FDA proposes guidance on endpoints for multiple myeloma therapeutics accelerated approval trials
The US Food and Drug Administration (FDA) has outlined its thinking on how to design and execute clinical trials in which sponsors can use minimal residual disease (MRD) and complete response (CR) as primary endpoints when developing drugs and biologics to treat multiple myeloma and to receive accelerated approval designation. The agency noted that the current requirements for such drugs are infeasible, and using the endpoints may allow sponsors to get their products approved faster.FDA said that it has approved 20 new drugs and 44 new biologics for the treatment of multiple myeloma since 2003. The agency noted that while the new therapeutics, along with advances in supportive care, have significantly improved overall survival expectations for patients with multiple myeloma, demonstrating further increases in overall response rates may require infeasibly large clinical trials. Instead, it argued that using more sensitive response assessments may help speed the drug development process.
In 2024, FDA convened a meeting of its Oncologic Drug Advisory Committee (ODAC) where experts reviewed data looking at the relationship between MRD and long-term outcomes. Committee members agreed unanimously that MRD could be used to support accelerated approval of therapeutics for multiple myeloma; the draft guidance issued 20 January reflects their findings.
While FDA prefers that sponsors use randomized clinical trials, the guidance states that MRD can be used in single-arm studies to support accelerated approval for multiple myeloma therapeutics.
"Given that time-to-event endpoints such as [progression free survival (PFS)] and [overall survival (OS)] are also interpretable in randomized trials, sponsors can conduct one trial evaluating MRD for accelerated approval, with the trial continuing to evaluate later time-to-event endpoints (e.g., PFS/OS) to support traditional approval," the draft guidance states. "Randomized trials are recommended for evaluating combination regimens.”
The guidance lists general drug development considerations for sponsors, including ensuring that the control arm of a clinical study evaluating a multiple myeloma therapeutic is equipoised; that randomized trials should be designed to assess long-term clinical endpoints; that randomized trials should also be fully enrolled before beginning to prevent situations that would jeopardize trial integrity; and that the sponsor should justify the magnitude of the treatment difference between MRD negativity rate between the study arms in a randomized trial.
FDA also details its thinking on trial design and statistical considerations in the guidance, including asking sponsors to justify their use of MRD as an endpoint based on the specific populations and disease setting. Furthermore, the agency wrote that trials designed with MRD as a primary endpoint should enroll patients with measurable disease, and the trial protocol should clearly specify the assessment schedule for MRD endpoints and justify them.
The guidance includes recommendations from FDA using CR as an endpoint for accelerated approval. The agency noted that its analysis has found an association between CR and long-term outcomes.
"Like MRD, CR rate can be used as an endpoint to support accelerated approval in trials evaluating drug and biological products intended to treat patients with multiple myeloma," the agency added.
However, to use CR as an endpoint, FDA notes that it should be assessed as the overall CR rate rather than a CR rate at a specific time, there needs to be adequate follow-up with patients to ensure its durability, and the durability for CR should be assessed from time to achievement of CR to progression or death.
FDA emphasized that the guidance is only for using MRD and CR trials for developing multiple myeloma therapeutics and does not address patient selection, enrichment, stratification in clinical trials, or for treatment decisions in those trials. The agency also directed sponsors to other guidances for questions specific to its accelerated approval program and on the use of biomarkers, such as MRD, when developing therapeutics for hematologic malignancies.
FDA is accepting comments on the draft guidance on www.regulations.gov under docket no. FDA-2025-D-2616 through 22 March.
Draft guidance
