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Pink Sheet – No Vote, No Mandate? FDA Opioid Meeting Shows Limits Of Non-Voting Panels

Pink Sheet – No Vote, No Mandate? FDA Opioid Meeting Shows Limits Of Non-Voting Panels

US Food & Drug Administration officials routinely emphasize one key point in framing the questions they pose to their expert advisory committees: the agency values the discussion of the issues by the invited experts much more than the final count on any vote they may take.

Commissioner Robert Califf has urged that the agency apply that philosophy more directly, by holding more meetings that do not incorporate any formal votes at all.

As part of a broader rethinking of the use of advisory committees, Califf suggested that the agency move away from “gladiator votes” that in his view falsely frame the committee’s role as making a regulatory decision (Yes, a drug should be approved; no, the safety database is not good enough, etc.) rather than simply advising on the state of the broader community they represent (treating clinicians do see a need for this sort of therapy; a certain toxicity is not as easily managed as the sponsor makes it sound, etc.).

“I think the best advice really is not should this drug be approved or not,” Califf said during the February Prevision Policy/Friends of Cancer Research Biopharma Congress. “That decision is made by full-time civil servants. The advice is about where is the field, what’s important, what matters. And I think we need to do more of that.” (Also see “US FDA Advisory Committees’ Future: Drug-Agnostic Panels, More Debate Time” – Pink Sheet, 22 Feb, 2023.)

An 19 April advisory committee discussion of a proposed trial design intended to answer a decade old request for long-term studies of extended-release/long-acting opioid formulations offers an interesting case study in how those types of meetings may not, in fact, serve FDA well.

To be clear, the Anesthetic & Analgesic Drugs Advisory Committee was not a “typical” product focused advisory committee meeting. This was not a review of a pending new drug application where the agency is contemplating whether to grant approval. Instead, this was a discussion of how best to design a post-marketing study in inherently challenging circumstances. (Also see “Opioid Long-Term Effectiveness Trial Design Gets Middling Review From FDA Panel” – Pink Sheet, 20 Apr, 2023.)

In other words, it is the type of meeting where it has never been all that unusual for FDA to pose a list of discussion questions without asking for a vote.

The Virtues Of Calling A Vote

And yet, in this instance, there was an obvious “yes or no” question on the table: after the first effort to answer long-term safety questions about opioids via a post-marketing study failed due to poor enrollment, FDA and the opioid product sponsors have been trying to agree on an approach that could work. And the agency came to its committee with a proposed trial design, using an enriched enrollment randomized withdrawal (EERW) approach.

While the agency had plenty of questions for the committee about details of the protocol, at its heart FDA was asking the panel whether it agrees with the agency’s view –as expressed in the pre-meeting briefing documents – that “the EERW design, while not ideal, appears to offer the best compromise to answer this public health question.” (Also see “Opioid Long-Term Effectiveness: FDA Postmarket Trial Design Offers ‘Best Compromise’” – Pink Sheet, 17 Apr, 2023.)

As the discussion unfolded, the benefit of asking for a vote soon became apparent. The committee certainly agreed that there is an inherent trade off in coming up with a trial design that is feasible versus one that would be extremely informative – but FDA and the opioid sponsors are already all too aware of that.

What they really needed was support for the position that, given the history and the current reality of opioid prescribing, the proposed EERW approach should proceed as the best possible option—or a rejection of the approach that, painful though it might be, would mean going back to the drawing board to come up with something else to try instead (or – perhaps – to just drop the idea altogether).

In other words, it really was a “yes or no” question – and FDA was not going to get much out of hearing committee members express the pros and cons without ultimately taking a stance.

Division of Anesthesiology, Addiction Medicine, and Pain Medicine Director Rigoberto Roca certainly appeared to reach that conclusion, asking at one point if each committee member could respond directly to the question of whether the EEWR trial is “fit for purpose” to demonstrate whether there are long-term benefits to continued opioid treatment, or whether the design is too confounded to allow for interpretable results.

That prompted an off-line procedural debate with the advisory committee staff, and Committee ChairBrian Bateman (Stanford) ultimately told Roca that he was “advised” that he could not call on each member in turn to respond to a “discussion” question.

In the end, however, virtually all of the committee members did answer Roca – but in a fashion that makes it hard to describe their view as anything better than a tepid endorsement of the EERW approach.

Hard To Satisfy Critics With Mixed Commentary

That in turn certainly leaves FDA free to take the meeting as support for moving forward with the plan. However, it might not be wise for FDA to do so given the ongoing public and political attention to the opioid response.

The political stakes for FDA flowing out of the advisory committee were evident in real time, as the topic before the panel was raised simultaneously in a discussion taking place on Capitol Hill.

While the advisory committee was under way, Califf was testifying before the Senate Appropriations/FDA Subcommittee. West Virginia Democratic Sen. Joe Manchin used the opportunity to voice his concerns about the proposed EERW design – which he (siding with critics of the agency who spoke during the open public hearing) views as a flawed approached that is tainted by association with the pivotal trial designs already used to support opioid product approvals.

Manchin painted the advisory committee line-up as one-sided, since the “sponsor” group (academics presenting on behalf of the OPC) and FDA were in agreement about the EERW approach, as was the only invited speaker. Manchin argued that FDA was obligated to grant formal presentation time to speakers who disagree with that trial design. (As it happened, those speakers dominated the open public hearing).

Califf responded to Manchin by indicating that the concerns about the 19 April agenda were only raised the day before the panel meeting – providing no time for FDA to add other speakers. He also took the opportunity to reiterate FDA’s interest in authority to require “material safety advantages” when approving new opioids.

That leaves FDA and the opioid product sponsors in something of a bind. They could move forward with the EERW design based on a fair interpretation of the discussion that essentially all members of the committee agree that the study is feasible and that most thought it would deliver as least some information of potential value.

But it sure would be easier to respond to critics like Manchin by pointing to a clear majority vote in favor of using the design.