The FDA's accelerated approval program has proven largely successful over its 30-year history, with half of all accelerated approvals converting to traditional approval in a median time of 3.2 years, according to a comprehensive analysis published in Therapeutic Innovation & Regulatory Science. The findings challenge recent criticisms of the pathway following controversial approvals like aducanumab (Aduhelm) for Alzheimer's disease.
Since its establishment in 1992 during the AIDS epidemic, the accelerated approval pathway has approved 278 drug applications through December 2021. The program allows FDA to approve drugs for serious or life-threatening conditions based on surrogate endpoints that are reasonably likely to predict clinical benefit, rather than waiting for demonstration of effects on irreversible morbidity or mortality.
Program Evolution and Current Focus
The accelerated approval program has undergone significant transformation in its therapeutic focus. In the first decade (1992-2001), 65% of accelerated approvals were for infectious diseases, consistent with the program's original intent to expedite HIV treatments. However, the landscape has shifted dramatically, with 83% of accelerated approvals in the most recent decade (2012-2021) being for oncology indications.
This evolution reflects the development of targeted therapies in oncology and the availability of more well-established oncology surrogate endpoints. The median time from accelerated approval to traditional approval has also improved significantly, dropping from 3.9 years in the first decade to 2.3 years in the most recent decade.
Conversion and Withdrawal Patterns
As of December 31, 2021, FDA has converted 139 accelerated approvals (50%) to traditional approval based on studies confirming clinical benefit. The agency has withdrawn 32 accelerated approvals (12%), either voluntarily by sponsors or involuntarily after FDA proceedings.
Notably, FDA's oversight has become more proactive over time. The median time from approval to withdrawal decreased substantially from 10.4 years for approvals granted between 1992-2001 to 3.5 years for those granted between 2012-2021. This improvement stems partly from FDA's use of Oncologic Drug Advisory Committee (ODAC) meetings to identify and publicly discuss dangling accelerated approvals.
Outstanding Confirmatory Trials
Of the 278 total accelerated approvals, 107 (38%) remain pending completion and FDA review of confirmatory trials as of December 2021. However, 77 of these have been marketed for less than 3.2 years, which falls within the reasonable timeframe for confirmatory trial completion.
The remaining 30 accelerated approvals have been pending for more than 3.2 years. Of these, 22 are considered on-time according to original or revised milestones, while 5 are classified as "dangling" approvals and 3 as "delinquent."
Financial Implications and Government Oversight
A parallel analysis by the Department of Health and Human Services Office of Inspector General revealed significant financial implications of delayed confirmatory trials. The government estimated that Medicare and Medicaid spent more than $18 billion from 2018 to 2021 for 18 drugs corresponding to 35 drug applications with incomplete confirmatory trials past their original planned completion dates.
The OIG analysis found that of 104 drug applications with incomplete confirmatory trials, 35 (34%) have at least one trial past its original planned completion date. 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.
Milestone Revisions and Challenges
FDA has demonstrated flexibility in managing the program by allowing milestone revisions when justified. Among the 12 cases with revised milestones in recent years, three were due to COVID-19 pandemic impacts, two resulted from dependencies on delayed studies, and four oncology cases required additional time to accumulate progression-free survival events that occurred more slowly than anticipated.
For dangling approvals, FDA is actively evaluating whether products should remain on the market. In three cases, enrollment challenges or changes in the treatment landscape rendered trials infeasible, though FDA indicated alternative options exist to confirm clinical benefit.
Program Management and Future Considerations
The analysis emphasizes that concerns about the accelerated approval program are based on a small number of examples rather than the overall program performance. Between 2020 and 2021, eight dangling approvals were voluntarily withdrawn following FDA discussions and ODAC meetings, demonstrating the agency's proactive management approach.
FDA has implemented several improvements, including 2014 guidance requiring that confirmatory trials be underway or protocols agreed upon at the time of accelerated approval. The agency continues to publicly track milestone progress on its website, though calls for increased transparency include posting revised milestone dates and detailed explanations for study deadline extensions.
The authors conclude that any legislative or regulatory changes to the program should be based on cumulative experience rather than outliers, emphasizing the need to avoid creating disincentives that would reduce access to life-saving treatments under the accelerated approval pathway.
