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Regulatory Focus – Experts propose changes to FDA’s Accelerated Approval Program

Regulatory Focus – Experts propose changes to FDA’s Accelerated Approval Program

A new white paper from the Friends of Cancer Research offers a blueprint for reimagining the US Food and Drug Administration (FDA) Accelerated Approval Program for drugs and biologics that treat serious and life-threatening illnesses.

The white paper, released during the group’s annual meeting, recommends explicitly adding a more comprehensive risk-benefit assessment to the surrogate endpoints currently used as the basis for approval, a framework that would move the US closer to the approaches used in Europe and Canada. The recommendations were formulated by a working group that included representatives from Friends of Cancer Research, industry, patients and the FDA.

For example, drug toxicity could be considered within the context of patient quality of life and the availability of treatment, the working group asserted. “It may be appropriate to award [Accelerated Approval] to a drug with a lower [overall response rate] if the drug is less toxic or has a positive impact on patient-reported outcomes or function – and a confirmatory trial would aim to verify that benefit vs. risk was maintained in the post-market setting,” the group wrote.

The Accelerated Approval Program, which was created in 1992 in response in the HIV/AIDS epidemic, is now used predominantly in the approval of oncology and hematology treatments.

Under the most recent statutory update to the program in 2012, an accelerated approval is granted if the product “has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit” or on a “clinical endpoint that can be measured earlier than irreversible morbidity and mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit.” FDA also is charged with considering the severity, rarity or prevalence of the condition, as well as the availability of other treatments.

The FDA review process already includes a benefit-risk assessment as part of all approvals, but the agency is bound by the legal framework, which focuses on surrogate and intermediate clinical endpoints as the basis for approval.

“This poses challenges,” R. Angelo de Claro, MD, of the FDA Oncology Center of Excellence and a member of the working group, said at the Friends of Cancer Research annual meeting. “For example, we have used the same endpoint – one example is response rate – as a basis for accelerated approval and traditional approval. In addition, establishing [what is] reasonably likely to predict for clinical benefit is challenging for other disease areas, as well. Reconsideration of the basis of accelerated approval could grant FDA more flexibility to have more therapies available for serious and life-threatening diseases.”

The balance of flexibility and clarity in the accelerated approval process is important for industry, said Josh Bilenker, MD, CEO of Loxo Oncology at Lilly, who was also a member of the working group.

Clarity is key to industry because capital allocation and resourcing decisions are made far in advance and require many stakeholders, he said. “The flexibility part comes to be more important when data are being generated. We’d like to have the ability to go into the agency with that data package and figure out the best path forward that is responding to a specific moment, a specific drug, and it’s associated data, and every drug is unique in that respect.”

The working group recommended several modifications to the pre-approval phase of the Accelerated Approval Program, including:

  • A standardized approach to the definition of “available therapy” in the context of the specific disease setting or population, including biomarker positive and novel refractory disease states.
  • Additional guidance on surrogate endpoints, such as duration of response and overall response rate, and how they will be weighted by the agency in a benefit-risk assessment, as well as the development of new surrogate endpoints.
  • Consideration of heterogeneity in trial populations and potentially awarding accelerated approval to subpopulations of “excellent responders.”
  • Expanded use of synthetic or external control arms to support approvals in single-arm trials where traditional control arms are not feasible.

Additionally, the group proposed modifications for the post-approval phase of the program, including:

  • Initiation of confirmatory studies, and enrollment of a pre-determined number of patients, at the time a New Drug Application or Biologics License Application is filed.
  • A more flexible process for confirmatory trials and potential drug withdrawals, including a possible annual update of post-market requirements and review of new data.
  • Increased use of real-world evidence to supplement confirmatory trial results.…