The Food and Drug Administration bureaucracy can be as principled and stubborn as any in Washington. This week the agency is trying to stop unproven therapies for late‑stage melanoma and Duchenne muscular dystrophy from sailing through on hope and marketing.
President Trump pushed out Marty Makary and his deputy Vinay Prasad this spring in large part because they had scuttled treatments for life‑threatening and rare diseases. We’ve chronicled over the past year how the agency repeatedly demanded reliable evidence for approving treatments and scrutinized trial results.
The FDA under acting Commissioner Kyle Diamantas in recent months appeared to be going soft. The agency is reconsidering many treatments rejected by the previous regime and has scheduled public hearings with outside experts to review medicines. Alas, it now appears that FDA staffers who share Dr. Prasad’s insistence on evidence are digging in — and good for them.
The FDA this week released briefing documents prepared by staff ahead of advisory meetings for Replimune’s melanoma immunotherapy (Thursday) and Capricor Therapeutics’s cell therapy for Duchenne (Wednesday) that lay out the agency’s well‑founded reasons for questioning the treatments. This is a necessary effort to inform the outside experts, many of whom aren’t intimately familiar with the treatments or diseases.
Consider Replimune’s RP1, which the agency’s original review panel recommended for approval after its trial showed that a third of metastatic patients who received the treatment after the cancer progressed on other immunotherapies went into remission. Tumors vanished in one of six. Melanoma specialists heralded the results as unprecedented. Yet Dr. Prasad overruled the staff — correctly.
When his rejection sparked an uproar among patients and physicians, he convened a new staff panel and asked it to look at the data again. No surprise, the panel agreed with him and raised serious doubts about the treatment — for instance, the staff observed that maybe biopsies had zapped the tumors. If only the drug had such miraculous effects.
This week’s briefing document repeats such doubts and treats the data honestly. Staff excluded from the efficacy calculation patients who had RP1 injected in all of their tumors, but only from the numerator and not denominator. This accounting choice reduced RP1’s response rate from 33.6% to 15.7% — and the lower number is the honest one.
The staff acknowledged that patients who received and benefited from RP1 lived a median of 30.6 months without cancer progressing, versus 4.4 months on their prior immunotherapy. Selecting the patients who benefited and comparing them to their own past is not evidence. You don’t need a high school diploma to see why the FDA said it “found this comparison to be uninterpretable.”
About half of patients with metastatic melanoma will get worse on first‑line immunotherapies within a year, at which point they have scant options. That is exactly why FDA staffers insist that Replimune should have run a randomized controlled trial. A trial that would have taken years is worth taking, and it is not unethical because some desperate patients would have received a placebo — it is the most reliable way to learn whether the treatment works, and the desperate deserve nothing less than the truth.
Meanwhile, the agency last summer declined to approve Capricor’s treatment for patients with advanced Duchenne muscular dystrophy because it concluded — rightly — that the company’s randomized control trial was too small to determine definitively that the treatment worked.
Capricor resubmitted its application in February with results from a larger placebo‑controlled trial of mostly wheelchair‑bound boys. This trial showed the treatment slowed decline in patients’ ability to use their arms by 54% and weakening of their cardiac muscles by 91%. The staff accused Capricor of overstating the data, and the record justifies the accusation.
The FDA says Capricor changed the methodology for its planned statistical analysis after the trial began, so its results should be treated cautiously. Capricor says it adjusted the methodology after expanding the number of patients in its trial based on feedback it had earlier received from the FDA. If Capricor changed the methodology after the data were in view, that is precisely the kind of post hoc maneuver the rules are meant to prevent.
Capricor also says it revised the methodology before “unblinding” patients and knowing the trial results. Never mind — the FDA’s concern is exactly right: patients in the trial weren’t truly blinded because side effects would have caused them to suspect they were receiving a placebo. FDA says this would somehow have resulted in less cardiac atrophy on MRIs. That is not mysterious.
The company last year complained that it was blindsided by the FDA rejection after having followed the agency’s guidance. The agency is not retaliating because the company spoke out; it is applying the same standards. The FDA has long had a bureaucratic culture of independence that doesn’t abide being bullied. Dr. Prasad made it worse by driving out division leaders and staffers who didn’t share his anti‑industry dogmatism — until President Trump removed him after he had scuttled treatments for life‑threatening and rare diseases.
The result is a leadership vacuum. We hope the experts this week heed the staff’s briefings and ignore the companies’ marketing, which underscore why the FDA needs permanent leaders who share Dr. Prasad’s evidence‑first principles.
