Contains Nonbinding Recommendations 
 
Emergency Use Authorization for 
Vaccines to Prevent COVID-19 
Guidance for Industry 
 
This guidance is intended to remain in effect until November 7, 2023, 
unless superseded by a revised final guidance before that date. For 
further information, refer to 85 FR 15417, March 13, 2023, and 
https://www.federalregister.gov/documents/2023/03/13/2023-
05094/guidance-documents-related-to-coronavirus-disease-2019-covid-
19. 
 
 
   
Contains Nonbinding Recommendations 
Emergency Use Authorization for 
Vaccines to Prevent COVID-19 
 
Guidance for Industry  
 
Document issued on March 31, 2022. 
 
This document supersedes the guidance of the same title issued on  
May 25, 2021. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
March 2022   
Contains Nonbinding Recommendations 
  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 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 number 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, and from the FDA webpage 
titled Search for FDA Guidance Documents available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.  
 
Additional copies of this guidance are also available from the Office of Communication, 
Outreach and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver 
Spring, MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email 
ocod@fda.hhs.gov, or from the Internet at https://www.fda.gov/vaccines-blood-
biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances. 
 
Questions 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above. 
   
Contains Nonbinding Recommendations 
Table of Contents 
 
I.  INTRODUCTION ................................................................................................................... 1 
II.  BACKGROUND ...................................................................................................................... 2 
III.  CRITERIA AND CONSIDERATIONS FOR THE ISSUANCE OF AN EUA FOR A 
COVID-19 VACCINE ............................................................................................................. 3 
IV.  KEY LOGISTIC RECOMMENDATIONS FOR THE REQUEST FOR AN EUA FOR 
A COVID-19 VACCINE ......................................................................................................... 4 
V.  PRIORITIZATION OF REQUESTS FOR ISSUANCE OF AN EUA FOR A COVID-19 
VACCINE ................................................................................................................................ 5 
VI.  RECOMMENDATIONS REGARDING INFORMATION AND DATA TO BE 
INCLUDED IN A REQUEST FOR AN EUA FOR A COVID-19 VACCINE .................. 6 
A.  Regulatory .................................................................................................................... 6 
B.  Chemistry, Manufacturing, and Controls ................................................................. 7 
C.  Safety and Effectiveness Information ...................................................................... 10 
VII.  CONSIDERATIONS FOR CONTINUING CLINICAL TRIALS FOLLOWING 
ISSUANCE OF AN EUA FOR A COVID-19 VACCINE ................................................. 12 
VIII.  CONSIDERATION OF AN EUA FOR A COVID-19 VACCINE BY AN FDA 
ADVISORY COMMITTEE ................................................................................................. 12 
IX.  REFERENCES ...................................................................................................................... 14 
APPENDIX 1:  SUBMISSION OF INFORMATION IN PREPARATION FOR A VRBPAC 
MEETING .............................................................................................................................. 16 
A.  Preparation and submission of briefing materials for the Advisory Committee 
meeting ........................................................................................................................ 16 
B.  Process ........................................................................................................................ 16 
APPENDIX 2:  Evaluation of Vaccines to Address Emerging SARS-CoV-2 Variants .............. 18 
A.  Background ................................................................................................................ 18 
B.  Introduction ............................................................................................................... 18 
 
i 
   
Contains Nonbinding Recommendations 
Emergency Use Authorization for 
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 plays a critical role in protecting the United States (U.S.) from threats such as emerging 
infectious diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic.  FDA is 
committed to providing timely guidance to support response efforts to this pandemic.   
 
FDA is issuing this guidance to provide sponsors of requests for Emergency Use Authorization 
(EUA) for COVID-19 vaccines with recommendations regarding the data and information needed to 
support the issuance of an EUA under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for an 
investigational vaccine to prevent COVID-19 for the duration of the COVID-19 public health 
emergency.  This document supersedes the guidance of the same title issued in May 2021 (which 
superseded the guidance of the same title issued October 2020 and reissued February 2021). 
 
This policy is intended to remain in effect only for the duration of the public health emergency 
related to COVID-19 declared by the Secretary of Health and Human Services (HHS) on January 31, 
2020, effective January 27, 2020, including any renewals made by the HHS Secretary in accordance 
with section 319(a)(2) of the Public Health Service Act (PHS Act) (42 U.S.C. 247d(a)(2)). 
 
Given this public health emergency, and as discussed in the Notice published in the Federal Register 
of March 25, 2020, titled Process for Making Available Guidance Documents Related to 
Coronavirus Disease 2019, (85 FR 16949) available at https://www.govinfo.gov/content/pkg/FR-
2020-03-25/pdf/2020-06222.pdf, 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 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. 
 
The contents of this document do not have the force and effect of law and are not meant to bind the 
public in any way, unless specifically incorporated into a contract.  This document is intended only to 
provide clarity to the public regarding existing requirements under the law.  FDA guidance 
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Contains Nonbinding Recommendations 
documents, including this guidance, should be viewed only as recommendations, unless specific 
regulatory or statutory requirements are cited.  The use of the word should in FDA guidances means 
that something is suggested or recommended, but not required. 
 
 
II.  BACKGROUND 
 
There is currently a respiratory disease pandemic caused by a novel coronavirus.  The virus has been 
named SARS-CoV-2 and the disease it causes has been named Coronavirus Disease 2019 
(COVID-19).  On January 31, 2020, 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, 
there was a Presidential declaration of a national emergency in response to COVID-19.2   
 
The COVID-19 pandemic presents an extraordinary challenge to global health.  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 was first developed prior to issuance of an EUA or license for a COVID-19 vaccine 
but has been revised to take into account the EUAs currently in place for COVID-19 vaccines and 
the U.S.-licensed vaccines for the prevention of COVID-19.  This guidance describes FDAs current 
recommendations regarding the data and information needed to support the issuance of an EUA 
under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for an investigational vaccine to prevent 
COVID-19, including chemistry, manufacturing, and controls information (CMC); nonclinical data 
and information; and clinical data and information, as well as administrative and regulatory 
information.  In addition, the guidance provides recommendations regarding key information and 
data that should be submitted to a relevant investigational new drug application (IND) or cross-
referenced master file (MF) prior to submission of an EUA request in order to facilitate FDAs 
complete and timely review of such a submission, including convening the Vaccines and Related 
Biological Products Advisory Committee (VRBPAC).  This guidance also discusses FDAs current 
thinking regarding the circumstances under which the issuance of an EUA for a COVID-19 vaccine 
would be appropriate, providing additional context to the discussion regarding EUAs in the guidance 
for industry entitled Development and Licensure of Vaccines to Prevent COVID-19 (Ref. 1). 
 
These recommendations are specific to COVID-19 vaccines, which are complex biological products 
that are intended to be administered to millions of individuals, including healthy people, to prevent 
disease.  These vaccines have the potential for broad use under an EUA.  The recommendations in 
this guidance are not necessarily applicable to drugs and biological products intended for treatment 
of COVID-19, for which there may be significantly different considerations under the standard set 
forth in section 564 of the FD&C Act (21 U.S.C. 360bbb-3), reflecting the products characteristics 
 
1 Secretary of Health and Human Services, Determination that a Public Health Emergency Exists (originally issued Jan. 
31, 2020, and subsequently renewed), 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://trumpwhitehouse.archives.gov/presidential-actions/proclamation-declaring-national-
emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/.  On February 24, 2021, there was a Presidential 
Declaration continuing the national emergency concerning the COVID-19 pandemic beyond March 1, 2021.  See 
Continuation of the National Emergency Concerning the Coronavirus Disease 2019 (COVID-19) Pandemic (Feb. 24, 
2021), available at https://www.federalregister.gov/documents/2021/02/26/2021-04173/continuation-of-the-national-
emergency-concerning-the-coronavirus-disease-2019-covid-19-pandemic.   
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Contains Nonbinding Recommendations 
and anticipated clinical uses. 
 
Sponsors engaged in the development of vaccines to prevent COVID-19 should refer to the guidance 
for industry entitled Development and Licensure of Vaccines to Prevent COVID-19 (Ref. 1), the 
guidance for industry and investigators entitled COVID-19 Public Health Emergency:  General 
Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological 
Products (Ref. 2), and the guidance for industry and other stakeholders entitled Emergency Use 
Authorization of Medical Products and Related Authorities (Ref. 3). 
 
