“It’s a rare window into seeing how the FDA makes decisions because the proceedings are open unlike many of the other decisions they make,” Audrey Zhang, a medical student at the New York University School of Medicine, said on why she decided to embark on crunching the numbers from 376 votes by FDA advisory committee meetings from 2008 to 2015.

The data, published in The Milbank Quarterly, found that the FDA took the same action as recommended by the advisory committee 78% of the time.

“What I’ve often heard quoted is, ‘more than 90%,’ but after looking at our comprehensive sample of advisory committees, we found that the rate of agreement was actually a little lower than that,” Zhang told BioWorld Insight.

Not surprisingly, the degree of consensus, defined as the proportion of advisory committee members voting for the majority action, was linked to the discordance, with higher consensus more likely to result in the FDA taking the same action as the advisory committee recommended (p<0.001).

Earlier this year, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee split 8-8 on the approval of dual SGLT1 and SGLT2 inhibitor, Zynquista (sotagliflozin, Lexicon Pharmaceuticals Inc. and Sanofi SA), as an adjunct to insulin in treating type 1 diabetes, citing an increased risk of diabetic ketoacidosis. The FDA followed with a complete response letter a few months later. (See BioWorld, Jan. 18, 2019, and March 25, 2019.)

Zhang and colleagues also looked at the rates of conflicts of interest among advisory committee members, the influence of public demand – both public speakers at the conference as well as media interest, defined as news articles in the New York Times, Wall Street Journal and Washington Post in the six months before the advisory committee meeting – and the unmet need of the drug, defined by orphan drug status or the use of special regulatory programs.

“Ultimately, none of these were found to be significant predictors of disagreement between an advisory committee’s recommendations and the FDA’s actions,” the report concluded.

The lack of influence on discordance by conflicts of interest for advisory committee members may be due to the FDA Amendments Act of 2007, which limited the number of members who could have conflicts. The level has remained low even after the cap was lifted by the FDA Safety and Innovation Act in 2012.

On the public influence, the report notes that “it is possible, though, that this study may not have fully captured the effect of recent trends toward an increasing number of public speakers or sponsorships, and thus further scrutiny is warranted.”

Coming after the cutoff for the data analysis, Exondys 51 (eteplirsen, Sarepta Therapeutics Inc.) is arguably the most famous drug approved with the backing of the public. The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 3-7 with three abstentions against full approval and 5-8 with no abstentions against accelerated approval of the drug, although one member said he meant to vote in favor of accelerated approval. Nevertheless, the FDA approved the Duchenne muscular dystrophy drug after a lot of public outcry and internal debate at the agency. (See BioWorld, April 27, 2016, and Sept. 20, 2016.)

More/less restrictive

In 75% of the discordant decisions, the FDA was harsher than the committee’s recommendation, with almost all of the more restrictive decisions coming from the FDA denying drug approvals or supplemental indications.

Unlike advisory committees, the FDA has the ability to directly ask for detailed information or additional studies from sponsors, allowing the ability to delay a decision.

“In doing so, the FDA is able to take advantage of both a mechanism and a longer timeline not available to the advisory committee to reduce uncertainty about the product being evaluated. Overall, these tendencies are captured by the FDA’s appearing to have a higher threshold than the advisory committees for enacting new approvals, supplements, or safety actions under conditions of uncertainty,” the report noted.

For decisions on safety, the FDA was likely to be less restrictive, with the agency failing to adopt safety actions recommended by the committees. In fact, 48% of all advisory committee votes on safety resulted in discordance with the FDA, with only one of the 13 discordant actions resulting in a more restrictive stance.

Zhang hypothesizes that the less restrictive action on safety may come from the agency’s desire to preserve its credibility, “The pattern of behavior, in which the FDA tended to not institute new actions of any kind, suggests that this may be a factor.”