A few controversial approvals in the last decade have clouded the public perception of the Accelerated Approval (AA) pathway. The Congress last year gave the FDA an additional mandate to enforce timely completion of the post-market clinical trial commitments thereby increasing the burden of maintaining the approval on the sponsors. The AA pathway’s credibility relies on post-market studies which may take years to complete in turn leading to the accusation that the manufacturers game the system to reap economic benefits from their drugs that may not be working as projected at the time of accelerated approval based on limited safety and efficacy data. The revised policy addresses this issue.
Under the current laws, the FDA will not approve a drug unless the confirmatory trial has already started at the time of granting approval. In situations where recruiting or keeping patients in the study would become difficult after the drug is on the market, the FDA may require all patient enrollment to be completed before granting approval. The new guidance about this policy clarifies that sponsors must set enrollment goals, provide detailed study plans, and meet important deadlines such as the study’s completion dates in agreement with the FDA at the time of the approval and submit progress reports every 180 days thereafter. If a company does not follow these rules or fails to complete the trial on time, the FDA can withdraw the drug’s approval.
At the time a drug is designated for the AA pathway, companies should meet with the FDA to discuss their plan for the confirmatory trial. This topic should ideally be discussed at the End-of-Phase 2 (EOP2) meeting or around the time the registration trails are initiated. During these discussions, the company and the FDA need to agree on the post-market confirmatory trial’s design and how it will prove the drug’s benefits. The trial must be realistic, well-planned, and designed to show that the drug works as intended.
The FDA’s criteria for considering a confirmatory trial to be “underway” are having realistic benchmarks (including, e.g., participant recruitment goal, extent of site activation, proportion of primary endpoint events accrued) that could be assessed at the time of the anticipated accelerated approval to facilitate FDA’s determination of whether the trial is underway. Aspects such as completion date, a solid plan to finish the trial on time, and evidence that patient enrollment has started would be evaluated and agreed upon by the FDA and company. Companies must explain why their timeline is reasonable, and the FDA will review progress, including how many patients have joined, how quickly they are joining, and how many study sites are active. If enrollment isn’t finished before approval, companies need to provide a timeline for completing it afterward. They should also set clear goals, such as the number of patients recruited or study sites activated, to prove the trial is on track. If these goals are missed, the company must explain why and describe how they will address the delays.
For rare diseases or special situations, the FDA might allow flexibility. For example, if a trial uses early data from smaller studies to support approval, it can continue after the drug is approved. Trials might also be simpler for rare diseases, especially if there are very few patients available. In cases where a trial depends on an event that hasn’t occurred yet, such as a disease outbreak, the FDA may not require it to begin before approval.
During the post-approval phase of the drug, the FDA will constantly evaluate if the sponsor’s progress to date and plans for post approval conduct of the trial provide sufficient assurance to expect timely completion of the trial. To ensure the confirmatory trial enrolls and retains sufficient U.S. participants, the sponsor’s enrollment strategy should prioritize early U.S. recruitment, and U.S. recruitment should be closer to completion at the time of accelerated approval.
The new guidance and the associated enforcement may trigger strategic planning by the sponsors much before pursuing the AA pathway to evaluate if there is value in this pathway for their products or if the challenges make conventional approval more reasonable.