 
III.  CRITERIA AND CONSIDERATIONS FOR THE ISSUANCE OF AN EUA FOR A 
COVID-19 VACCINE 
 
On February 4, 2020, pursuant to section 564(b)(1)(C) of the FD&C Act (21 U.S.C. 360bbb-
3(b)(1)(C)), 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.  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 pandemic, pursuant to section 
564(b)(1) of the FD&C Act (21 U.S.C. 360bbb-3(b)(1)).3 
 
Based on this declaration and determination, FDA may issue an EUA after FDA has determined that 
the following statutory requirements are met (section 564 of the FD&C Act (21 U.S.C. 360bbb-3)) 
(Ref. 3): 
 
  The chemical, biological, radiological, or nuclear (CBRN) agent referred to in the March 27, 
2020, EUA declaration by the Secretary of HHS (SARS-CoV-2) can cause a serious or life-
threatening disease or condition. 
 
  Based on the totality of scientific evidence available, including data from adequate and well-
controlled trials, if available, it is reasonable to believe that the product may be effective to 
prevent, diagnose, or treat such serious or life-threatening disease or condition that can be 
caused by SARS-CoV-2. 
 
  The known and potential benefits of the product, when used to diagnose, prevent, or treat the 
identified serious or life-threatening disease or condition, outweigh the known and potential 
risks of the product.   
 
  There is no adequate, approved, and available alternative to the product for diagnosing, 
preventing, or treating the disease or condition.4 
 
3 This EUA declaration is distinct from, and is not dependent on, the declaration by the Secretary of HHS of a public 
health emergency related to COVID-19, issued on January 31, 2020, and subsequently renewed, under section 319 of the 
PHS Act.  See supra note 1.  The issuance of an EUA for a COVID-19 vaccine is not based on that January 2020 
declaration of a public health emergency and, therefore, an EUA may remain in effect beyond the duration of the public 
health emergency declaration if all other statutory conditions are met. 
4 For example, a potential alternative product may be considered unavailable if there are insufficient supplies of the 
approved alternative to fully meet the emergency need.  See section III.B.1.d of Emergency Use Authorization of 
Medical Products and Related Authorities guidance (Ref. 3). 
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Contains Nonbinding Recommendations 
 
In the case of investigational vaccines being developed for the prevention of COVID-19, any 
assessment regarding an EUA will 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. 
 
FDA acknowledges that an EUA for a COVID-19 vaccine may be requested to allow for the 
vaccines rapid and widespread deployment for administration to millions of individuals, including 
healthy people, potentially following interim results from one or more clinical trials meeting pre-
specified success criteria described in the analysis plan submitted to FDA.  In this scenario, for a 
COVID-19 vaccine for which there is adequate manufacturing information to ensure quality and 
consistency, issuance of an EUA would require a determination by FDA that the vaccines benefits 
outweigh its risks based on data from at least one well-designed Phase 3 clinical trial that 
demonstrates the vaccines safety and efficacy in a clear and compelling manner.  
 
It is FDAs expectation that, following submission of an EUA request and issuance of an EUA, a 
sponsor would continue to collect data in any ongoing trials and would also work towards 
submission of a Biologics License Application (BLA) as soon as possible5.  FDAs 
recommendations regarding the safety and effectiveness data and information outlined in section VI 
of this guidance are essential to ensure that clinical development of a COVID-19 vaccine has 
progressed far enough that issuance of an EUA for the vaccine would not interfere with the ability of 
an ongoing Phase 3 trial to demonstrate effectiveness of the vaccine to support licensure and to 
continue safety assessments, including investigating the potential for vaccine-associated enhanced 
respiratory disease (ERD).  The ability of a sponsor to accrue this information about a COVID-19 
vaccine is critical to ongoing assessment of its benefits and risks.  FDA notes that there would need 
to be an adequate plan for safety data collection among individuals vaccinated under an EUA. 
 
 
IV.  KEY LOGISTIC RECOMMENDATIONS FOR THE REQUEST FOR AN EUA FOR 
A COVID-19 VACCINE  
 
A sponsor6 considering the submission of an EUA request for an investigational COVID-19 vaccine 
should contact the Center for Biologics Evaluation and Researchs (CBERs) Office of Vaccines 
Research and Review (OVRR) as early in development as possible to discuss expectations and 
considerations for the sponsors particular vaccine. 
 
FDA also recommends that vaccine sponsors engage in early communication with CBERs Office of 
Compliance and Biologics Quality (OCBQ), Division of Manufacturing and Product Quality to 
discuss facility issues related to manufacturing of the particular vaccine. 
 
 
5 In earlier versions of this guidance, FDA included language stating that it expected sponsors to continue to collect 
placebo-controlled data in an ongoing trial for as long as feasible after submission of an EUA request and issuance of an 
EUA.  FDA has modified this language because access to a safe and effective authorized or approved COVID-19 vaccine 
may preclude the ethical continuation of blinded, placebo-controlled follow-up in ongoing clinical trials.  Additionally, 
trial participants may choose to withdraw from trial follow-up for any reason, including to receive a vaccine available to 
them under an EUA. 
6 For purposes of this guidance, the term sponsor is used when referring to the applicant, submitter, or person 
requesting an EUA. 
4 
   
Contains Nonbinding Recommendations 
In order to facilitate a complete and timely review of a request for an EUA for a COVID-19 vaccine, 
including scheduling of a meeting of FDAs VRBPAC, the following information should be 
submitted in advance of submission of an EUA request: 
 
  A detailed description of the chemistry, manufacturing, and controls information and data 
described in section VI.B of this guidance should be submitted to a relevant IND or cross-
referenced MF(s) at least one month prior to submission of an EUA request. 
 
  FDA strongly encourages the vaccine sponsor to provide FDA with notice within 24 hours 
after any interim analysis has been completed, on the basis of which submission of an EUA 
request is planned, by contacting OVRR, and to discuss proposed timelines for submission of 
an EUA request. 
 
 
V.  PRIORITIZATION OF REQUESTS FOR ISSUANCE OF AN EUA FOR A COVID-19 
VACCINE 
 
The issuance of an EUA is discretionary.  FDAs decision to review and process an EUA request, 
and ultimately issue an EUA if the relevant statutory criteria are met, is based on a determination, on 
a case-by-case basis, that such action is necessary to protect the public health in an emergency.  It is 
an authorization that the government may issue when necessary to protect the public health in an 
emergency (see section 564 FD&C Act (21 U.S.C. 360bbb-3(a)(1)), which states, in relevant part, 
subject to the provisions of this section, the Secretary may authorize the introduction into interstate 
commerce...a drug, device, or biological product intended for use in an actual or potential 
emergency).  FDAs January 2017 guidance entitled, Emergency Use Authorization of Medical 
Products and Related Authorities, (Ref. 3) describes factors that FDA intends to use in its 
prioritization of EUA requests, such as the public health need for the product, the availability and 
adequacy of the information concerning the likelihood that the product may be safe and effective in 
preventing, treating, or diagnosing the condition, and whether the product is included in government 
stakeholder stockpiles. 
 
When FDA assesses investigational COVID-19 vaccines for use under EUA, FDAs review includes:  
stringent evaluation of product quality, including a determination that the facilities producing the 
product meet appropriate standards; evaluation of the conduct of clinical trials; and assessment of 
trial data integrity.  As noted in section IV of this guidance, early interaction with the Agency is 
critical.  FDA intends to decline to review and process EUA requests in cases where it is not feasible 
for the Agency to verify any one of these characteristics.  Additionally, given the need to address 
urgent public health priorities, FDA may need to further prioritize among the EUA requests it 
receives for COVID-19 vaccine candidates.  For the remainder of the current pandemic, FDA may 
decline to review and process further EUA requests other than those for vaccines whose developers 
have engaged in an ongoing manner with the Agency during the development of their manufacturing 
process and clinical trials program as described in this guidance, Emergency Use Authorization for 
Vaccines to Prevent COVID-19.  These COVID-19 vaccine developers will have had the benefit of 
FDA feedback early and throughout the development process.  Therefore, their EUA requests are 
more likely to contain the comprehensive data and information needed to demonstrate that issuance 
of an EUA is appropriate, and the Agency is more likely to be able to confirm the validity of the 
clinical and manufacturing information submitted in the EUA request. 
 
