10/7/2020 From: "Schlaifer, Meredith" Date: Wednesday, October 7, 2020 at 6:45 AM To: FOIA Subject: FDA FOIA request 2020-7155 EXTERNAL SENDER Good morning, In response to your FOIA request, the EUA Guidance is posted at https://www.fda.gov/regulatory-------information/search-fda-guidance-documents/emergency-use-authorization-vaccines-prevent-covid-19. Thank you, Meredith J. Schlaifer, M.S., J.D. FOIA Officer, Office of the Commissioner Division of Freedom of Information U.S. Food and Drug Administration Tel: 301-796-0583 meredith.schlaifer@fda.hhs.gov II U.S. FOOD& DRUG ADM I HIST ATION AMEHICAN PVERSIGHT https://outlook.office365.com/mail/inbox/id/AAQkAGJmZjIxNGNhLTM3ZDAtNDFkNy1hZjNjLTVhN2Y1ODc1NWFkNAAQAK96xUrntsNAks5QQtYGLMM%3D 1/1 Contains Nonbinding Recommendations Emergency Use Authorization for Vaccines to Prevent COVID-19 Guidance for Industry October 2020 U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research A I AN PVERSIGHT MULTI-HHS-FDA-20-2407-A-000001 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 Agency’s good guidance practices. Comments may be submitted at any time for Agency consideration. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Submit electronic comments to https://www.regulations.gov. All comments should be identified with the docket 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-relatedguidance-documents-industry-fda-staff-and-other-stakeholders, the FDA webpage titled “Search for FDA Guidance Documents,” available at https://www.fda.gov/regulatory-information/searchfda-guidance-documents, and the FDA webpage titled “Biologics Guidances,” available at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-informationbiologics/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-D1137 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. A\/1 ·~1c,AN PVERSIGHT MULTI-HHS-FDA-20-2407-A-000002 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. RECOMMENDATIONS REGARDING INFORMATION AND DATA TO BE INCLUDED IN A REQUEST FOR AN EUA FOR A COVID-19 VACCINE .................. 5 A. B. C. Regulatory .................................................................................................................... 5 Chemistry, Manufacturing, and Controls ................................................................. 6 Safety and Effectiveness Information ........................................................................ 9 VI. CONSIDERATIONS FOR CONTINUING CLINICAL TRIALS FOLLOWING ISSUANCE OF AN EUA FOR A COVID-19 VACCINE.................................................. 11 VII. CONSIDERATION OF AN EUA FOR A COVID-19 VACCINE BY AN FDA ADVISORY COMMITTEE ................................................................................................. 11 APPENDIX 1: SUBMISSION OF INFORMATION IN PREPARATION FOR A VRBPAC MEETING ............................................................................................................... 13 A. B. Preparation and submission of briefing materials for the Advisory Committee meeting ........................................................................................................................ 13 Process ........................................................................................................................ 13 VIII. REFERENCES ...................................................................................................................... 15 AMERICAN PVERSIGHT i MULTI-HHS-FDA-20-2407-A-000003 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 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 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 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/202006222.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 Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 371(h)(1)(C)) and 21 CFR 10.115(g)(2)). This guidance document is being implemented immediately, but it remains subject to comment in accordance with the Agency’s good guidance practices. In general, FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be 1 VERSIGHT MULTI-HHS-FDA-20-2407-A-000004 Contains Nonbinding Recommendations viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required. II. BACKGROUND There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus has been named “SARS-CoV-2” and the disease it causes has been named “Coronavirus Disease 2019” (COVID-19). On January 31, 2020, the Secretary of HHS issued a declaration of a public health emergency related to COVID-19 and mobilized the Operating Divisions of HHS. 1 In addition, on March 13, 2020, the President declared a national emergency in response to COVID-19. 2 The SARS-CoV-2 pandemic presents an extraordinary challenge to global health. There are currently no FDA-licensed vaccines to prevent COVID-19. Commercial vaccine manufacturers and other entities are developing COVID-19 vaccine candidates using different technologies including RNA, DNA, protein, and viral vectored vaccines. This guidance describes FDA’s current recommendations regarding the data and information needed to support the issuance of an Emergency Use Authorization (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 FDA’s complete and timely review of such a submission, including convening the Vaccines and Related Biological Products Advisory Committee (VRBPAC). This guidance also discusses FDA’s 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 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 1 Secretary of Health and Human Services Alex M. Azar, Determination that a Public Health Emergency Exists. (Jan. 31, 2020, renewed Apr. 21, 2020, and July 23, 2020), available at https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx. 2 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak (Mar. 13, 2020), available at https://www.whitehouse.gov/presidential-actions/proclamation-declaring-nationalemergency-concerning-novel-coronavirus-disease-covid-19-outbreak/. 2 VERSIGHT MULTI-HHS-FDA-20-2407-A-000005 Contains Nonbinding Recommendations 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. 360bbb3(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 United States 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 lifethreatening disease or condition. • Based on the totality of scientific evidence available, including data from adequate and wellcontrolled 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. 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. 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. A I AN PVERSIGHT 3 MULTI-HHS-FDA-20-2407-A-000006 Contains Nonbinding Recommendations FDA acknowledges that an EUA for a COVID-19 vaccine may be requested to allow for the vaccine’s rapid and widespread deployment for administration to millions of individuals, including healthy people, potentially following interim results from one or more clinical trials meeting prespecified 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 its quality and consistency, issuance of an EUA would require a determination by FDA that the vaccine’s benefits outweigh its risks based on data from at least one well-designed Phase 3 clinical trial that demonstrates the vaccine’s safety and efficacy in a clear and compelling manner. It is FDA’s expectation that, following submission of an EUA request and issuance of an EUA, a sponsor would continue to collect placebo-controlled data in any ongoing trials for as long as feasible and would also work towards submission of a Biologics License Application (BLA) as soon as possible. FDA’s recommendations regarding the safety and effectiveness data and information outlined below 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 sponsor 4 considering the submission of an EUA request for an investigational COVID-19 vaccine should contact the Center for Biologics Evaluation and Research’s (CBER’s) Office of Vaccines Research and Review (OVRR) as early in development as possible to discuss expectations and considerations for the sponsor’s particular vaccine. FDA also recommends that vaccine sponsors engage in early communication with CBER’s Office of Compliance and Biologics Quality, Division of Manufacturing and Product Quality to discuss facility issues related to manufacturing of the particular vaccine. 