As part of FDA’s response to combat COVID-19, FDA convened its Vaccines and Related Biological Products Advisory Committee (VRBPAC). The committee met on October 22, 2020, to discuss the development, authorization, and licensure of vaccines to prevent COVID-19. FDA asked VRBPAC to discuss the following:
- FDA’s approach to safety and effectiveness data as outlined in two recent FDA guidance documents on the development of COVID-19 vaccines and on Emergency Use Authorization (EUA) for COVID-19 vaccines
- Considerations for continuation of blinded Phase III clinical trials if an EUA has been issued for an investigational COVID-19 vaccine
- Studies following licensure and/or issuance of an EUA for COVID-19 vaccines
In this blog we provide a VRBPAC meeting recap for those who may have missed the event and would like to learn more about FDA’s current thinking on COVID-19 vaccine development.
Vaccine Approvals and EUAs
FDA noted that, for FDA approval, COVID-19 vaccines must meet the same legal requirements and standards as those required for other approved, preventive vaccines. FDA noted that only vaccines that are shown to be safe and effective, and that can be manufactured in a consistent manner, will be approved.
Regarding EUAs, FDA can authorize the emergency use of an investigational vaccine when no adequate approved alternatives exist. For the authorization, FDA must determine that the product may be effective, and that its known and potential benefits outweigh its known and potential risks. FDA noted that it will require adequate manufacturing information to ensure quality and consistency. FDA indicated that EUA assessments are done on a case-by-case basis, considering population, product characteristics, pre-clinical and clinical data, and scientific evidence supporting the EUA.
As currently constructed, an EUA is not subject to FDA requirements for informed consent (21 CFR part 50). However, recipients of a vaccine under an EUA must receive an informational fact sheet.
Regarding serologic testing, FDA noted that the role of such testing is still evolving and that its utility in establishing the absence or presence of infection, reinfection, or immunity remains undefined.
Meeting participants discussed vaccine development supported by Operation Warp Speed (OWS), a public-private partnership involving the Department of Health and Human Services, the Department of Defense, and others. OWS aims to facilitate and accelerate the development, manufacture, and distribution of COVID-19 vaccines, therapeutics and diagnostics. Of six vaccine candidates that OWS currently supports, four are currently being studied in large Phase III clinical trials. While there is strong interest in a single-dose vaccine, most of the current candidates that OWS supports are two-dose vaccines because of the need to meet certain other important criteria beyond the number of doses involved.
Diversity in Clinical Trials
The meeting included discussion about minorities being disproportionately affected by COVID-19 and being inadequately represented in clinical trials. The importance of engaging those most affected and having diversity across the studies was noted. FDA strongly encourages the enrollment of populations most affected by COVID-19, and specifically racial and ethnic minorities.
As of the date of this VRBPAC meeting, only one OWS-supported study includes pediatric subjects. VRBPAC discussed whether children should be included in more clinical trials or whether, instead, immunobridging might be done (in other words, extrapolating results from COVID-19 studies of adults to infer results in children). Some VRBPAC members expressed a preference for having robust safety data from adults before studying a COVID-19 vaccine in children. FDA noted that COVID-19 vaccine developers should plan for pediatric studies because submission of a pediatric study plan to FDA will be required under the Pediatric Research Equity Act if a vaccine is approved for adult use.
COVID-19 Vaccine Confidence
During the meeting, public concerns were expressed about a COVID-19 vaccine, including concerns that center on:
- the speed of the development process and safety of a vaccine if one is quickly available
- distrust of government and government agencies
- distrust of healthcare systems and the medical establishment
- concerns that politics and economics will be prioritized over science
- fear in minority groups that a vaccine won’t work for them or their community, or will be unsafe for them
- fear based on past experiences, such as the Tuskegee experiment
As noted during the meeting, vaccines can only be effective if vaccination (uptake) is widespread, and we must have public trust in clinical trials and successful products in order to have widespread uptake. Meeting presentations indicated that specific efforts are underway to improve confidence in vaccine trials. Those efforts include maintaining safeguards for volunteers and study conduct, engaging with stakeholders from underserved minorities hit hard by the pandemic, and committing to transparency.
Regarding the two recent FDA guidance documents, VRBPAC seemed to agree with FDA’s approach to safety and effectiveness data, in terms of the general principles and standards outlined in those documents. However, VRBPAC noted the importance of ensuring that minorities are represented in the clinical trials and had questions about study outcome measures for vaccine development and follow-up duration from Phase III studies to assess the benefit-risk profile for an EUA.
Regarding considerations for continuation of blinded Phase III clinical trials if an EUA were to be issued for an investigational COVID-19 vaccine, VRBPAC noted that this is a thorny issue. The Committee had robust discussion about ethical considerations, potential content of informed consent documents, and the feasibility of continuing blinded Phase III studies after EUA issuance. VRBPAC noted that if the blinded Phase III studies could not continue, follow-up studies in observational settings might be done instead. VRBPAC’s position seemed to be that the Phase III studies should continue, with blinds maintained for as long as feasible, and that study participants should not necessarily be crossed over automatically to active (investigational) vaccine.
Regarding studies following licensure and/or issuance of an EUA for COVID-19 vaccines, VRBPAC discussed the importance of safety studies, including in children, and longer term follow-up to identify safety signals that might not show up earlier; studies in sub-populations and in those disproportionately affected; studies that look at gender differences in immune response; studies of severe COVID-19 infection; studies that generate data on the coadministration of a COVID-19 vaccine with other routine vaccination(s); and studies not only by product but also by platform, because products may have common safety issues based on a shared platform.
FDA noted that it will convene another VRBPAC meeting if FDA receives a Biologics License Application (a marketing application) for a COVID-19 vaccine.
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