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Contains Nonbinding Recommendations 
VI.  RECOMMENDATIONS REGARDING INFORMATION AND DATA TO BE 
INCLUDED IN A REQUEST FOR AN EUA FOR A COVID-19 VACCINE 
 
As stated in the Emergency Use Authorization of Medical Products and Related Authorities 
January 2017 guidance (Ref. 3), FDA recommends that a request for an EUA include a well-
organized summary of the available scientific evidence regarding the products safety and 
effectiveness, risks (including an adverse event profile) and benefits, and any adequate, approved, 
available alternatives to the product.  FDA recommends that the following information be submitted 
in a request for an EUA for a COVID-19 vaccine or, as applicable, that this information be submitted 
in a relevant IND or cross-referenced MF before an EUA request is submitted. 
 
A.  Regulatory 
 
The following information should be submitted in a request for an EUA for a COVID-19 
vaccine: 
 
1.  A description of the product and its intended use (e.g., identification of the serious or 
life-threatening disease or condition for which the product may be effective; where, 
when, and how the product is anticipated to be used; and/or the population(s) for 
which the product may be used).  The submission should address the following 
details: 
  Proposed use(s) under EUA  
  Proposed dosing regimen(s) and method(s) of administration for use under EUA 
  Rationale for dosing regimen 
  Information to support the use, dosing and administration of the vaccine in the 
following populations, as applicable: 
  Adults 
o
  Pediatric age groups 
o
  Other specific populations (e.g., geriatric individuals, pregnant or lactating 
o
individuals, immunodeficient individuals);  
 
2.  Available safety and effectiveness information for the product;  
 
3.  A discussion of risks and benefits, including available information concerning the 
threat posed by SARS-CoV-2 and how that threat would be addressed by the product 
under the proposed use under the EUA.  As noted above, for a preventive COVID-19 
vaccine to be potentially administered to millions of individuals, including healthy 
individuals, data adequate to inform an assessment of the vaccines benefits and risks 
and support issuance of an EUA would include not only meeting the prespecified 
success criteria for the studys primary efficacy endpoint, but also additional safety 
and effectiveness data as described below in section VI.C.3 of this guidance.  The 
discussion of the risks and benefits in the EUA request should include an assessment 
of the risks and benefits for the proposed use under the EUA, including a discussion 
of the following: 
  Any steps taken to mitigate risk or optimize benefit 
  Any recommended restrictions to ensure safe use 
  Any situations under which the product should not be used (i.e., contraindications) 
  Important information that should be considered prior to use of the EUA product; 
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Contains Nonbinding Recommendations 
 
4.  The need for the product, including identification of any approved alternative 
product(s) and their availability and adequacy for the proposed use; 
 
5.  A description of the products FDA approval status; whether the product is under an 
investigational application (e.g., if an IND is in effect or has been submitted); whether 
the product is approved in a foreign country for either the proposed use or another 
use; and information on the use of the medical product by either a foreign country or 
an international organization (e.g., the World Health Organization (WHO)).  The 
submission of the EUA request should include a brief summary of any related 
submissions to FDA and indicate which one(s) were cross-referenced in a letter to this 
file.  This information may include:  
  Related IND number(s) and a brief description of the stage of clinical testing  
  Related Pre-IND number(s) 
  Related MF number(s) and brief description of the contents; 
 
6.  Information comparable to an FDA-approved package insert; drafts of the Fact 
Sheets to be furnished to health care professionals or authorized vaccine 
administrators, as well as those to be furnished to recipients of the product, which are 
described in section E of the Emergency Use Authorization of Medical Products and 
Related Authorities guidance (Ref. 3) and typically are part of pre-EUA discussions; 
and plans for providing such information in an emergency;  
 
7.  Information regarding the supply chain, which will help FDA to assess anticipated 
availability of the vaccine for its intended recipients and whether anticipated storage 
and distribution conditions will affect the vaccines safety and effectiveness, including 
the following details: 
  Whether the product will be supplied to the U.S. Government or Vendor Managed 
Inventory (VMI) 
  Anticipated quantity of finished product on hand and the surge capabilities of the 
manufacturing site(s) 
  Details of the distributor(s) for the vaccine and plans for distribution.  
 
B.  Chemistry, Manufacturing, and Controls 
 
The EUA request should include information on chemistry, manufacturing, and controls; a 
list of each site where the product, if authorized, is or would be manufactured, relevant 
information about each site, and the current status of the manufacturing site(s) with respect to 
current good manufacturing practice (CGMP) requirements (Refs. 4, 5). 
 
As noted above, in order to facilitate a complete and timely review of an EUA request, FDA 
expects that a detailed description of the manufacturing process and controls will be provided 
in a relevant IND or cross-referenced MF(s) as it becomes available but not less than one 
month prior to submission of an EUA request.  Any manufacturing and process control data 
that will not be available at the time of submission of an EUA request should be discussed 
with FDA well in advance of the submission of the EUA request and identified in the 
submission. 
 
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Contains Nonbinding Recommendations 
Following notice by a sponsor of intent to submit an EUA request as noted above, FDA will 
continue to work with the sponsor regarding resolution of any necessary manufacturing site 
issues resulting from a site visit or other information submitted.  FDA will assess CGMP 
compliance for each manufacturing site using all available tools and information. 
 
1.  Manufacturing 
 
Sufficient data should be submitted to support drug substance (DS) and drug product (DP) 
manufacturing to ensure the quality and consistency of the vaccine product that is 
produced.  FDA generally expects a minimum of three Process Performance Qualification 
(PPQ) lots per manufacturing facility to support the consistency of vaccine quality.  In 
addition, critical process parameters and in-process controls of specific unit operations 
should be qualified/validated.  Evidence should be provided that all DS and DP 
manufacturing sites, including testing sites, are adequately qualified/validated to ensure 
that the equipment/process meets all predetermined specifications/intended purposes, and 
the production process is controlled and operates with quality oversight consistent with 
CGMP requirements.  If more than one manufacturing facility is used to produce DS and 
DP, data should be provided to support the consistency of vaccine quality between 
manufacturing sites.  
 
2.  Control of Drug Substance and Drug Product 
 
Product data as described below should be provided to support FDAs determination 
regarding the safety and effectiveness of the vaccine:   
 
a.  Documentation establishing that critical source materials used in manufacturing 
are adequately controlled, including history and qualification of cell banks and 
virus banks, identification of all animal-derived materials used for cell culture and 
virus growth, and DP excipients. 
 
b.  An evaluation and mitigation plan for potential adventitious agents. 
 
c.  Data to demonstrate that the DS is sufficiently characterized in order to identify 
and understand the critical properties that impact performance and stability. 
 
d.  A detailed description of the quality control system for all stages of 
manufacturing, including the testing program for in-process/intermediate product 
quality and DS and DP quality for release.   
 
e.  Analytical methods and qualification/validation data for all quality-indicating 
assays.  Validation data for assays used to evaluate critical vaccine qualities such 
as purity, identity, and potency are expected. 
 
f.  The DS and DP development history and manufacturing changes introduced in 
Phase 1, 2, 3 and EUA lots, including analytical comparability of DS lots with 
these changes.  Quality release data and supplementary characterization tests to 
assess the impact of the changes on the DS quality attributes should be provided. 
 
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Contains Nonbinding Recommendations 
g.  A tabular listing of all clinical studies and DP lot numbers used in each study 
including DS lot genealogy, manufacturing processes used, and the manufacturing 
site, as well as the Certificates of Analysis (CoAs) for all clinical lots used in 
clinical studies and information on any lots that were initiated but not accepted for 
release. 
 
h.  A stability plan including safety and stability-indicating tests and available 
stability data from all developmental, clinical, and commercial lots.  Data to 
support short-term stability, reflecting storage conditions during transport and 
distribution and in clinics and covering the time from dose preparation to 
administration expected. 
 
i.  Appropriate quality specifications should be established for all DP lots used under 
EUA and testing results for the final vaccine lots should be submitted to the IND 
at the time of product distribution. 
 
j.  Aseptic-process information, including the appropriate validation studies. 
 
k.  A description of sterile filtration and sterilization processes, as well as validation 
studies.  Depyrogenation of container-closure systems, if applicable, should also 
be provided. 
 
l.  Storage conditions, including the container-closure integrity, should be validated 
and this information should be provided. 
 
3.  Facilities  
 
a.  Facility information should be submitted to demonstrate that the facilities are of 
suitable size and adequately designed to prevent contamination, cross-
contamination, and mix-ups. 
 
b.  Utility information, including validation information, should be provided for all 
utilities.  For the heating, ventilation, and air conditioning (HVAC) system, it is 
important to demonstrate control by including area classifications, pressure 
differentials, and containment features where needed. 
 
c.  Manufacturing equipment should be qualified, and a list of critical equipment for 
DS and DP should be submitted. 
 
d.  Facility and equipment cleaning should be validated, and the validation should be 
submitted for review. 
 
e.  A quality control unit should be established and have the responsibility for 
oversight of manufacturing, and review and release of components, containers and 
closures, labeling, in-process material, and final products.  The quality control unit 
should have the responsibility for approving validation protocols and reports, 
investigating deviations, and instituting corrective and preventive actions. 
 
