By Lisa Larrimore Ouellette, Nicholson Price, Rachel Sachs, and Jacob S. Sherkow
On October 22, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) met to discuss the development, authorization, and licensure of COVID-19 vaccines. The meeting was not focused on any particular vaccine candidate; rather, it gave the FDA an opportunity to seek more general guidance about the process from outside experts. In this post, we explain what advisory committees like VRBPAC do, what happened at the meeting last week, and what this means for the COVID-19 vaccine timeline.
What do FDA advisory committees like VRBPAC do?
The FDA uses 31 advisory committees to provide the agency with independent recommendations on regulatory matters based on reviews of evidence from the agency, product sponsors, and members of the public. For example, VRBPAC has 17 members from outside the FDA, including academics, government scientists, and industry representatives, with expertise covering relevant scientific, clinical, statistical, and legal issues. Membership is supposed to be “fairly balanced,” including “ethnic, gender, and geographic diversity, as well as people with recognized expertise and judgment in a specific field” and “industry and consumer representation.” The FDA also has strict conflict of interest rules, and three VRBPAC members are recused from COVID-19 meetings due to their involvement in research on COVID-19 vaccines. They have been replaced by temporary members.
The work of these expert advisory committees matters to agency decisionmaking. In a review of the 376 advisory committee meetings held between 2008 and 2015, Audrey Zhang, Jason Schwartz, and Joseph Ross found that the FDA reached a final decision that contradicted the advisory committee’s recommendation in just 22% of cases. In those cases of disagreement, the FDA tended to be less likely to approve new products than more likely to do so.
More than half of advisory committee meetings are product-specific, in which the FDA asks its advisory committees to make recommendations about particular products, including whether they ought to be approved or subject to additional safety restrictions. But many meetings are more general, such as those asking an advisory committee to help the agency determine how to evaluate classes of products.
Advisory committees play an important role in providing the FDA with additional expert perspectives on novel issues. But they also provide other benefits. Perhaps most notably, they increase the transparency of an often-opaque process. The FDA typically discloses very little information about its approval process and the evidence used in support of approvals, in part because of concerns involving the disclosure of trade secrets. Information provided to the FDA’s advisory committees, however, is made publicly available on the FDA’s website. This transparency can help improve public trust in the FDA, which is of particular concern in the COVID-19 context.
What happened at the October 22 VRBPAC meeting?
On October 22, the VRBPAC held an open, online, public meeting concerning its standards for approving a vaccine against COVID-19. (The meeting was simultaneously broadcast on CSPAN and YouTube.) Prior to the meeting, the Committee made the agenda and briefing materials publicly available; the meeting featured presentations from Committee members, staff from the FDA, CDC, NIH, BARDA, the Reagan-Udall Foundation, and a variety of members from industry. Introductions alone took 23 minutes to complete; the meeting lasted almost nine hours.
Somewhat surprising for lay observers was the absence of a discussion of any particular vaccine candidate, including the four currently in Phase III clinical trials in the US. Instead, the meeting focused on the standards of such trials and the legal authority (and limits) for approval. While a nine-hour meeting focusing on the particulars of vaccine safety and efficacy standards sounds...dense...there were a number of broader, important takeaways likely to be of larger interest.
First, and most important, the VRBPAC gave a number of reassurances that it would advise the FDA to continue to uphold rigorous safety standards despite political pressure to quickly approve a vaccine. It was clear that even if an Emergency Use Authorization (EUA)—a shortcut to the typical and more formal approval process—were available for a vaccine, it could not be used without the completion of a clinical trial (through Phase III). In addition, the Committee noted that it would strongly encourage the completion of ongoing trials even when another vaccine candidate is authorized or approved so that the Agency can track outcomes.
