FDA's Accelerated Approval Program Causes Concerns Over Delays in Confirmatory Trials


The purpose of this study



The FDA's approval of aducanumab (Aduhelm), a drug intended to treat Alzheimer's disease, raised concerns about FDA's accelerated approval process. Following that announcement, the OIG announced that it would evaluate the accelerated approval process. In this data snapshot, we focus on confirmatory trials, since it is emerging that sponsors of drug applications granted accelerated approval often fail to complete their statutorily required confirmatory trials on time, and that FDA oversight is lacking.



Through the accelerated approval pathway, FDA can approve drugs that treat serious or life-threatening diseases and provide meaningful therapeutic benefit over existing treatments before confirmatory trials are completed. This pathway requires drug sponsors to meet the same FDA safety and efficacy standards as traditionally approved drugs. However, they do not need to demonstrate clinical benefit before approval, rather the potential for predicted clinical benefit is reasonably likely. FDA has the authority to require sponsors to conduct confirmatory trials after approval to ensure that the drugs provide the clinical benefits predicted. Sponsors conduct such trials on a timeline agreed to by FDA and the sponsor while these drugs are available to the public. A drug application can be withdrawn by FDA under certain conditions, including if a confirmatory trial fails to verify the predicted clinical benefit, or if sponsors voluntarily withdraw a drug.



Study procedure



From 1992 through December 2021, we analyzed data for accelerated approval drug applications approved by FDA's Center for Drug Evaluation and Research (CDER). Based on FDA's Postmarketing Commitments Database as of May 2022, we used the most recent publicly available data. Additionally, we conducted structured interviews with FDA staff. By analyzing Medicare claims data from 2018 through 2021, we calculated how much Medicare Parts B, C, and D paid for accelerated approval drugs that failed to complete their confirmatory trials on schedule. Our analysis was limited to all corresponding National Drug Codes and ICD-10 diagnosis codes corresponding to the indication of each accelerated approval drug. In parallel, we analyzed Transformed Medicaid Statistical Information System (T MSIS) data.



The findings



In the past 25 years, FDA's CDER has approved 278 drug applications through accelerated approval since the accelerated approval pathway started in 1992. 104 of the 278 drug applications granted accelerated approval have incomplete confirmatory trials. Among those 104 trials, 34 percent (35 of 104) are past their original completion date. In addition, four drug applications have confirmatory trials that are significantly late-ranging from more than five years to nearly 12 years past their original completion dates. A further 13 percent of all accelerated approval drug applications have been withdrawn since the pathway was established, half of which have been withdrawn since January 2021.



As of May 5, 2022, Medicare and Medicaid are estimated to have spent over $18 billion on the 18 drugs which correspond to the 35 drug applications granted accelerated approval with incomplete confirmatory trials after their original completion dates.






Those with serious illnesses that lack adequate treatments may benefit from the accelerated approval pathway. When sponsors complete confirmatory trials promptly, they provide evidence of the drugs' clinical benefits. In those cases, FDA permits patients to access drugs that can help them, while Medicare and Medicaid cover the costs of effective treatments. Sponsors, however, do not always complete trials promptly for a variety of reasons. A drug may remain on the market-and be given to patients-for years without being shown to have the predicted clinical benefit. Insurers such as Medicare and Medicaid pay billions for treatments that are not clinically beneficial. A key aspect of FDA's mission is to protect the public health by ensuring that human drugs and biologics are safe, effective, and secure.




The full report can be found here: https://oig.hhs.gov/oei/reports/OEI-01-21-00401.pdf



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