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Contains Nonbinding Recommendations 
C.  Safety and Effectiveness Information 
 
The EUA request should include the following safety and effectiveness information, which 
will inform FDAs determination regarding the products benefit-risk profile: 
 
1.  Bioassays for assessment of clinical endpoints 
 
The diagnostic bioassays that were used to assess study endpoints of clinical studies 
supportive of the EUA request should be identified.  FDA expects that the standard 
operating procedures (SOPs) and validation reports for the final assay methods, and a list 
of all laboratories where the clinical samples have been tested, will be submitted to 
support the EUA request. 
 
2.  Nonclinical:  
 
a.  A list of the nonclinical studies conducted to support vaccine effectiveness and 
safety (e.g., characterization of markers associated with enhanced disease, 
biodistribution, shedding, and attenuation) should be provided, along with the 
timelines for study completion and submission of final study reports for all 
ongoing nonclinical studies as applicable. 
 
b.  A final study report, if available, for a Developmental and Reproductive 
Toxicology (DART) study, or the timeline for study completion and submission of 
the final study report, should be provided in order to inform potential emergency 
use of the vaccine in pregnant women. 
 
3.  Clinical 
 
a.  FDA acknowledges the potential to request an EUA for a COVID-19 vaccine 
based on an interim analysis of a clinical endpoint from a Phase 3 efficacy study.  
Issuance of an EUA requires a determination that the known and potential benefits 
of the vaccine outweigh the known and potential risks.  For a preventive COVID-
19 vaccine to be potentially administered to millions of individuals, including 
healthy individuals, data adequate to inform an assessment of the vaccines 
benefits and risks and support issuance of an EUA would include not only meeting 
the prespecified success criteria for the studys primary efficacy endpoint as 
described in the guidance for industry entitled Development and Licensure of 
Vaccines to Prevent COVID-19 (Ref. 1) (i.e., a point estimate for a placebo-
controlled efficacy trial of at least 50%, with a lower bound of the appropriately 
alpha-adjusted confidence interval around the primary efficacy endpoint point 
estimate of >30%), but also additional safety and effectiveness data as described 
below in this section.  The timing of interim analyses planned for a Phase 3 study 
would thus ideally be aligned with the ability of the analyses to meet these criteria. 
 
b.  An EUA request for a COVID-19 vaccine should include all safety data 
accumulated from Phase 1 and 2 studies conducted with the vaccine, with focus on 
serious adverse events (SAEs), adverse events of special interest, and cases of 
severe COVID-19 among study subjects.  We recognize that the Phase 1 and 2 
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safety data likely will be of a longer duration than the available safety data from 
the Phase 3 trial at the time of submission of an EUA request.  The Phase 1 and 2 
data are intended to complement the available data from safety follow-up from 
ongoing Phase 3 studies. 
 
c.  Data from Phase 3 studies should include a median follow-up duration of at least 
two months after completion of the full vaccination regimen to help provide 
adequate information to assess a vaccines benefit-risk profile, including:  adverse 
events; cases of severe COVID-19 disease among study subjects; and cases of 
COVID-19 occurring during the timeframe when adaptive (rather than innate) and 
memory immune responses to the vaccine would be responsible for a protective 
effect. 
 
In addition, FDA does not expect to be able to make a favorable benefit-risk 
determination that would support an EUA without Phase 3 data that include the 
following, which will help the Agency to assess the safety of the vaccine: 
 
i.  Local and systemic solicited adverse reactions collected for the protocol-
defined duration of follow-up in an adequate number of subjects to 
characterize reactogenicity in each protocol-defined age cohort 
participating in the trial; 
 
ii.  All safety data collected up to the point at which the database is locked to 
prepare the submission of the EUA request, including a high proportion of 
enrolled subjects (numbering well over 3,000 vaccine recipients) followed 
for SAEs and adverse events of special interest for at least one month after 
completion of the full vaccination regimen;7 and 
 
iii. Sufficient cases of severe COVID-19 among study subjects to support low 
risk for vaccine-induced ERD (a total of 5 or more severe COVID-19 cases 
in the placebo group would generally be sufficient to assess whether the 
severe COVID-19 case split between vaccine vs. placebo groups supports 
a favorable benefit-risk profile or conversely raises a concern about ERD). 
 
d.  Vaccine safety and COVID-19 outcomes in individuals with prior SARS-CoV-2 
infection, who might have been asymptomatic, are important to examine because 
screening for prior infection is unlikely to occur prior to administration of 
COVID-19 vaccines under EUA.  An EUA request should therefore include 
subgroup analyses of safety and efficacy endpoints stratified by prior infection 
status at study entry, as determined by pre-vaccination serology or medical 
history. 
 
 
7 As noted in FDAs guidance for industry entitled Development and Licensure of Vaccines to Prevent COVID-19 
(Ref. 1), 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 the younger adult and elderly populations, provided that no significant safety concerns arise during clinical 
development that would warrant further evaluation. 
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e.  The EUA request should include a plan for active follow-up for safety (including 
deaths and hospitalizations, and other serious or clinically significant adverse 
events) among individuals administered the vaccine under an EUA in order to 
inform ongoing benefit-risk determinations to support continuation of the EUA. 
 
 
VII.  CONSIDERATIONS FOR CONTINUING CLINICAL TRIALS FOLLOWING 
ISSUANCE OF AN EUA FOR A COVID-19 VACCINE 
 
FDA does not consider availability of a COVID-19 vaccine under EUA, in and of itself, as grounds 
for stopping blinded follow-up in an ongoing clinical trial.  An EUA request should include strategies 
that will be implemented to ensure that ongoing clinical trials of the vaccine are able to assess long-
term safety and efficacy (including evaluating for vaccine-associated ERD as well as decreased 
effectiveness as immunity wanes over time) in sufficient numbers of subjects to support vaccine 
licensure.  These strategies should address how ongoing trial(s) will handle loss of follow-up 
information for study participants who choose to withdraw from the study in order to receive the 
vaccine under an EUA.   
 
 
VIII.  CONSIDERATION OF AN EUA FOR A COVID-19 VACCINE BY AN FDA 
ADVISORY COMMITTEE 
 
FDA expects to convene an open session of FDAs VRBPAC prior to the issuance of any EUA for a 
COVID-19 vaccine, to discuss whether the available safety and effectiveness data support 
authorization of an EUA for the specific request under review.  This discussion, which will be 
specific to the particular vaccine that is the subject of the EUA request, will be separate from, and in 
addition to, any general discussion by the VRBPAC regarding the development, authorization, and/or 
licensure of vaccines to prevent COVID-19.  A VRBPAC meeting may also include a closed session, 
if it is deemed necessary, to discuss proprietary CMC issues. 
 
FDA expects to convene the VRBPAC for consideration of an EUA request for a COVID-19 vaccine 
that, on its face, contains the information required under section 564 of the FD&C Act (21 U.S.C. 
360bbb-3) and includes the recommended data and information described above.  FDA intends to 
provide briefing materials to the VRBPAC members as far in advance of any scheduled meeting as 
practicable and intends to post a publicly available version of the briefing materials on the FDA 
webpage no later than two full business days before the day the advisory committee meeting is 
scheduled to occur. 
 
To facilitate discussion by the VRBPAC, an EUA request should be accompanied by briefing 
materials summarizing data to support the safety and effectiveness of the vaccine to be considered at 
the open session of the VRBPAC, and if requested by FDA, separate briefing materials related to 
manufacturing of the vaccine for a closed session.  The purpose of any closed session would be 
limited to the review and discussion of manufacturing information that is considered confidential 
commercial or trade secret information exempt from public disclosure. 
 
Timely consideration of the EUA request by the VRBPAC would be further facilitated by submission 
of briefing materials for the open session that the sponsor states are fully releasable.  For additional 
information regarding the process for preparation and review of briefing materials for open FDA 
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advisory committee meetings, sponsors should consult the guidance for industry entitled Advisory 
Committee Meetings  Preparation and Public Availability of Information Given to Advisory 
Committee Members (Ref. 6), although the time frames set forth in the appendix of that guidance 
may not be applicable to a meeting of the VRBPAC for a COVID-19 vaccine.  Please see Appendix 
1 for more information regarding submission of information in preparation for a VRBPAC meeting 
to consider a request for an EUA for a COVID-19 vaccine. 
   
