A Debate on Evidentiary Standards for Accelerated Approvals will Continue at the Oncologic Drugs Advisory Committee Meeting

On October 28, 2021, the Oncologic Drugs Advisory Committee Meeting will hear an update where the confirmatory trial demonstrated a worse overall survival in the melphalan flufenamide treatment arm compared to the control arm (link).

Based on the update provided, the committee will have a general discussion focused on next steps for the product including whether the indication should remain on the market while additional trial(s) are conducted.

Here is a brief history of melphalan flufenamide (PEPAXTO) dervied from summary basis of approval using Vivpro-RIA application:

February 25, 2021, melphalan flufenamide was approved in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.

The efficacy of PEPAXTO in combination with dexamethasone was evaluated in HORIZON [NCT02963493], a multicenter, single-arm trial. As noted in the FDA review, an advisory committee meeting or other external consultations was not conducted in the first review cycle. The major efficacy outcome measure was overall response rate (ORR) and Duration of Response (DoR) assessed according to the International Myeloma Working Group (IMWG) Criteria by investigators. Efficacy was established using 97 patients with the median time to first response was 2.1 months (range: 1.0 to 6.1 months).

July 28, 2021, FDA alerted patients and health care professionals about clinical trial results showing an increased risk of death associated with PEPAXTO (melphalan flufenamide). FDA published the results of the OCEAN trial [NCT03151811].

FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cut-off date of February 3, 2021. There were 495 randomized patients included in the efficacy analysis. For overall survival, there were 117/246 (48%) deaths on the melphalan flufenamide investigational arm and 108/249 (43%) deaths on the pomalidomide control arm

October 28, 2021, the Oncologic Drugs Advisory Committee Meeting will hear an update where the confirmatory trial demonstrated a worse overall survival in the melphalan flufenamide treatment arm compared to the control arm.

The history of this application could be important for discussion.

June 18, 2015 (Type C Meeting), through June 30, 2020 until submitting the NDA the sponsor had a series of interactions with the FDA Agency. The expressed concerns with the use of single-arm trial to support an NDA (New Drug Application). However, FDA’s Integrated Assessment of Effectiveness found the evidence was sufficient to recommend approval.