When FDA and Advisory Committees Disagree: Study Investigates Gaps

Regulatory NewsRegulatory News | 15 July 2019 |  By 

While only about one in five US Food and Drug Administration (FDA) new drug approvals or safety decisions run counter to outside advisory committee advice, a new study published Monday in the Milbank Quarterly looks further into what happens when both sides disagree.

Of the 404 advisory committee meetings that involved voting questions (out of a total of 759 meetings between 2008 and 2015), the study looked at 376 meetings, with 271 (72%) for initial product approvals, 78 (21%) for supplemental indication meetings and 27 (7%) for safety action meetings.

Authors from New York University School of Medicine and Yale School of Medicine found that 22% of FDA’s final actions were discordant with an advisory committee’s recommendations. “Of these, 75% resulted in the FDA making more restrictive decisions after favorable committee recommendations, and 25% resulted in the agency making less restrictive decisions after unfavorable committee recommendations,” they write.

Of those 21 decisions in which the FDA took a less restrictive stance (i.e. issued a favorable decision after an unfavorable advisory committee recommendation), 12 (57%) concerned safety actions, eight (38%) novel product approvals and one (5%) supplemental indication.

Of the 62 decisions in which FDA took a more restrictive stance (i.e. issued an unfavorable decision after a favorable recommendation by the advisory committee), 48 (77%) concerned novel product approvals, although 29 of those novel products later went on to win approval.

And although it’s rarer for there to be discordance between a restrictive advisory committee and a more lenient FDA, it’s usually these approvals that receive the most attention.

For instance, FDA recently granted accelerated approval to Karyopharm’s $22,000 per month multiple myeloma drug selinexor after FDA’s Oncologic Drugs Advisory Committee voted 8-5 against accelerated approval. The Mayo Clinic’s Vincent Rajkumar called it one of the two FDA approval decisions in multiple myeloma that he disagrees with. And Vinay Prasad, associate professor medicine at Oregon Health and Science University, criticized the FDA’s decision in his latest podcast, noting the drug’s toxicity and an 8.9% rate of fatal adverse events (AEs) attributed to the drug in the clinical trial, which he called “a high rate of fatal AEs.”

A similar uproar came when FDA approved the first Duchenne’s muscular dystrophy drug in 2016 despite advisory committee objections and questions about the trial that the decision was based on.

Although these types of decisions might generate the most headlines, overall, the study found FDA to be more conservative than its expert committees. 

“Disagreement was more common in which the FDA was less likely than its advisory committees to enact new product approvals, supplemental indications, or safety actions, reflecting a more conservative approach to resolving ongoing regulatory uncertainty,” the study says.

Study author Audrey Zhang, a researcher at Yale School of Medicine, also explained to Focus the difficulties in analyzing advisory committee recommendations by only examining a single, up-or-down voting question per meeting.

The study “necessarily involves collapsing some categories (for instance, choosing a single efficacy vs safety vs approval question), as well as losing some of the nuance captured in advisory committee discussions, which we recognize is a key limitation. For instance, we would miss when committee members express hesitation associated with their vote,” she said.

She also noted one factor associated with a significantly higher chance of discordance was if a committee meeting involved safety actions, which were defined as label changes to include new warnings, a Risk Evaluation and Mitigation Strategy or to withdraw a product. “Of the 27 committee meetings involving safety actions, 13 resulted in discordant FDA actions, 12 of which involved a less restrictive FDA action (failure to implement a safety action within 1 year),” Zhang said.

“Discordance was associated with lower degrees of advisory committee consensus and was more likely for agency actions focused on medical product safety than for novel approvals or supplemental indications. Statements by public speakers, advisory committee conflicts of interest, and media coverage were not associated with discordance between the committee and the agency,” she added.

Association Between Food and Drug Administration Advisory Committee Recommendations and Agency Actions, 2008–2015


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