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IX.  REFERENCES 
 
1.  Development and Licensure of Vaccines to Prevent COVID-19; Guidance for Industry, June 
2020, https://www.fda.gov/media/139638/download. 
 
2.  COVID-19 Public Health Emergency:  General Considerations for Pre-IND Meeting 
Requests for COVID-19 Related Drugs and Biological Products; Guidance for Industry and 
Investigators, May 2020, https://www.fda.gov/media/137927/download. 
 
3.  Emergency Use Authorization of Medical Products and Related Authorities; Guidance for 
Industry and Other Stakeholders, January 2017, https://www.fda.gov/media/97321/download. 
 
4.  Guidance for Industry:  Process Validation:  General Principles and Practices, January 2011, 
https://www.fda.gov/media/71021/download. 
 
5.  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. 
 
6.  Advisory Committee Meetings  Preparation and Public Availability of Information Given to 
Advisory Committee Members; Guidance for Industry, August 2008, 
https://www.fda.gov/media/75436/download. 
 
7.  Polack, F.P., et al., 2020, Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine, N. 
Engl. J. Med., 383:2603-2615, https://www.nejm.org/doi/full/10.1056/NEJMoa2034577. 
 
8.  Baden, L.R., et al., 2021, Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine, 
384:403-416, N. Engl. J. Med., https://www.nejm.org/doi/full/10.1056/NEJMoa2035389. 
 
9.  Rambaut, A., et al., 2020, Preliminary Genomic Characterization Of An Emergent SARS-
Cov-2 Lineage In The UK Defined By A Novel Set Of Spike Mutations, 
https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-
lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563. 
 
10.  Li, J., et al., 2021, The Emergence, Genomic Diversity and Global Spread of SARS-CoV-2, 
Nature, 600: 408-419, https://doi.org/10.1038/s41586-021-04188-6. 
 
11.  SARS-CoV-2 Variant Classifications and Definitions, 
https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html.   
 
12.  Cao, Y., et al., 2021, Omicron Escapes the Majority of Existing SARS-CoV-2 Neutralizing 
Antibodies, Nature, https://doi.org/10.1038/s41586-021-04385-3; 
https://www.nature.com/articles/s41586-021-04385-3_reference.pdf. 
 
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13.  Branal, L.T., et al., 2021, Outbreak Caused by the SARS-CoV-2 Omicron Variant in Norway, 
November to December 2021, Euro Surveill, https://doi.org/10.2807/1560-
7917.ES.2021.26.50.2101147.  
 
14.  Wu, K., et al., 2021, mRNA-1273 Vaccine Induces Neutralizing Antibodies Against Spike 
Mutants From Global SARS-Cov-2 Variants, BioRxiv, 
https://www.biorxiv.org/content/10.1101/2021.01.25.427948v1. 
 
   
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APPENDIX 1:  SUBMISSION OF INFORMATION IN PREPARATION FOR A VRBPAC 
MEETING 
 
A.  Preparation and submission of briefing materials for the Advisory Committee 
meeting 
 
For an open session of the VRBPAC, please plan to submit final and fully releasable briefing 
materials at the time of submission of an EUA request for a COVID-19 vaccine.   
 
As noted in section VIII of this guidance, for certain EUA requests, FDA may determine that 
a closed session of the VRBPAC to discuss proprietary CMC information would be 
appropriate.  In such circumstances, sponsors would not be expected to submit fully 
releasable briefing materials and should consult with OVRR regarding the submission of 
briefing materials for the closed session. 
 
B.  Process  
 
Final sponsor-prepared and FDA-prepared briefing documents will be made available to the 
public no later than two full business days prior to the meeting date on the FDA webpage 
under the respective Advisory Committee Meeting. 
 
Publications need not be submitted with the briefing materials.  If you choose to submit 
publications, the electronic submission should contain your actual briefing materials in one 
file and the publications in a separate file.  The briefing materials should include a references 
section that lists these publications.  Only the briefing materials will be posted on the FDA 
webpage; the file of publications will be sent to the committee members but will not be 
posted. 
 
In addition to the fully releasable briefing materials, to facilitate timely consideration of the 
EUA request by the VRBPAC, the following additional information should be provided by 
the sponsor at the time of submission of the EUA request: 
 
1.  Point of Contact for Advisory Committee Related Matters 
 
At the time of submission of the EUA request, please provide primary and alternative 
points of contacts name, title, address, e-mail address and phone numbers. 
 
2.  List of Investigators 
 
At the time of submission of the EUA request, please provide as a searchable electronic 
copy, a list of investigators, and the clinical sites for all clinical trials supporting the 
submission(s) under review. 
 
3.  Meeting Participants 
 
At the time of submission of the EUA request, please provide a list of all presenters and 
responders who will be representing you at the meeting, along with their affiliation(s).   
   
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Representational activities include presenting, responding to questions, and/or sitting in 
the Sponsor/Industry section at the meeting. 
 
Please note that there are restrictions for any current or former advisory committee 
members, or other past or present Special Government Employees (SGEs), to attend the 
meeting representing the sponsors before the Agency (5 CFR Part 2635). 
 
The goal is to avoid situations in which a current or former advisory committee member 
and/or consultant might inadvertently violate the law concerning representational 
activities.  It is a violation of ethics statute 18 U.S.C. 208 for a Federal Employee 
(including but not limited to full-time and part-time employees of the National Institutes 
of Health, Centers for Disease Control and Prevention, Department of Defense, and 
Veterans Affairs) to represent a third party before another Agency.  Please note that 
Federal Employees will not be permitted to represent your company at the meeting. 
 
4.  Meeting Day Presentation Materials (slides) 
 
It is recommended that your planned speakers slides be numbered for ease of reference 
during the meeting by the committee members.  Please provide us with an electronic 
version of the slide presentation five business days prior to the Advisory Committee 
meeting.  If back-up slides are presented, we ask that you provide the backup slides in the 
same file as your core presentation.  All slides will be also posted on FDAs webpage.  
Therefore, they must meet the requirements of section 508 of the Rehabilitation Act.8 
 
   
 
8 Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794(d)).  See also Requirements Checklists for Section 508, 
available at https://www.fda.gov/about-fda/internet-accessibility/requirements-checklists-section-508. 
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APPENDIX 2:  EVALUATION OF VACCINES TO ADDRESS EMERGING SARS-COV-2 
VARIANTS  
 
A.  Background 
 
In the U.S. there are currently two licensed COVID-19 vaccines (Comirnaty (COVID-19 
Vaccine, mRNA) and Spikevax (COVID-19 Vaccine, mRNA)); three COVID-19 vaccines 
are currently authorized for emergency use (Janssen COVID-19 Vaccine, Moderna COVID-
19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine).  Additionally, numerous COVID-19 
vaccines are in development in the U.S. and globally, many in advanced clinical trials.  The 
U.S.-licensed and authorized vaccines and many investigational COVID-19 vaccines are 
designed to elicit a protective immune response to the SARS-CoV-2 Spike (S) protein, the 
major structural protein of the virus that has an essential role in attachment and infection of 
host cells.  Several COVID-19 vaccines (e.g., mRNA vaccines and adenovirus-vectored 
vaccines expressing the S protein) have been shown to be effective in clinical studies (Refs. 
7-8).  Evidence has accumulated from laboratory studies, pre-clinical animal studies, and 
clinical studies that indicates a neutralizing antibody response, primarily directed to the S 
protein, makes an important contribution to the protective response elicited by COVID-19 
vaccines based on S protein antigens.  Nevertheless, the relative contribution of neutralizing 
antibody to protection elicited by current vaccines is not defined, and it is likely that the role 
of neutralizing antibody in protection may differ depending on the type of vaccine.  Further, 
the level of neutralizing antibody that reliably predicts protection has not been established. 
 
Like most RNA viruses, SARS-CoV-2 is constantly evolving, and new variants have emerged 
that improve virus fitness for transmission.  SARS-CoV-2 variants that include mutations in 
the S protein were identified within a few months after the start of the pandemic.  
Understanding the potential risk of SARS-CoV-2 variants to those previously unexposed to 
the virus, to previously infected individuals, and to recent vaccinees, is an area of intense 
research focus.  The emergence of SARS-CoV-2 variants with multiple mutations in the S 
protein (e.g., Alpha (B.1.1.7 lineage), Delta (B.1.617.2 and AY lineages) and Omicron 
(B.1.1.529 and BA lineages)) have raised concerns because of their increased transmission 
rates and because of evidence that current COVID-19 vaccines (herein referred to as 
prototype vaccines) licensed or authorized under EUA or otherwise in clinical development 
provide reduced protection against these variants (Refs. 9-11), at least with respect to mild 
disease (Refs. 12-14).  With the expectation that new SARS-CoV-2 variants will continue to 
emerge over time, available COVID-19 vaccines may need to be modified to adequately 
protect against disease caused by these variants.  
 
