Earlier this year, the United States Department of Health and Human Services Office of the Inspector General (HHS OIG) conducted a review of the Food and Drug Administration (FDA) accelerated approval pathway for prescription drugs, to better understand the extent to which the FDA’s review varied throughout the accelerated approval pathway.
In the report, HHS OIG notes that FDA evaluates evidence to determine effectiveness of a drug differently in the accelerated approval pathway and the traditional approval pathway. Under the traditional pathway, sponsors generally design trials to assess an effect on a clinical endpoint that directly reflects patient benefits (i.e., how patients feel, function, or survive), and the trials need to demonstrate that the drug has a clinical benefit. In the accelerated approval pathway, sponsors can assess an effect on a surrogate endpoint (i.e., a marker) and demonstrate that the drug’s effect is reasonably likely to predict a clinical benefit. Neither the FDA nor federal law define “reasonably likely” in this context.
In conducting the review, HHS OIG examined FDA’s review of nineteen drugs and 5 biologics approved by the accelerated approval pathway (a total of 24 drugs). HHS OIG determined whether and how the FDA deviated from its recommended or typical practices in the accelerated approval pathway. One of the chosen drugs that HHS OIG reviewed was aducanumab (Aduhelm), focusing on whether the main issues of concern raised about aducanumab’s approval were present in approvals of other drugs in the sample. There were nine other drugs sampled that were “identified as concerning during interviews with stakeholders,” for a total of 10 “concerning” drugs and 14 randomly selected drugs.
HHS OIG requested the administrative files for the 24 drugs. The agency also reviewed agendas, minutes, and transcripts for advisory committee meetings convened by FDA for the drugs in the sample, as well as relevant FDA policies and procedures. Two drugs in the sample had approvals in the 1990s and the administrative files for those drugs did not have sufficient information to determine whether the sponsors followed their original analysis plans.
HHS OIG found that 21 of the 24 drugs moved through the accelerated approval pathway without raising the kinds of concerns that surfaced during the review and approval of aducanumab, while three drugs did raise similar concerns. The processes for approving aducanumab (a drug to treat Alzheimer’s disease), eteplirsen (a drug to treat Duchenne muscular dystrophy), and hydroxyprogesterone caproate (HPC, a drug to reduce the risk of preterm birth in certain women) deviated from the other 21 approvals. Some of the areas of concern include: the FDA evaluated analyses were not included in the sponsor’s original analysis plans; concerns about the drugs raised by FDA reviewers and/or advisory committees; and meetings with sponsors were not fully documented in the administrative files. Even still, FDA approved all three of the drugs, despite concerns from its own reviewers and/or advisory committees.
Additionally, all three of the drugs that raised concerns in HHS OIG’s review continued to raise concerns after their approvals. The report notes that aducanumab and HPC were both ultimately removed from the market while eteplirsen’s trial to confirm clinical benefit has been delayed.
Overall, HHS OIG did find that for 21 of the 24 drugs sampled, there was a “consistent approach through the pathway and the approval of advisory committees that had been convened, with no formal scientific disputes or informal agreements.”
At its conclusion, HHS OIG recommended that the FDA: (1) define specific factors that would require the agency’s accelerated approval council to advise on certain drug applications and (2) take steps to ensure appropriate documentation of meetings with sponsors is included in drug approval administrative files. FDA concurred with the second recommendation.
Importantly, HHS OIG was not conducting a compliance review and did not independently assess the appropriateness of decisions made by the FDA.