FDA’s Accelerated Approval (AA) pathway has often been a subject of public criticism due to the apparent approval of inefficient drugs based on preliminary and/or partial efficacy data. However, the AA is a conditional approval that can be withdrawn if the conditions are not met. This week, the FDA released a new guidance document whose primary purpose seems to be to show the expedited withdrawal process for AA drugs.
The AA pathway was created in 1992 to expedite the approval of AIDS drugs. At that time, it had become obvious that definitive endpoints measuring the treatment of AIDS would delay the approval of new drugs for the life-threatening infection. So, surrogate endpoints such as reduction in the viral load and increase in the CD4+ counts were accepted as reasonable measures of the effectiveness of new drugs. And it worked. Within a few years, multiple AIDS drugs were approved via the AA pathway helping control the AIDS epidemic. Since then about 300 drugs have been approved via the AA pathway, 85% of which were for cancer. Like AIDS, definitive endpoints for cancer are elusive, justifying the use of surrogate endpoints.
However, it was always required that drugs approved via the AA pathway be further evaluated in post-market confirmatory studies, and the approval of drugs that failed confirmatory studies, be withdrawn. Over 32 years of the AA pathway, the withdrawal of unconfirmed drugs did not get as much publicity as those that stayed in the market. To date, 15% of oncology drugs approved via the AA pathway have been withdrawn based on not meeting the post-market commitments. The main criticism of the pathway, in addition to the core premise of approval based on preliminary data, is the delay in the withdrawal of approved drugs that failed post-market studies. It could take 3-6 years on average for the AA drug approvals to be withdrawn, owing to delays in completing the confirmatory studies and the extended appeal process, all the while continued marketing of the drugs. Since, almost all these drugs are for serious, life-threatening conditions with unmet medical needs, the delays translated to huge financial windfalls for the manufacturers.
In December 2022, Congress mandated the FDA via the Consolidated Appropriations Act to create a process to expedite the withdrawal of drugs approved via the AA pathway lacking confirmatory data. Under the law, the FDA can require that “a confirmatory trial be underway prior to accelerated approval or within a specified time period after the date of accelerated approval.” The AA approval must be made on the determination that an effect on the endpoint used to support approval––a surrogate endpoint or an intermediate clinical endpoint––is reasonably likely to predict clinical benefit. Additionally, the manufacturer must commit to a deadline to submit the final confirmatory study protocol, targets for enrollment progress, and other milestones such as the target date for study completion. The label of the marketed drug must include a succinct description of the limitations of the usefulness of the drug and any uncertainty about anticipated clinical benefits, manufacturers must submit half-yearly reports on the progress of the confirmatory studies, and the FDA would publish those updates for the public. The FDA can withdraw the approval if the manufacturer fails to meet any of the post-market commitments. Under the expedited withdrawal process, the entire duration from the time the FDA determines that the conditions for an approval withdrawal have been met and the actual withdrawal could be 30-60 days.
The new Guidance Document describes in detail the conditions for AA approval and almost half of the document discusses the expedited withdrawal process. The document demonstrates that the FDA is serious about enforcing the strict conditions for market sustenance of drugs approved via the accelerated approval pathway.
