Contains Nonbinding Recommendations 
Development and Licensure of 
Vaccines to Prevent COVID-19 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
October 2023   
Contains Nonbinding Recommendations 
  Preface 
 
Public Comment 
 
This guidance is being issued to assist the Agency and sponsors in the clinical development and 
licensure of vaccines for the prevention of coronavirus disease 2019 (COVID-19).  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 
Agencys 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 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 ocod@fda.hhs.gov 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 ocod@fda.hhs.gov or at 800-835-4709 or 240-402-8010.   
Contains Nonbinding Recommendations 
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 
A.  General Considerations ...................................................................................................... 6 
B.  Toxicity Studies (Refs. 9-12) .............................................................................................. 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 
A.  General 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   
Contains Nonbinding Recommendations 
Development and Licensure of 
Vaccines to Prevent COVID-19 
Guidance for Industry 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) 
  on this topic. It does not establish any rights for any person and is not binding on FDA or the public. 
  You can use an alternative approach if it satisfies the requirements of the applicable statutes and 
  regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance 
  as listed on the title page. 
 
 
I.  INTRODUCTION 
 
FDA is issuing this guidance to assist sponsors in the clinical development and licensure of vaccines 
for the prevention of Coronavirus Disease 2019 (COVID-19) which is caused by severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2).  FDA is committed to providing timely 
guidance to support the response to COVID-19.  
 
The recommendations described in the guidance are expected to assist the Agency and sponsors in 
the clinical development and licensure of vaccines for the prevention of COVID-19 and reflect the 
Agencys current thinking on this issue. 
 
Given the need to ensure that sponsors are aware of our current recommendations to facilitate timely 
development of vaccines to prevent COVID-19, this guidance is being implemented without prior 
public comment because FDA 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 Agencys good 
guidance practices. 
 
In general, FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys 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. 
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Contains Nonbinding Recommendations 
 
 
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. This guidance 
describes FDAs current recommendations regarding the data needed to facilitate clinical development 
and licensure of vaccines to prevent COVID-19. A1 t this time, the goal of new vaccine development 
programs to prevent COVID-19 should be to pursue traditional approval via direct evidence of vaccine 
safety and efficacy in protecting humans from SARS-CoV-21  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 the 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.1  FDA is committed to supporting all scientifically sound approaches to 
attenuating the clinical impact of C2 OVID-19. 
 
There are many candidate 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 
 
1 Novel devices used to administer COVID-19 vaccines raise additional issues which are not addressed in this guidance. 
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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. 1). 
 
  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. 
 
  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. 2). 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 (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). 
 
  FDA recommends that vaccine manufacturers engage in early communication with 
CBERs 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). 
 
 
 
 
IV.  NONCLINICAL DATA  KEY CONSIDERATIONS 
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A.  General 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 models2  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. 3-8). Although clinical use of COVID-19 vaccines has 
not been associated with ERD, 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. 9-12) 
 
  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). 
 
 
2 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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Contains Nonbinding Recommendations 
 
  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. 21CFR312.23(a)(8)For example, if the 
COVID-19 vaccine candidate is made using a platform technology that has been used 
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 nonclinical laboratory studies (GLP) (21 CFR Part 58). Such studies 
should be completed and analyzed 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 toxicologic 
reports to accelerate proceeding to FIH clinical 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 is 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 enzyme linked immunosorbent assays (ELISA) should be considered 
to characterize the humoral response. Evaluation of cellular responses 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 or pseudovirion virus. The assays used 
for immunogenicity 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. Taking into 
consideration the particular candidate vaccine, studies in animal models (e.g., rodents 
and non-human primates) may be 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. 
 
  For COVID-19 vaccine candidates for which 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 
 
A.  General 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 new vaccine development 
programs to prevent COVID-19 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 typical 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. 
 
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B.  Trial Populations 
 
  Once sufficient pre-clinical data are available, FIH and other early phase studies 
(which typically expose 10100 participants to each vaccine candidate being 
evaluated) should first enroll healthy adult participants who are at low risk of severe 
COVID-19. 
 
