The FDA is proposing that a single trial could support both accelerated and full approval of oncology therapeutics. At first glance this seems to be a promising development. Though, as one reads more carefully into the new draft guidance document, another theme stands out: the FDA seems to be encouraging sponsors to avoid single-arm trials for accelerated approval and instead conduct randomized, controlled trials.

The below is from a key passage in the first paragraph of Section III:

"Given the limitations of single-arm trials, a randomized controlled trial is the preferred approach to support an application for accelerated approval. Sponsors can, as appropriate, elect to conduct a single randomized controlled trial to support an accelerated approval and to verify clinical benefit (i.e., follow a “one-trial” approach) or, they can conduct separate trials – one to support the accelerated approval and another, a confirmatory trial, to verify clinical benefit."

The document goes on to say that there are some limited circumstances in which a single-arm trial may still be acceptable to support accelerated approval.  In this scenario a follow-up randomized, controlled trial would still be required to demonstrate clinical benefit to support full approval. This new language emphasizing RCTs is a shift from the current guidance related to accelerated approval pathways, and it comes at a cost.

How should a sponsor evaluate this new development?  The opportunity to win both accelerated and full approval from a single trial sounds appealing at first.  However, RCTs that seek full approval would need to be fully powered, which usually requires a large sample size and long follow up (for PFS and OS).  Before launching such an expensive undertaking, the sponsor would probably need to generate robust clinical data from Phase 1b or 2 for two purposes. The first is to support an appropriate risk-benefit profile for the new drug that would satisfy IRBs and investigators that the RCT is ethically appropriate.  The second is to reassure stakeholders and company leadership that the RCT is a sound investment.

It seems that the net effect of this will be that sponsors will still want to conduct phase 2 and then a subsequent phase 3 trial, but accelerated approval will likely come after an early read-out from phase 3. This raises the bar for attaining "accelerated" approval relative to past practices. FDA seems to have removed its foot from the accelerator pedal and instead is pressing on the brakes.

Considering the possible increase in time and expense related to a single trial under these new FDA ground rules preferring RCTs, sponsors may find splitting the difference by designing only a single RCT phase 3 trial to be the most attractive option.

At this stage, the proposed guidance certainly leaves many questions yet to be answered:

  • How much cost will this add to Accelerated Approvals?
  • How much larger will trials need to be to compensate for the control arm and to pick up rare adverse events (AEs)?
  • Will this lead to fewer indications being eligible for single-arm trials?
  • Is there upside for some Mechanisms of Action (MOAs) and modalities?
  • Will it stifle any ability to postpone post-marketing confirmatory trials?
  • What impact will this have on EU trials?
  • Does this have the chance to decrease the time between conditional approval and full approval?

FDA is accepting feedback until May 26th:

Recent Drug Development White Paper:

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