After quitting FDA adcomm in protest of Aduhelm decision, Harvard's Aaron Kesselheim finds agency has an approval bias

The ill-fated launch of Biogen’s Alzheimer’s disease treatment Aduhelm raised many questions, including this: Why did the FDA sign off on the drug after an independent advisory committee recommended against it?

One of those who wondered was Harvard Professor Aaron Kesselheim, M.D., a former member of the committee who was one of three to quit the panel in protest after the FDA approved Aduhelm in 2021.

In attempting to find an answer, Kesselheim assembled a small group of researchers to study FDA decisions from 2010 to 2021 where the regulator sought input from one of its advisory groups.

Kesselheim and his team discovered that the FDA was much more likely to follow the panel advice when the recommendation was positive. The findings were published early this month in JAMA Health Forum.

Of the 147 occasions when an advisory committee was gathered to assess a new drug application and came up with a positive recommendation, the FDA followed with an approval 142 times, the team found. But on the 60 occasions when an advisory panel voted against a drug application, the FDA followed with just 40 rejections.

The results indicate that the regulator leans more toward approvals, with perhaps the best example being Aduhelm. During that advisory committee meeting of 11 members in November 2020, 10 recommended against approval, with one abstention.

“Reforms are necessary to clarify the FDA’s commitment to independent expert advice as an integral part of its regulation of prescription drugs,” Kesselheim’s group concluded.

In response, the FDA did not try to explain the discrepancy but pointed to several reasons its decisions may vary from advisory committee recommendations.

"Issues may arise during FDA’s review process that may not be discussed in the public forum of an AC meeting, such as proprietary manufacturing issues or a failed manufacturing inspection," a spokesperson wrote in an email. "There also may be some situations where additional data or analyses do not become available until after the AC meeting.

"Occasionally, FDA and the AC may simply have a difference of opinion regarding the interpretation of the underlying facts and data," the agency's spokesperson continued. "Moreover, it is possible that the AC’s advice is inconsistent with FDA’s policy positions or past decisions."

In a commentary published alongside the Kesselheim study, University of Southern California Professor Genevieve Kanter, Ph.D., of the Price School of Public Policy, took the analysis a step further.

The FDA is no longer asking committees to determine whether a drug should be endorsed, she said in an interview. The advisory panels instead are being used to guide the agency toward easier paths to approval, Kanter says.

In the Aduhelm case, "the advisory committee was roundly convinced that the drug had no effect on key clinical endpoints,” Kanter wrote. “Seeing that pivotal study findings on the clinical endpoints were unpersuasive, the agency found an alternative route to approval using surrogate endpoint and did not reconvene its implacable advisory committee.”

One factor that may be pressuring the FDA to favor approvals is the increased influence of patient advocacy groups, Kanter noted. Another is the increasingly cushy relationship between industry and the FDA.

“Pro-approval bias need not be problematic as long as it reflects the public’s priorities of speedy access to new treatments and high risk tolerance,” Kanter wrote. “If, on the other hand, it reflects the influence of pharma, this bias is deeply concerning.”

Another finding from the Kesselheim report that Kanter cited was the declining frequency of advisory committee meetings—from a high of 50 in 2012 to a low of 18 in both 2020 and 2021.

During the interview, Kanter speculated that the FDA’s increased and broader use of the accelerated pathway for drug approvals has lessened the need for advisory committee input.

“What we're seeing is structural changes in how FDA is treating certain kinds of drugs,” Kanter said. “And with that, there’s become more unilateral decisions.”

For its part, the FDA rejected the notion that it has an approval bias. The agency maintains that it has been transparent about its decisions.

"FDA will generally explain in the publicly posted application approval package … how the advice received from the advisory committee was incorporated into the final benefit/risk determination and address any discrepancy between its decision and the advisory committee’s advice," its spokesperson said.