B.  Introduction 
 
The following describes FDAs current thinking regarding the CMC, nonclinical data, and 
clinical data needed to support an amendment to an EUA under section 564 of the FD&C Act 
(21 U.S.C. 360bbb-3) for a vaccine for the prevention of COVID-19.  These 
recommendations pertain to modified COVID-19 vaccines for the prevention of COVID-19, 
where the vaccine is made by the same process and manufacturer as an authorized or 
approved prototype vaccine but is modified in order to enhance efficacy against COVID-19  
   
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caused by a SARS-CoV-2 variant(s).  It should be recognized that FDAs thinking regarding 
data needed to authorize a modified COVID-19 vaccine may evolve as additional information 
is accrued with SARS-CoV-2 variants and corresponding vaccines.   
 
Of note, the recommendations detailed below are specifically for pandemic COVID-19 
vaccines that express the S protein and are made under the assumptions that neutralizing 
antibody to SARS-CoV-2 S is a major component of the vaccine protective response (or for a 
given vaccine construct, is likely to vary in proportion to the protective response), that an 
immune marker predictive of protection has not been established, and that it is not feasible to 
conduct clinical disease endpoint efficacy studies rapidly enough to respond to the emergence 
of SARS-CoV-2 variants that may escape immunity conferred by prototype vaccines.  
Assuming the prototype vaccine has been authorized under an EUA or is approved, it is 
expected that the modified COVID-19 vaccine against a SARS-CoV-2 variant made by the 
same manufacturer and process as the prototype COVID-19 vaccine would be authorized 
through an EUA amendment to the EUA for the prototype COVID-19 vaccine. 
 
This Appendix does not address how it will be determined that a vaccine based on a new viral 
sequence is needed, determining which protein sequences should be expressed by such a 
vaccine, or approaches to follow-up of modified vaccines to ensure that they retain adequate 
effectiveness, and do not lose efficacy due to evolution of new viral variants.  This document 
also does not address considerations for multivalent COVID-19 vaccines. 
 
Other issues that FDA continues to consider, but are not discussed in this Appendix, include, 
and are not limited to: 
  data indicating the need for a modified vaccine, 
  what entity evaluates, decides and recommends whether a modified vaccine is 
needed, and 
  the role of FDAs VRBPAC in determining the need for a modified vaccine in the 
U.S. 
 
A request for an EUA amendment for the modified vaccine should address the following: 
 
1.  Chemistry, Manufacturing, and Controls 
 
The EUA amendment should include information on CMC; a list of each site where the 
modified product, if authorized, is or would be manufactured, relevant information about 
each site and the current status of the manufacturing site(s) with respect to CGMP 
requirements. 
 
FDA expects that much of the manufacturing process and controls, as well as the facilities 
for vaccine production, for the modified COVID-19 vaccine will be identical to that of the 
prototype COVID-19 vaccine.  However, updated CMC data will need to be generated for 
the modified COVID-19 vaccine, as a scientific matter.  The CMC data to support the 
modified vaccine formulation may differ depending on the vaccine platform, but at a 
minimum should include critical aspects of product characterization, a potency assay, and 
data on stability generated using the modified COVID-19 vaccine.  Any changes made to 
the manufacturing process and process control should be discussed with FDA in advance 
of the EUA amendment submission. 
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2.  Nonclinical  
 
A list of the nonclinical studies conducted to support vaccine effectiveness and safety 
(e.g., characterization of markers associated with enhanced disease, biodistribution, 
shedding, and attenuation) obtained with the prototype COVID-19 vaccine made by the 
same manufacturer and process should be provided. 
 
In general, for a modified COVID-19 vaccine directed against a SARS-CoV-2 variant and 
made by the same manufacturer and process, conducting additional repeat dose toxicity 
studies or DART studies may not be warranted.  Data from the vaccine platform or from 
the prototype vaccine will be considered in making this decision. 
 
Data from studies in a relevant animal model receiving the prototype COVID-19 vaccine 
and the modified COVID-19 vaccine directed against SARS-CoV-2 variant(s) and 
subsequently challenged with wild-type viruses representing clinically relevant circulating 
variants, including the variant(s) of interest, are encouraged as they contribute to the 
totality of the evidence supporting the authorization of a modified COVID-19 vaccine.  
Vaccine manufacturers may submit the draft protocols for such studies to FDA.  It should 
be recognized that conduct of challenge studies with any live SARS-CoV-2 requires a 
BSL-3 containment facility.  These challenge/protection studies may be performed in 
parallel with the clinical immunogenicity studies described below. 
 
3.  Clinical data 
 
a.  Clinical data to support effectiveness of a modified vaccine 
The effectiveness of a modified COVID-19 vaccine against a particular SARS-CoV-2 
variant of concern (VOC) can be evaluated based on: 
  The efficacy of primary vaccination with the manufacturers authorized or 
approved prototype COVID-19 vaccine made by the same process and for 
which a clinical disease endpoint efficacy study has been conducted that met 
FDA pre-specified success criteria, AND 
  Comparison of immune responses (assessed by neutralizing antibody) induced 
by the modified vaccine and the prototype vaccine.   
The immunogenicity studies to assess the effectiveness of a modified COVID-19 
vaccine against a particular VOC administered as primary vaccination, a first booster 
dose and a second booster dose are described below in this section (Appendix 2 
B.3.a.).  Each of these studies is described as having a contemporaneous comparator 
group who receive the prototype vaccine; however, serum samples from study 
subjects administered the prototype vaccine in a previously conducted study, if 
available, may be used in lieu of a contemporaneous comparator group if evaluated 
using the same assay(s) and provided that the prototype vaccine and modified vaccine 
groups are well-balanced with respect to factors that may affect interpretation of the 
immune response.  Ideally, the modified vaccine would be evaluated in subjects 
spanning the age range for the authorized use of the prototype vaccine for primary and 
booster vaccination.  If a more limited age range is studied it may, in certain 
situations, be reasonable to extrapolate the data to other age groups for which the 
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prototype is authorized or approved.  We acknowledge that certain aspects of the 
immunogenicity evaluations outlined below in this section (Appendix 2 B.3.a.) may 
be challenging, and in situations where available data support that certain studies or 
analyses would be infeasible, we would consider alternative approaches with 
appropriate justification.  The assessment of effectiveness of a modified COVID-19 
vaccine will take into account the totality of the immunogenicity data from the 
primary, secondary and descriptive analyses. 
 
Primary Vaccination:  Sponsors should conduct an immunogenicity study in which 
previously unvaccinated persons are randomized to receive either the modified 
COVID-19 vaccine or the prototype COVID-19 vaccine.  The modified vaccine dose 
and dosing regimen should be the same as authorized (or approved) for the prototype 
vaccine.  If high SARS-CoV-2 seroprevalence precludes conducting studies in a 
SARS-CoV-2 naive population, the prototype vaccine and modified vaccine groups 
should ideally be well balanced with respect to SARS-CoV-2 infection history based 
on baseline serostatus (presence of nucleocapsid antibody) and/or laboratory 
confirmed COVID-19, and with respect to neutralizing antibody titer prior to 
vaccination.  Subgroup analyses should be conducted to evaluate immunogenicity 
based on these variables.  
 
Immune response comparisons and analyses to demonstrate effectiveness of a 
modified COVID-19 vaccine administered for primary vaccination are outlined below 
and in Table 1. 
 
Primary immunogenicity analyses:  The primary analysis should be a comparison of 
Geometric Mean Titer (GMT) against the particular VOC, elicited by the modified 
and prototype vaccine.  The study should be designed and adequately powered to 
demonstrate statistical superiority of the GMT elicited by the modified vaccine as 
compared to the prototype vaccine.  Ideally, the primary analysis would test for 
super superiority (margin of >1.5-fold for GMT ratio) to statistically exclude non-
inferiority of the prototype vaccine compared with the modified vaccine.  However, it 
would be acceptable to test for simple superiority (margin of >1-fold for GMT 
ratio) in the primary analysis and to test for super superiority as a secondary 
immunogenicity analysis.   
 
