Turmoil Led to Pazdur Overriding BLA Decision: Report
A new report from STAT describes drug review turmoil at FDA that led to FDA Oncology Center of Excellence director Richard Pazdur overriding CBER reviewers and management in the surprise rejection last month of Replimune’s priority-reviewed BLA for its melanoma therapy RP1 (vusolimogene oderparepvec). RP1 is a herpes virus-based immunotherapy being studied in combination with Bristol Myers Squibb’s Opdivo. The BLA’s review was likely affected by recent leadership changes, staff departures, and internal dysfunction, according to STAT.
In the 7/22 complete response letter, CBER said it could not approve RP1 in combination with nivolumab due to concerns about the clinical trial data, Replimune said at the time. The Center found the pivotal IGNYTE trial insufficient as an “adequate and well-controlled” investigation. It also said the study’s heterogeneous patient population made the results difficult to interpret and pointed to unresolved issues in the design of a confirmatory trial, including questions about the contribution of each drug component.
The review concerns were not raised by CBER or its then-director Vinay Prasad, rather Pazdur made the rejection decision after being consulted due to CBER’s mishandling of the review, according to STAT. Pazdur reportedly overruled CBER staff and Prasad, who were in agreement that the BLA should be approved. “This was Rick Pazdur’s doing,” an anonymous FDA official told STAT. Prasad resigned from the agency shortly after the RP1 decision amid external criticism tied to other controversial FDA actions (see story).
Replimmune CEO Sushil Patel has pushed back, saying the company was surprised by the rejection and that the trial design had been previously agreed upon with FDA and issues cited in the rejection letter were new and not raised during earlier review updates. The company has requested an FDA Type A meeting to “find a path forward for the timely accelerated approval of RP1 without which the development of RP1 for advanced cancer patients with limited options will not be viable,” he said.
Meanwhile, a group of 22 melanoma and oncology experts, including the clinical trial investigators from the IGNYTE trial, have written an open letter to FDA leadership asking that the data be re-reviewed. They offered counterbalance statements to the points contained in the complete response letter.
For example, the letter notes that the experts have the “fortunate position” of being involved in the research of 16 different FDA-approved drugs with 31 melanoma indications. Addressing the CBER reviewers’ concerns about the IGNYTE trial’s heterogeneous patient population, they said current melanoma guidelines “show multiple treatment pathways in both the adjuvant and advanced disease setting funneling to the point of IGNYTE eligibility in the case of refractory disease. This means that this real-world patient population will be, by necessity, heterogeneous. Importantly, these patients converge into the common biologic entity known as ‘PD-1 refractory disease’ in which there is global consensus amongst treating immunotherapists that follow-on treatment responses are unlikely and prognosis is poor. Sub-segmenting these patients to artificially obtain statistical homogeneity serves no practical purpose and denies treatment opportunity to those in great need.”