  As the understanding of COVID-19 pathogenesis continues to evolve, 
o
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. 13). 
 
  Older adult participants (e.g., over 55 years of age) may be enrolled in FIH 
o
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. 
 
  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. 
 
  Preliminary immunogenicity data from early phase development should 
o
include assessments of neutralizing vs. total antibody responses and Th1 vs. 
Th2 polarization. 
 
  Additional data to further inform potential risk of vaccine-associated ERD and 
o
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. 
 
  Initiation of late phase trials should be preceded by adequate characterization 
o
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. 
 
  Results of non-clinical studies evaluating protection and/or histopathological 
o
markers of vaccine-associated ERD following SARS-CoV-2 challenge and 
COVID-19 outcomes from earlier clinical development are other potentially 
important sources of information to support clinical trials with thousands of 
participants. 
 
  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. 
 
  FDA strongly encourages the enrollment of populations most affected by 
o
COVID-19, specifically racial and ethnic minorities.  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.   
 
  FDA encourages vaccine developers to consider early in their development 
o
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. 14).  
 
  It is important for developers of COVID-19 vaccines to plan for pediatric 
o
assessments of safety and effectiveness, given the epidemiology of COVID-
19, 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. 15).  The 
pathogenesis of COVID-19, and the safety and effectiveness of COVID-19 
vaccines, may be different in children compared with adults. Additionally, 
very young children are likely to be seronegative to SARS-CoV-2. 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 with the review division 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. 
 
  An individually randomized controlled trial with 1:1 randomization between 
o
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. 
 
  An efficacy trial that evaluates multiple vaccine candidates against a single 
o
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. 
 
  If the availability of a COVID-19 vaccine proven to be safe and effective 
o
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 vaccine induced immune responses wane. 
 
  Efficacy trials should include plans for continued follow up and analysis of safety and 
effectiveness outcomes as appropriate.  
 
  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. 
 
  Acute cases of COVID-19 should be virologically confirmed (e.g., by RT- 
o
PCR). 
 
  SARS-CoV-2 infection, including asymptomatic infection, can be monitored 
o
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, 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: 
  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 
o
 
  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: 
 
  Clinical signs at rest indicative of severe systemic illness (respiratory rate  30 
o
per minute, heart rate  125 per minute, SpO2  93% on room air at sea level 
or PaO2/FiO2 < 300 mm Hg) 
  Respiratory failure (defined as needing high-flow oxygen, noninvasive 
o
ventilation, mechanical ventilation or ECMO) 
  Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring 
o
vasopressors) 
  Significant acute renal, hepatic, or neurologic dysfunction 
o
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  Admission to an ICU 
o
  Death 
o
 
  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 COVID-19 vaccine is effective, the primary efficacy endpoint point 
estimate for a placebo-controlled clinical disease efficacy trial and the lower bound 
confidence interval should be appropriately justified. 
 
  The same statistical success criterion should be used for any interim analysis 
o
designed for early detection of efficacy. 
 
  For non-inferiority comparison to a COVID-19 vaccine already proven to be 
effective, for a study evaluating clinical disease the statistical success criterion for 
the lower bound of the appropriately alpha-adjusted confidence interval around 
the primary relative efficacy point estimate should be appropriately justified.  
 
  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: 
 
  Solicited local and systemic adverse events for at least 7 days after each study 
o
vaccination in an adequate number of study participants to characterize 
reactogenicity (including at least a subset of participants in late phase efficacy 
trials). 
 
  Unsolicited adverse events in all study participants for at least 2128 days 
o
after each study vaccination. 
 
  Serious and other medically attended adverse events in all study participants 
o
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). 
 
  All pregnancies in study participants for which the date of conception is prior 
o
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 serious adverse events and other adverse events 
of special interest that may represent signals of a vaccine-associated serious risks.  
 
  Studies should include pre-specified criteria for halting based on the 
o
occurrence, frequency, and severity of certain adverse events. 
 
