidence for a potential safety concern we may proceed to conduct large
studies, and we may coordinate with our federal, academic and private partners to further assess
the potential risk after vaccination. In addition, when potential safety issues arise, they are often
presented to various U.S. government advisory committees, including the Vaccines and Related
Biological Products Advisory Committee, the Advisory Committee on Immunization Practices,
the Vaccines Advisory Committee, and the Advisory Committee on Childhood Vaccines, and are
often discussed with experts from other countries and from the World Health Organization
(WHO). Federal agencies that assist in population-based vaccines safety studies include the
Centers for Medicaid and Medicare (CMS), the Department of Defense (DoD), and the Indian
Health Services (IHS). In addition, we generally communicate and work with international
regulatory authorities and international partners to conduct studies in vaccine safety.
The Vaccine Safety Datalink (VSD) project has actively monitored vaccine safety in more than
9.1 million people nationwide, over 3% of the US population. The VSD can monitor vaccine
safety with near real-time surveillance systems, which is particularly important for new vaccines.
If there is a vaccine safety signal in the VSD, chart reviews and case series analyses are done
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when assessing the possible association between a vaccine and an adverse event. If needed,
VSD is able to use its large health care database to further evaluate specific vaccine safety
concerns.
The Clinical Immunization Safety Assessment (CISA) is a national network of six medical
research centers with expertise conducting clinical research related to vaccine safety. The goals
of CISA are: to study the pathophysiologic basis of adverse events following immunization using
hypothesis-driven protocols; to study risk factors associated with developing an adverse event
following immunization using hypothesis-driven protocols, including genetic host-risk factors; to
provide clinicians with evidence-based guidelines when evaluating adverse events following
immunization; to provide clinicians with evidence-based vaccination or revaccination guidelines;
and to serve as a regional referral center to address complex vaccine safety inquiries. Advances
in genetics and immunology continue to help us further assess the safety of vaccines, and FDA
has established a genomics evaluation team for vaccine safety.
Finally, the Sentinel Initiative is a national electronic system that will continue to improve
2008 by FDA, the Sentinel System will enable FDA to actively query diverse automated
record systems, administrative and insurance
claims databases, and registries ssues quickly and securely. The
Sentinel Initiative will cover 100 million people in the U.S. It is also anticipated that Sentinel
will facilitate the development of active surveillance methodologies related to signal detection,
strengthening, and validation.
24

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Case 1:21-cv-02815-CKK Document 13-1 Filed 11/02/21 Page 1 of 161

IN THE UNITED STATES DISTRICT COURT

DECLARATION OF PETER MARKS, M.D., Ph.D.

United States 2016. In this

and blood products, and cellular, tissue, and gene therapies.

facts stated herein. This declaration is based on my personal knowledge, my background,

training, and experience and my review and consideration of information available to me in my

official duties. My conclusions have been reached in accordance therewith.

U.S.C. § 321(g)(1)(B). Vaccines are approved for

C. § 355. 42 U.S.C. § 262(a), (j).

applicant consents to inspection of the manufacturing facility. 42 U.S.C. § 262(a)(2)(C). FDA

License Applications (BLA) Process, https://www.fda.gov/vaccines-blood-

Guidance, Compliance & Regulatory Information (Biologics), https://www.fda.gov/vaccines-

blood-biologics/guidance-compliance-regulatory-information-biologics; Vaccine and Related

Biological Product Guidances, https://www.fda.gov/vaccines-blood-biologics/biologics-

guidances/vaccine-and-related-biological-product-guidances; Vaccine Development 101,

severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age

known as Pfizer-BioNTech Covid-19 vaccine, was available under an emergency use

key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19. FDA has

risks of the product; and (3

product. 21 U.S.C. § 360bbb-3(c).2

for clinical trials conducted under an

of the EUA. See Letter to

12 through 15 years old; for a third dose in certain populations

9. Additionally, FDA determined

using Pfizer-BioNTech, Comirnaty, or both (e.g., first dose of Pfizer-BioNTech followed by

authorized to receive Comirnaty for the second dose, or vice versa.

comparing it with a biological product manufactured by a different company. Under 42 U.S.C.

§ 262(k)(4), FDA may determine that a biological product

product. is defined at 42 U.S.C. § cal product

The statutory interchangeability

Comirnaty, pp. 12-13 (August 23, 2021), available at

biological products); EUA Reauthorization at 11 (Sept. 22, 2021), available at

EUA, it is your choice to receive or do not apply when these lots or

for Regulatory Action ttached as Exhibit D.

(Sept. 22, 2021), available at https://www.fda.gov/media/144414/download.

are designed to help ensure that therapies for serious

See Guidance for Industry, Expedited Programs for

Serious Conditions Drugs and Biologics (May 2014), available at

https://www.fda.gov/media/86377/download. Fast Track designation was granted for Comirnaty

on July 7, 2020. See Exhibit D, SBRA at 5.

15. In addition to granting

approval. Vaccines typically undergo three phases of clinical trial. See

-blinded).5 The study population for Phase 2/3

diabetes, and infection with HIV, hepatitis B or hepatitis C. Id. at 16.

17. In accordance with protocol (the plan that describes the

objectives, design, methodology, statistical considerations, and organization of a clinical trial,

see Glossary of Clinical Trial Terms, available at

0the,in%20other%20protocol%20referenced%20documents), participants ages 16 and older in

since the December 2020 issuance of the EUA

and Services Administration, 2017 (https://www.hrsa.gov/sites/default/files/hrsa/vaccine-

compensation/vaccine-injury-table.pdf.), FDA determined that a BLA for a COVID-19 vaccine

Licensure of Vaccines to Prevent COVID-19, at 15 (June 2020), attached as Exhibit E. Because

for C4591001 is May 2023, see

18. BNT162-01 an ongoing Phase 1/2, open-label, dose-finding study with 24

assessed, among other things, its

available are three Statistical Reviews; an

https://www.fda.gov/vaccines-blood-biologics/comirnaty (click on Approval History, Letters,

Reviews, and Related Document COMIRNATY).