Makary Defends FDA Drug Decisions
During a CNBC interview at a 5/4 Milken Institute conference, FDA commissioner Marty Makary forcefully defended the agency against mounting criticism of recent drug rejections, arguing the agency is “following the science” while accelerating broader reforms aimed at speeding approvals and restoring U.S. biotech competitiveness.
Makary pushed back on media reports and industry backlash tied to several high-profile decisions — including the rejection of a melanoma therapy from Replimune — saying FDA determinations are grounded in consistent internal scientific review rather than external pressure.
“I don’t work for any company, I work for the American people,” Makary said, emphasizing that “three independent review teams” reached the same conclusion on the therapy in question. He rejected claims that internal reviewers had recommended approval, pointing instead to the agency’s publicly released complete response letter as the authoritative record.
In a 4/10 letter, the agency said a reanalysis of Replimune’s vusolimogene oderparepvec in combination with nivolumab for advanced melanoma determined that the clinical data and additional evidence failed to demonstrate “substantial evidence of effectiveness.” FDA’s rejection centered on shortcomings in two studies: the Phase 2 RPL-001-16 trial and the ongoing Phase 3 RP1-104 study.
For RPL-001-16, reviewers reiterated longstanding concerns about the single-arm trial design, which did not allow the agency to isolate the contribution of vusolimogene oderparepvec when used alongside nivolumab. The agency also cited heterogeneity in the patient population and multiple issues with how tumor responses were assessed, including the confounding effects of surgical procedures, reinjection of tumors, and inconsistent application of standard RECIST criteria. Notably, FDA found that more than half of responding patients lacked non-injected lesions, making it difficult to determine whether the therapy produced systemic anti-tumor effects.
The RP1-104 study, intended as a confirmatory Phase 3 trial, was also deemed insufficient to support approval at this stage, FDA said. The resubmission included an early, unplanned analysis representing just 10% of the planned enrollment, with response assessments conducted solely by investigators and lacking key durability data.
The agency emphasized that it had repeatedly advised Replimune — dating back to 2021 — to conduct a randomized controlled trial capable of demonstrating efficacy and isolating the contribution of each component of the combination therapy.
According to prior reporting, Richard Pazdur, then-head of FDA’s Oncology Center of Excellence, intervened in the earlier review to overrule a decision by CBER director Vinay Prasad, who had supported approval of the therapy under the agency’s accelerated approval framework. Pazdur ultimately determined that the application did not meet the evidentiary threshold required for approval, aligning with concerns about the interpretability of the single-arm data and the inability to disentangle the treatment effect of the oncolytic virus from nivolumab.
Makary framed the agency’s recent move to publish more decision letters as part of a “radical transparency” initiative designed to counter what he described as selective or misleading narratives from drug sponsors. “The full story is in our response letters,” he said, adding that companies may present favorable interpretations of data that are not supported by regulatory standards. He cited instances where sponsors did not follow FDA-recommended trial designs — such as including appropriate control arms — limiting the agency’s ability to determine efficacy under statutory requirements for “substantial evidence.”
The commissioner also dismissed allegations of internal dysfunction reported in recent media coverage (see earlier story), calling such accounts “old gossip” and denying claims that he has centralized decision-making or restricted information flow within the agency.
The interview highlighted a growing tension between the FDA and segments of the oncology and biotech communities over the evidentiary bar for approval, particularly in serious diseases with limited treatment options. Critics have argued that the agency is rejecting therapies that show promising early results and could qualify for accelerated approval pathways. Makary countered that breakthrough designation or early signals of efficacy do not guarantee approval without adequate clinical trial evidence. “About half of breakthrough-designated drugs are ultimately approved,” he said. “If the clinical trials show it works, it’s going to get approved. It’s that simple.”
Makary used the interview to spotlight an expansive reform agenda, including efforts to reduce development timelines and administrative burden. He argued that nearly half of drug development time is currently “dead time” spent on administrative processes rather than active research, and said new approaches aim to compress timelines significantly.
The commissioner also warned that the U.S. risks losing its leadership in biotechnology, noting that China has surpassed the U.S. in early-stage clinical trial activity. “When I came into office, they were doing four times as many Phase 1 trials,” he said.
Despite the push for speed, Makary repeatedly stressed that the agency will not compromise evidentiary standards under pressure from companies, investors, or patient advocacy campaigns. “A small set of companies…dial up tremendous pressure in the media” when trials fail, he said. “But if your drug works, it will get approved.”