  FDA recommends use of an independent data safety monitoring board 
o
(DSMB) (Ref. 16) for safety signal monitoring, especially during later 
stage development. 
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VI.  POST-LICENSURE SAFETY EVALUATION  KEY CONSIDERATIONS 
 
A.  General 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: 
  The number of subjects receiving a COVID-19 vaccine in pre-licensure 
o
clinical studies may not be adequate to detect some adverse reactions that may 
occur infrequently. 
  Pre-licensure safety data in some subpopulations likely to receive a COVID-19 
o
vaccine (e.g., pregnant individuals, or individuals with medical comorbidities) 
may be limited at the time of licensure. 
  For some COVID-19 vaccines, the safety follow-up period to monitor for 
o
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. 
 
  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. 17). 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 specific safety concerns such as myocarditis and 
pericarditis 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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  Submission of reports of specific adverse events of special interest (AESI) 
o
in an expedited manner beyond routine required reporting; 
  Submission of adverse event report summaries at more frequent intervals than 
o
specified for routine required reporting; 
  A pharmacoepidemiologic study to further evaluate (an) important identified 
o
or potential risk(s) from the clinical development program, or other 
uncommon or delayed-onset AESI (Ref. 18) 
  A pregnancy exposure registry that actively collects information on 
o
vaccination during pregnancy and associated pregnancy and infant outcomes 
or a pregnancy safety study using population -based data sources (Ref. 19). 
 
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. 20, 21). 
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 for the 
reasons described above 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 
Vesicular Stomatitis Virus-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 (see section 
506(c)(2) of the FD&C Act (21 U.S.C. 356(c)(2)) and 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.  
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IX.  REFERENCES 
 
1.  Guidance for Industry: Process Validation: General Principles and Practices, January 2011, 
https://www.fda.gov/media/71021/download. 
 
2.  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. 
 
3.  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. 
 
4.  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. 
 
5.  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. 
 
6.  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. 
 
7.  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/. 
 
8.  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/. 
 
9.  Guidance for Industry: Considerations For Plasmid DNA Vaccines For Infectious Disease 
Indications, November 2007, https://www.fda.gov/media/73667/download. 
 
 
10.  Guidance for Industry: Considerations For Developmental Toxicity Studies For Preventive 
And Therapeutic Vaccines For Infectious Disease Indications, February 2006, 
https://www.fda.gov/media/73986/download. 
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11.  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. 
 
12.  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. 
 
 
13.  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. 
 
14.  Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials; Draft 
Guidance for Industry, April 2018, https://www.fda.gov/media/112195/download.* 
 
15.  Draft Guidance for Industry: How to Comply with the Pediatric Research Equity Act, 
September 2005, https://www.fda.gov/media/72274/download.* 
 
16.  Guidance for Industry: Establishment and Operation of Clinical Trial Data Monitoring 
Committees, March 2006, https://www.fda.gov/media/75398/download. 
 
17.  Guidance for Industry: E2E Pharmacovigilance Planning, April 2005, 
https://www.fda.gov/media/71238/download. 
 
18.  Guidance for Industry: Good Pharmacovigilance Practices and 
Pharmacoepidemiologic Assessment, March 2005, 
https://www.fda.gov/media/71546/download 
 
19.  Postapproval Pregnancy Safety Studies; Draft Guidance for Industry, May 2019, 
https://www.fda.gov/media/124746/download.* 
 
20.  Postmarketing Studies and Clinical Trials  Implementation of Section 505(o)(3) of 
the Federal Food, Drug, and Cosmetic Act, Draft Guidance for Industry: April 2011, 
https://www.fda.gov/media/131980/download 
 
21.  Postmarketing Studies and Clinical Trials  Implementation of Section 505(o)(3) of 
the Federal Food, Drug, and Cosmetic Act, Draft Guidance for Industry: October 2019,  
https://www.fda.gov/media/148646/download *. 
 
* When finalized, this guidance will represent FDAs current thinking on this topic. 
20