A second co-primary analysis should be a comparison of seroresponse rates against 
the particular VOC, elicited by the modified and prototype vaccine.  The study should 
be designed and adequately powered to demonstrate non-inferiority of the 
seroresponse rate elicited by the modified vaccine as compared to the prototype 
vaccine, using a non-inferiority margin of <5% for seroresponse rate difference.  
Alternatively, the co-primary analysis of seroresponse rates could test for superiority 
(simple superiority margin of >0% or super superiority margin of >10% for 
seroresponse rate difference).  If the co-primary analysis of seroresponse rates will 
test for non-inferiority, FDA would expect that additional descriptive analyses of 
seroresponses against clinically relevant variants, including the particular VOC, 
support the benefit of the modified vaccine over the prototype vaccine.  Determination 
of an appropriate seroresponse definition should be based on available data. 
 
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Additional immunogenicity analyses:  A secondary analysis should evaluate non-
inferiority of seroresponse rates and GMTs against the particular VOC that are 
induced by the modified vaccine relative to seroresponse rates and GMTs against the 
virus upon which the prototype was based that are induced by the prototype vaccine.  
Non-inferiority margins should be 10% for seroresponse rates and 1.5-fold for GMTs, 
respectively.  Alternate non-inferiority margins may be considered, with adequate 
justifications, on a case-by-case basis.  Additional descriptive analyses should 
compare the seroresponse rates and GMTs in each group against other clinically 
relevant VOCs (e.g., currently or recently circulating variants) and against the virus 
upon which the prototype was based.   
 
Table 1: Immune Response Comparisons and Analyses to Demonstrate Effectiveness 
of a Modified COVID-19 Vaccine Administered for Primary Vaccination 
 
Immune response 
Modified Vaccine Group  Prototype Vaccine Group 
analyses 
Primary: Superiority*  GMT   GMT  
V V
Primary: Non-
SRR   SRR  
V V
inferiority** 
Secondary: Non-
IR   IR  
V O
inferiority 
Secondary: Super 
Superiority  IR   IR  
V V
(if not primary) 
Additional Descriptive  IR   IR  
O O
Additional Descriptive  IR   IR  
R-V R-V
*Ideally the primary analyses will test for super superiority (margin of >1.5-fold for 
GMT ratio).  However, it would be acceptable to test for simple superiority (margin 
of >1-fold for GMT ratio) in the primary analysis and to test for super superiority as 
a secondary immunogenicity analysis. 
**Non-Inferiority margin of <5% for SRR difference.  Alternatively, the co-primary 
analysis of SRR could test for superiority (simple superiority margin of >0% or super 
superiority margin of >10% for SRR difference). 
GMT  = GMT against the particular VOC targeted by the modified vaccine  
V
SRR  = Seroresponse rate against the particular VOC targeted by the modified 
V
vaccine 
IR = seroresponse rate and GMT against the particular VOC targeted by the modified 
V
vaccine 
IR = seroresponse rate and GMT against the virus upon which the prototype is based 
O
IRR-V= seroresponse rate and GMT against other clinically relevant VOCs 
 
First Booster Dose:  Sponsors should conduct an immunogenicity study in which 
persons who have previously completed primary vaccination with the prototype 
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COVID-19 vaccine, administered according to the authorized (or approved) dose and 
dosing regimen, are randomized to receive a booster dose of either the modified 
COVID-19 vaccine or the prototype COVID-19 vaccine.  Alternate study designs can 
be considered, for example a study in which subjects who have completed primary 
vaccination with other authorized (or approved) prototype vaccines are randomized to 
receive a booster dose with either the prototype vaccine or the modified vaccine.  If 
the study population is heterogeneous with respect to previous vaccines received, the 
design should take into consideration factors that may affect interpretation of the 
immune response to the booster dose (i.e., the prototype vaccine and modified vaccine 
groups should ideally be well balanced with respect to vaccination history and SARS-
CoV-2 infection history based on baseline serostatus (presence of nucleocapsid 
antibody), laboratory confirmed COVID-19, and neutralizing antibody titer prior to 
the booster dose).  Subgroup analyses should be conducted to evaluate 
immunogenicity based on these variables.   
Immune response comparisons and analyses to demonstrate effectiveness of a 
modified COVID-19 vaccine administered as a first booster dose are outlined below 
and in Table 2. 
Primary immunogenicity analyses:  The primary analysis should be a comparison of 
GMTs against the particular VOC, elicited by the modified and prototype vaccine.  
The study should be designed and adequately powered to demonstrate statistical 
superiority of the GMT elicited by the modified vaccine as compared to the prototype 
vaccine.  Ideally, the primary analysis would test for super superiority (margin of 
>1.5-fold for GMT ratio) to statistically exclude non-inferiority of the prototype 
vaccine compared with the modified vaccine.  However, it would be acceptable to test 
for simple superiority (margin of >1-fold for GMT ratio) in the primary analysis 
and to test for super superiority as a secondary immunogenicity analysis. 
 
A second co-primary analysis should be a comparison of seroresponse rates against 
the particular VOC, elicited by the modified and prototype vaccine.  The study should 
be designed and adequately powered to demonstrate non-inferiority of the 
seroresponse rate elicited by the modified vaccine as compared to the prototype 
vaccine, using a non-inferiority margin of <5% for seroresponse rate difference.  
Alternatively, the co-primary analysis of seroresponse rates could test for superiority 
(simple superiority margin of >0% or super superiority margin of >10% for 
seroresponse rate difference).  If the co-primary analysis of seroresponse rates will 
test for non-inferiority, FDA would expect that additional descriptive analyses of 
seroresponses against clinically relevant variants, including the particular VOC, 
support the benefit of the modified vaccine over the prototype vaccine.  Determination 
of an appropriate seroresponse definition for a first booster dose should be based on 
available data. 
 
Additional immunogenicity analyses:  The following descriptive analyses should be 
conducted:  
  Comparison of the seroresponse rates and GMTs following the booster dose in 
each group against the virus upon which the prototype was based.  
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  Comparison of the seroresponse rates and GMTs following the booster dose in 
each group against other clinically relevant VOCs (e.g., currently or recently 
circulating variants). 
  Comparison of the immune response elicited by a booster dose of the modified 
vaccine against the particular VOC to that elicited following primary vaccination 
with the prototype vaccine against the virus upon which the prototype was based.  
  Comparison of the immune response elicited by a booster dose of the modified 
vaccine to that elicited following primary vaccination with the prototype vaccine 
against the virus upon which the prototype was based.  
  Comparison of the immune response elicited by a booster dose of the modified 
vaccine to that elicited following primary vaccination with the prototype vaccine 
against other clinically relevant VOCs.  
The descriptive comparisons to the immune response after primary vaccination may 
be limited to a comparison of GMTs.  
Table 2: Immune Response Comparisons and Analyses to Demonstrate Effectiveness 
of a Modified COVID-19 Vaccine Administered as a First Booster Dose 
Prototype Primary 
Immune response  Modified Booster  Prototype Booster 
Vaccination Vaccine 
analyses  Vaccine Group  Vaccine Group 
Group* 
Co-Primary: 
GMT   GMT   NA 
V V
Superiority** 
Co-Primary: Non-
SRR   SRR   NA 
V V
inferiority*** 
Secondary: Super 
Superiority 
GMT   GMT   NA 
V V
(if not primary) 
 
Additional Descriptive  IR   IR   NA 
O O
Additional Descriptive  IR   IR   NA 
R-V R-V
Additional Descriptive  IR   NA  IR  
V O
Additional Descriptive  IR   NA  IR  
O O
Additional Descriptive  IR   NA  IR  
R-V R-V
*Comparisons to the immune response following primary vaccination may be comparisons to sera 
obtained in different studies and may be limited to GMTs.  
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**Ideally the primary analysis of GMTs will test for super superiority (margin of >1.5-fold for 
GMT ratio).  However, it would be acceptable to test for simple superiority (margin of >1-fold for 
GMT ratio) in the primary analyses and to test for super superiority as secondary analysis of GMT. 
***Non-Inferiority margin of <5% for SRR difference.  Alternatively, the co-primary analysis of 
SRR could test for superiority (simple superiority margin of >0% or super superiority margin of 
>10% for SRR difference). 
NA = Not Applicable 
GMT  = GMT against the particular VOC targeted by the modified vaccine  
V
SRR  = Seroresponse rate against the particular VOC targeted by the modified vaccine 
V
IR = seroresponse rates and GMT against the particular VOC targeted by the modified vaccine 
V
IR = seroresponse rates and GMT against the virus upon which the prototype is based 
O
IRR-V= seroresponse rates and GMT against other clinically relevant VOCs 
 
