- October 20, 2020
Last month (in September 2020), Agency officials, including FDA Commissioner Stephen Hahn and Center for Biologics Evaluation and Research (CBER) Director Peter Marks, indicated that additional guidance on COVID-19 vaccine EUAs would be forthcoming. At the time, the Washington Post and other outlets reported that FDA was looking at a median of two (2) months of follow-up of Phase 3 trial participants following their last vaccine, which would make a vaccine authorization before the November election unlikely. However, reports quickly emerged that the White House was reviewing the guidance, and on Monday (05 OCT 2020) the New York Times reported that the guidance had indeed been blocked.
On Tuesday (06 OCT 2020) morning, FDA appeared to sidestep the White House by releasing five (5) pages of advice given to vaccine makers on COVID-19 vaccine EUAs in briefing documents for its upcoming Vaccines and Related Biologics Advisory Committee meeting. The open session meeting, slated for 22 OCT 2020, will focus on the studies that should be conducted both pre- and post-licensure and to look at the immunogenicity and duration of effectiveness of COVID-19 vaccines, and will not pertain to any specific applications.
Hours later, in a surprise move, FDA released its COVID-19 vaccine EUA guidance in full.
“It’s great news that the FDA published the full guidance after a week in which it looked like political forces from HHS and the White House were going to suppress this information from being made public,” Aaron Kesselheim, Professor of Medicine at Harvard Medical School, told Focus.
The 15-page final guidance explains the statutory criteria for an EUA and provides recommendations for the regulatory, chemistry, manufacturing and controls (CMC), and safety and effectiveness information FDA expects to support an EUA request. “Being open and clear about the circumstances under which the issuance of an emergency use authorization for a COVID-19 vaccine would be appropriate is critical to building public confidence and ensuring the use of COVID-19 vaccines once available,” Marks said in a statement.
Kesselheim also noted that, “Fair standards, open communication, and allowing the hard-working FDA scientists to operate without undue political influence will be most useful in encouraging development of a useful vaccine and promoting public trust in it.”
In the guidance, FDA says that it expects vaccine makers to continue their Phase 3 studies after requesting or receiving an EUA and that the availability of a vaccine under an EUA is not “grounds for stopping blinded follow-up in an ongoing clinical trial.”
“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 writes. FDA recommends that sponsors considering an EUA submission contact CBER’s vaccines review and biologics quality offices early on to discuss expectations and manufacturing issues. Companies are also instructed to provide detailed CMC data at least one month before submitting an EUA request and to notify the Agency within 24 hours after an interim analysis that could be used as the basis for an EUA request has been completed.
Notably, the sections of the guidance on safety and effectiveness and CMC information largely mirror what was disclosed in the VRBPAC briefing documents, including the expectation that, “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.”
FDA is willing to be flexible about median follow-up time, Marks said in an interview with JAMA Editor-in-Chief Howard Bauchner on 05 OCT 2020. “If it turns out the median is seven weeks and not two months, that’s not going to be an issue.” He noted that it would take weeks for the Agency to review an EUA request, during which time more safety data would be accrued.
The guidance also explains that FDA will not be able to make a favorable benefit-risk determination without data on local and systemic adverse reactions from an adequate number of patients in each age cohort and safety data collected up to the point where the database is locked, which should include “well over 3,000 vaccine recipients.” The Agency adds that it will want to see at least five cases of severe COVID-19 in the placebo group to address concerns about vaccine-associated enhanced respiratory disease.
Additionally, the guidance makes clear that FDA plans to hold an open session VRBPAC meeting prior to issuing an EUA for a COVID-19 vaccine and includes recommendations for submitting information in preparation for an advisory committee meeting.
REFERENCE: RAPS Regulatory Focus/News Articles/2020/10; 06 OCT 2020; Michael Mezher