Since 1992, Accelerated Approval has facilitated earlier patient access to promising therapies that treat serious and life-threatening illnesses. While a traditional approval is often based on a therapy’s ability to demonstrate meaningful impact upon a clinical endpoint (e.g. overall survival), Accelerated Approval is granted based upon demonstration of an effect on a surrogate or intermediate endpoint likely to predict clinical benefit (e.g. response rate, progression free survival, duration of response). These endpoints provide initial evidence of efficacy that supports earlier access to therapies for patients and requires sponsors to verify and describe clinical benefit through post-market requirements (PMRs).
We recently developed a dashboard to assess the utilization of Accelerated Approval for oncology drug development using FDA’s publicly available data. More than 160 oncology therapies have received Accelerated Approval since the regulations were established. Sixty-nine applications (42%) were granted full approval after a median of 3.1 years based on the results of post-market studies. Twenty-five (36%) of these applications were converted to full approval based on overall survival, the rest were converted based on a surrogate endpoint. Only ten applications (6%) were withdrawn after a median of 3.8 years due to a failure to confirm clinical benefit through post-market research.
In some settings, surrogate or intermediate endpoints are well understood to be correlated with clinical benefit and can be used as the basis for full approval in those specific indications. For example, the surrogate endpoint cytogenic response was used as the basis for accelerated and full approval of eight drugs indicated to treat chronic myeloid leukemia (CML). In these instances, the extent of available evidence differentiates between the initial determination for Accelerated Approval and the confirmation of long-term benefit for full approval, demonstrating the role of holistic benefit risk assessments.
The 85 remaining therapies are in the process of confirming clinical benefit but have not fulfilled their PMRs and conversion to full approval or withdrawal has not yet been formally assessed. These therapies have been on the market for a median time of 1.2 years. Fifty-eight are on track to fulfill their PMR by the target completion date, 19 are delayed in fulfilling their PMRs due to protocol amendments, slow patient accrual, or other roadblocks that have occurred, and 8 do not have a status listed in FDA’s database of PMRs.
The dashboard highlighted several important observations:
Confirming the clinical benefit of Accelerated Approval through required post-market studies is essential to ensure patients have access to therapies that are safe and effective.
The difference observed in median time for completing confirmatory studies or withdrawal (3.1 and 3.8 years, respectively) indicates that in most instances it takes several years to generate the additional evidence to confirm benefit.
Challenges in conducting post-market studies may lead to delays in fulfilling PMRs. Establishing mechanisms that promote regular checks on the status of these requirements, such as submitting progress reports on PMRs to keep a drug on the market, would help ensure PMRs are fulfilled in a timely manner.
Most Accelerated Approvals are actively working towards fulfilling PMRs or have successfully confirmed clinical benefit. Although the withdrawal of Accelerated Approval applications is rare, the ability to withdraw an application remains an important feature of the program.
To continue reading about Friends’ work on Accelerated Approval see our 2020 annual meeting whitepaper on “Optimizing the Use of Accelerated Approval.”