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 FDA’s 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 V.B. 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 4 For purposes of this guidance, the term “sponsor” is used when referring to the applicant, submitter, or person requesting an EUA. A I AN PVERSIGHT 4 MULTI-HHS-FDA-20-2407-A-000007 Contains Nonbinding Recommendations request is planned, by contacting OVRR, and to discuss proposed timelines for submission of an EUA request. V. 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 wellorganized summary of the available scientific evidence regarding the product’s 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: o Adults o Pediatric age groups o Other specific populations (e.g., geriatric individuals, pregnant or lactating 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 vaccine’s benefits and risks and support issuance of an EUA would include not only meeting the prespecified success criteria for the study’s primary efficacy endpoint, but also additional safety and effectiveness data as described below in section C.3. 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 AMERICAN PVERSIGHT 5 MULTI-HHS-FDA-20-2407-A-000008 Contains Nonbinding Recommendations • • • 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; 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 product’s FDA approval status (FDA recognizes that, as of the date of publication of this guidance, there are no licensed COVID-19 vaccines); 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 crossreferenced 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 Master File 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 vaccine’s safety and effectiveness, including the following details: • Whether the product will be supplied to the United States Government (USG) 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. 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 AMERICAN PVERSIGHT 6 MULTI-HHS-FDA-20-2407-A-000009 Contains Nonbinding Recommendations 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. 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 FDA’s determination regarding the safety and effectiveness of the vaccine: a. Documentation establishing that critical source materials used in manufacturing is 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. AMERICAN PVERSIGHT 7 MULTI-HHS-FDA-20-2407-A-000010 Contains Nonbinding Recommendations 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. 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, crosscontamination, and mix-ups. b. Utility information, including validation information, should be provided for all utilities. For the 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 AMERICAN PVERSIGHT 8 MULTI-HHS-FDA-20-2407-A-000011 Contains Nonbinding Recommendations 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. C. Safety and Effectiveness Information The EUA request should include the following safety and effectiveness information, which will inform FDA’s determination regarding the product’s 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 COVID19 vaccine to be potentially administered to millions of individuals, including healthy individuals, data adequate to inform an assessment of the vaccine’s benefits and risks and support issuance of an EUA would include not only meeting the prespecified success criteria for the study’s 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 placebocontrolled 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. 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. AMERICAN PVERSIGHT 9 MULTI-HHS-FDA-20-2407-A-000012 Contains Nonbinding Recommendations 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, adverse events of special interest, and cases of severe COVID-19 among study subjects. We recognize that the phase 1 and 2 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 vaccine’s 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 protocoldefined 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 serious adverse events (SAEs) and adverse events of special interest for at least one month after completion of the full vaccination regimen; 5 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 5 As noted in FDA’s 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 younger adult and elderly populations, provided that no significant safety concerns arise during clinical development that would warrant further evaluation. 10 VERSIGHT MULTI-HHS-FDA-20-2407-A-000013 Contains Nonbinding Recommendations 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. 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. VI. 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 longterm 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. VII. CONSIDERATION OF AN EUA FOR A COVID-19 VACCINE BY AN FDA ADVISORY COMMITTEE FDA expects to convene an open session of FDA’s 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 any EUA request for a COVID-19 vaccine that, on its face, contains the information required under section 564 of 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 AMERICAN PVERSIGHT 11 MULTI-HHS-FDA-20-2407-A-000014 Contains Nonbinding Recommendations 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 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) (“Advisory Committee Meeting guidance”), 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. AMERICAN PVERSIGHT 12 MULTI-HHS-FDA-20-2407-A-000015 Contains Nonbinding Recommendations 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 above, 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 (AC) 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 contact’s 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). AMERICAN PVERSIGHT 13 MULTI-HHS-FDA-20-2407-A-000016 Contains Nonbinding Recommendations 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 AC 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 AC 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 fulltime 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 referencing 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 FDA’s webpage. Therefore, they must meet the requirements of section 508 of the Rehabilitation Act. 6 6 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. A I AN PVERSIGHT 14 MULTI-HHS-FDA-20-2407-A-000017 Contains Nonbinding Recommendations VIII. 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. A\/1 ·~1c,AN PVERSIGHT 15 MULTI-HHS-FDA-20-2407-A-000018