Second, the Committee reaffirmed its commitment to safety follow-ups even after a vaccine is authorized or approved. The post-approval follow-up study envisioned by the VRBPAC would contain roughly 3,000 participants—enough, one hopes, to track any serious adverse events arising late from the vaccine. At the same time, however, the Committee noted that this post-approval follow-up would not necessarily conform to the diversity standards otherwise needed for the clinical trials; in clinical trials, these requirements are crucially important to ensure the vaccine works in a immunologically diverse population. Whether this limitation of post-licensure studies will prevent the discovery of adverse event information remains unseen—and will likely remain unseen until long after a vaccine has come out. But for now, the VRBPAC—to its credit—is laudably committed to following up on any licensed vaccine after it has been deployed in the wild.
Third, the Committee was honest and forthcoming about growing anti-vaccine sentiment and a greater loss of trust in the FDA. This includes some pointed skepticism from minority populations regarding clinical trial participation—and especially the Black community given the historical backdrop of the Tuskegee Study and other abuses. The Committee’s very existence aims to combat this lack of trust, including by helping the agency follow the guidance of Coach John Wooden: “Be quick but don’t hurry.”
What does this mean for the COVID-19 vaccine timeline?
For starters, we can’t say exactly what the October 22 meeting will mean for the FDA. As noted, the VRBPAC is an advisory committee, not a decision committee. That said, the FDA follows its advice most of the time, and in a space where the FDA looks to be trying to maintain independence against administration pressure and to follow the science, the advice of the Committee seems especially likely to be heeded (assuming consistent FDA leadership). And FDA officials also contributed to the discussion.
The biggest implication from the Committee meeting was an apparent preference for using Expanded Access (EA) over EUAs for any early access to COVID-19 vaccines. Under an EUA, a vaccine could be authorized under more lenient standards, and with less data, than the normal approval process (though the FDA has implemented stronger standards for COVID-19 vaccine EUAs than is normal for the EUA process). In contrast, the FDA’s EA program does not provide widespread authorization: it allows more tightly controlled access to products that remain under investigation.
A key downside of a COVID-19 vaccine EUA is that it would complicate clinical trials, both for the authorized vaccine and for other trials. For the trial of the candidate that received the EUA, the sponsor would likely seek to unblind the trial and offer all participants the vaccine, including those who had previously received the placebo. This means that while the sponsor would have the results from the trial up to the EUA, it would have less continuing data about efficacy and adverse effects. For the trials of other vaccines, maintaining patient enrollment would be substantially harder once another vaccine had been authorized for use and became available. (Dr. Archana Chatterjee noted during the meeting that both of these concerns might be limited by the reality that doses of an authorized vaccine are likely to be in depressingly short supply for quite some time after authorization.)
These concerns would be less prevalent under an EA. The trials would continue—including for the full six months of safety data followup needed for an eventual vaccine approval, rather than the EUA’s two months—and there would be no authorized product driving the ending of either that product’s trial or the trials of other products. The official approval process, and the approval standard, would be the normal rigorous processes. Applying normal vaccine approval standards would hopefully help maintain public trust in the process—and even more importantly, it would help the agency actually get answers about vaccine safety and efficacy.
The first concern, in either case, should be to make sure that vaccine sponsors are able, and required, to collect adequate high-quality information about their candidates’ safety and efficacy. Though an EA seems less likely to kneecap ongoing trials and information collection because of the greater hurdles for patients to access products (including more robust informed consent), the risk exists for both EAs and EUAs, requiring careful management of ongoing trials so that they continue to collect useful data. When patients can easily access less-than-approved products, whether through EAs or EUAs, it becomes harder to enroll patients in clinical trials and to keep them there, degrading the information sponsors can collect. The case of convalescent plasma is a cautionary tale; while tens of thousands of patients have received plasma in an EA administered by the Mayo clinic, nominally associated with ongoing trials, these patients were rarely given plasma as part of randomized controlled trials—and the latest such RCT, conducted in India and published October 22, showed limited effectiveness.
Finally, the VRBPAC meeting is a laudable example of transparency and disclosure, including a range of views and frank discussion and open to public scrutiny. This is a very good thing. This is a time of decreased public trust of the FDA—and of science—by the public in general and minority communities in particular, who have been particularly hard hit by the virus. Making sure both to get the science right and to be seen getting the science right is absolutely crucial.
This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.
