Delays in Confirmatory Trials for Drug Applications Granted FDA's Accelerated Approval Raise Concerns

WHY WE DID THIS STUDY

FDA's 2021 approval of aducanumab (Aduhelm), a drug intended to treat Alzheimer's disease, raised concerns about FDA's accelerated approval pathway. Subsequently, OIG announced plans to conduct evaluations of the accelerated approval pathway. This data snapshot focuses on confirmatory trials, given ongoing concerns that sponsors of drug applications granted accelerated approval fail to complete their statutorily required confirmatory trials on schedule, and concerns that FDA's oversight of the trials is lax.

The accelerated approval pathway allows FDA to approve certain drugs that treat serious or life threatening diseases and offer meaningful therapeutic benefit to patients over existing treatments before confirmatory trials are completed. To gain approval in this pathway, drug sponsors must meet the same FDA's standards for safety and efficacy as traditionally approved drugs. However, they may rely on a surrogate or intermediate endpoint and do not need to show clinical benefit before approval, rather the potential for predicted clinical benefit is reasonably likely. Federal law grants FDA the authority to require sponsors to conduct confirmatory trials after approval to verify that the drugs do indeed provide the predicted clinical benefit. Typically, sponsors conduct such trials while these drugs are available to the public on a timeline agreed to by FDA and the sponsor. FDA can withdraw its accelerated approval of a drug application under certain conditions, including if confirmatory trial fails to verify the predicted clinical benefit; or sponsors can voluntarily withdraw a drug from the market.

HOW WE DID THIS STUDY

We analyzed data for accelerated approval drug applications approved by FDA's Center for Drug Evaluation and Research (CDER), from the pathway's inception in 1992 through December 2021. We used the most recent publicly available data as of May 2022 in FDA's Postmarketing Commitments Database. We also conducted structured interviews with FDA staff. We used claims data to calculate how much Medicare Parts B, C, and D spent in 2018 through 2021 for accelerated approval drugs whose confirmatory trials failed to meet their original planned completion date, limiting our analysis to all corresponding National Drug Codes and ICD-10 diagnosis codes associated with an accelerated approval drug's indication. We conducted a parallel analysis using Transformed Medicaid Statistical Information System (T MSIS) data.

WHAT WE FOUND

Since the accelerated approval pathway began in 1992, drug applications granted accelerated approval by FDA's CDER have steadily increased-with 278 approved between 1992 and December 31, 2021. Of all 278 drug applications granted accelerated approval, 104 have incomplete confirmatory trials. Of those 104, 34 percent (35 of 104) have at least one trial past its original planned completion date. And four drug applications have confirmatory trials that are significantly late-ranging from more than 5 years to nearly 12 years past their original completion dates, which FDA is addressing. Furthermore, since the inception of the pathway, 13 percent of all accelerated approval drug applications have been withdrawn, half of which were withdrawn since January 2021.

Finally, we estimated that Medicare and Medicaid spent more than $18 billion from 2018 to 2021 for the 18 drugs that correspond to the 35 drug applications granted accelerated approval with incomplete confirmatory trials past their original planned completion dates as of May 5, 2022.

WHAT WE CONCLUDE

The accelerated approval pathway holds promise for patients who face serious illnesses where adequate treatments are lacking. In the best-case scenarios, sponsors complete confirmatory trials promptly and provide evidence to confirm the drugs' clinical benefits. In those cases, FDA enables patients to access drugs that can help them and Medicare and Medicaid to pay for effective treatments. However, for a variety of reasons, sponsors do not always complete trials promptly. This can result in drugs staying on the market-and being administered to patients-for years without the predicted clinical benefit being verified. And insurers-including Medicare and Medicaid-paying billions for treatments that are not verified to have clinical benefit. Ensuring that FDA has the tools to effectively administer the accelerated approval pathway is crucial to FDA's mission to protect the public health by ensuring the safety, efficacy, and security of human drugs and biologics.