Second booster dose:  Sponsors should conduct an immunogenicity study in which 
persons who have completed primary and first booster vaccination with the prototype 
COVID-19 vaccine, administered according to the authorized or approved (primary 
vaccination) and authorized (booster vaccination) dose and dosing regimen, are 
randomized to receive a second booster dose of either the modified COVID-19 vaccine or 
the prototype COVID-19 vaccine.  Alternate study designs can be considered, for 
example a study in which subjects who have completed primary vaccination and first 
booster with any combination of authorized or approved (primary vaccination) and 
authorized (booster vaccination) prototype vaccines are randomized to receive a second 
booster dose with either the prototype vaccine or the modified vaccine.  If the study 
population is heterogeneous with respect to previous vaccines received, the design should 
take into consideration factors that may affect interpretation of the immune response to 
the second booster dose (i.e., the prototype vaccine and modified vaccine groups should 
ideally be well balanced with respect to vaccination history and SARS-CoV-2 infection 
history based on baseline serostatus (presence of nucleocapsid antibody), laboratory 
confirmed COVID-19, and neutralizing antibody titer prior to the second booster dose).  
Subgroup analyses should be conducted to evaluate immunogenicity based on these 
variables.   
 
Immune response comparisons and analyses to demonstrate effectiveness of a modified 
COVID-19 vaccine administered as a second booster dose are outlined below and in 
Table 3. 
 
Primary immunogenicity analyses:  One co-primary analysis should be a comparison of 
GMTs against the particular VOC, elicited by the modified and prototype vaccine.  The 
study should be designed and adequately powered to demonstrate statistical superiority of 
the GMT elicited by the modified vaccine as compared to the prototype vaccine.  Ideally, 
the primary analysis would test for super superiority (margin of >1.5-fold for GMT 
ratio) to statistically exclude non-inferiority of the prototype vaccine compared with the 
modified vaccine.  However, it would be acceptable to test for simple superiority 
(margin of >1-fold for GMT ratio) in the primary analyses and to test for super 
superiority as a secondary immunogenicity analysis.  
 
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A second co-primary analysis should be a comparison of seroresponse rates against the 
particular VOC, elicited by the modified and prototype vaccine.  The study should be 
designed and adequately powered to demonstrate non-inferiority of the seroresponse rate 
elicited by the modified vaccine as compared to the prototype vaccine, using a non-
inferiority margin of <5% for seroresponse rate difference.  Alternatively, the co-primary 
analysis of seroresponse rates could test for superiority (simple superiority margin of 
>0% or super superiority margin of >10% for seroresponse rate difference).  If the 
coprimary analysis of seroresponse rates will test for non-inferiority, FDA would expect 
that additional descriptive analyses of seroresponses against clinically relevant variants, 
including the particular VOC, support the benefit of the variant vaccine over the prototype 
vaccine.  Determination of an appropriate seroresponse definition for a second booster 
dose should be based on available data 
 
Additional Immunogenicity Analyses:  The following descriptive analyses should be 
conducted:  
  Comparison of the seroresponse rates and GMTs following the second booster 
dose in each group against the virus upon which the prototype was based.  
  Comparison of the seroresponse rates and GMTs following the second booster 
dose in each group against other clinically relevant VOCs (e.g., currently or 
recently circulating variants). 
  Comparison of the immune response elicited by a second booster dose of the 
modified vaccine against to that elicited following a first booster dose with the 
prototype vaccine against the particular VOC.  
  Comparison of the immune response elicited by a second booster dose of the 
modified vaccine to that elicited following a first booster dose with the prototype 
vaccine against the virus upon which the prototype was based. 
  Comparison of the immune response elicited by a second booster dose of the 
modified vaccine to that elicited following a first booster dose with the prototype 
vaccine against other clinically relevant VOCs.  
The descriptive comparisons to the immune response after the first booster dose may be 
limited to a comparison of GMTs.  
   
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Table 3: Immune Response Comparisons and Analyses to Demonstrate Effectiveness of a 
Modified COVID-19 Vaccine Administered as a Second Booster Dose 
Immune response  Modified Booster #2  Prototype Booster #2  Prototype Booster #1 
analysis  Vaccine Group  Vaccine Group  Vaccine Group* 
Co-Primary: 
GMT   GMT   NA 
V V
Superiority** 
Co-Primary: Non-
SRR   SRR   NA 
V V
inferiority*** 
Secondary: Super 
Superiority 
GMT   GMT   NA 
V V
(if not primary) 
 
Additional Descriptive  IR   IR   NA 
O O
Additional Descriptive  IR   IR   NA 
R-V R-V
Additional Descriptive  IR   NA  IR  
V V
Additional Descriptive  IR   NA  IR  
O O
Additional Descriptive  IR   NA  IR  
R-V R-V
*Comparisons to the immune response following the first booster dose may comparisons to sera 
obtained in different studies and may be limited to GMTs. 
**Ideally the primary analyses will test for super superiority (margin of >1.5-fold for GMT 
ratio).  However, it would be acceptable to test for simple superiority (margin of >1-fold for 
GMT ratio) in the primary analysis and to test for super superiority as a secondary 
immunogenicity analysis. 
NA = Not Applicable 
***Non-Inferiority margin of <5% for seroresponse rate difference.  Alternatively, the co-primary 
analysis of SRR could test for superiority (simple superiority margin of >0% or super superiority 
margin of >10% for seroresponse rate difference). 
GMT  = geometric mean titer against the particular VOC targeted by the modified vaccine 
V
SRR  = seroresponse rate against the particular VOC targeted by the modified vaccine 
V
IR = SRR and GMT against the particular VOC targeted by the modified vaccine 
V
IR = SRR and GMT against the virus upon which the prototype is based 
O
IRR-V= SRR and GMT against other clinically relevant VOCs 
 
b.  Clinical data to support safety of a modified vaccine  
 
Safety assessments, including solicited local and systemic adverse events assessed 
daily for at least 7 days after each study vaccination as well as serious and other 
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unsolicited adverse events assessed during the immunogenicity evaluation period, 
may be sufficient to support EUA of the modified COVID-19 vaccine.  However, 
evaluation of the modified COVID-19 vaccine in a larger safety database than initially 
planned for immunogenicity studies may be warranted if safety signals arise, and 
studies should also plan for longer-term assessments of serious and other medically 
attended adverse events. 
 
Assays for assessment of immunogenicity endpoints 
 
The assays used to assess immunogenicity endpoints of clinical studies should be 
identified.  Even though an immune marker predictive of protection against COVID-
19 has not been established to date, depending on the vaccine construct, neutralizing 
antibody may be considered a relevant measure of immunogenicity.   
 
Data demonstrating the ability of the modified COVID-19 vaccine to induce a 
neutralizing antibody response are needed, as a scientific matter.  These may be 
derived from virus neutralization assays (using pseudovirus or wildtype virus) 
assessing neutralization of SARS-CoV-2 viruses (including the virus from which the 
prototype vaccine was derived as well as variants of interest) with clinical serology 
samples obtained from persons immunized with the prototype and/or the modified 
COVID-19 vaccine construct. 
 
FDA expects that the SOPs and validation reports for the final assay methods, and a 
list of all laboratories where the clinical samples have been tested, will be submitted 
to support the EUA amendment. 
 
4.  Additional considerations 
 
Currently, it is not known whether the immunogenicity and safety profiles of vaccines 
against SARS-CoV-2 variants will be comparable to those of vaccines against the original 
SARS-CoV-2 virus and whether regular (e.g., annual) modifications will be needed.  
Thus, manufacturers should generate the data to support authorization of a modified 
COVID-19 vaccine as outlined above.  Further discussions will be necessary to decide 
whether in the future, certain or all modified COVID-19 vaccines may be authorized 
without the need for clinical studies. 
 
Developers are encouraged to perform exploratory studies regarding the ability of 
modified vaccines to boost immune responses to an appropriate level, even if the viral 
sequence being evaluated may not ultimately be selected for use in a modified vaccine.  
Such studies may provide important dose-finding and safety information. 
 
If a manufacturer plans to develop a modified monovalent vaccine against a variant, it 
will be important to ensure that the modified vaccine can be clearly distinguished from 
vaccines made by the manufacturer that target the original virus. 
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