After Replimune’s advanced melanoma drug was rejected for a second time, CEO Sushil Patel slammed the FDA for failing to exercise regulatory flexibility, while other experts bemoaned the agency’s lack of consistency. With new safety guidelines for gene editing therapies, the FDA has taken a first step toward fixing both problems.
In declining to approve Replimune’s advanced melanoma drug for the second time, the FDA “has not exercised regulatory flexibility to meet patients’ needs,” Sushil Patel, the biotech’s CEO, said in a strongly worded statement hours after the decision came down last Friday. For patient advocates, regulatory flexibility is the pinnacle of regulatory progress. But for regulators and biopharma companies, the question is more nuanced.
In Commissioner Marty Makary’s FDA, it’s “become more explicit that regulatory flexibility is appropriate, but not a waiver of rigor,” Rahul Gupta, president of GATC Health and former director of the White House Office of National Drug Control Policy, said during a BioSpace webinar last month.
And rigor is something that seems to be in demand on a population level. According to a recent Politico poll, a majority of Americans are in favor of slowing the approval of new drugs to ensure they are properly tested—even if it means delaying access to those therapies for patients who desperately need them.
While this runs counter to appeals from the likes of Sen. Ron Johnson (R-WI), the Rare Disease Advocacy, Biotechnology, and Investor Coalition (RDBI) and myriad other patient advocacy groups, it underscores the complexity of the situation.
A BioSpace LinkedIn poll delivered a more divided picture. In answer to the question of whether the FDA is striking an appropriate balance between flexibility and rigor, 34% of respondents said the agency is “too inflexible,” while 23% said the FDA is “too flexible.” A further 19% said the agency is striking an appropriate balance, while 24% were unsure.
This balancing act between rigor and access was on full display in the bruhaha surrounding the FDA’s first rejection of Replimune’s RP1, which was proposed in combination with Bristol Myers Squibb’s PD-1 inhibitor Opdivo.
In its first complete response letter (CRL) regarding the drug, sent last July, the FDA asserted that the numerically higher response in Replimune’s registrational trial “cannot be adequately interpreted due to heterogeneity of the RPL-001-16 trial patient population.” The agency specifically cited prior exposure to different therapies and severity of disease at baseline. In the second rejection letter, published April 10, a different group of reviewers—intended to “maintain objectivity and account for potential bias,” according to the FDA—also cited heterogeneity of the patient population as an issue.
Notably, this unwavering viewpoint within the agency diverged from the collective opinion of 22 scientists involved in the design and execution of the Phase 1/2 IGNYTE study. Far from a methodological shortcoming, these experts considered this heterogeneity to be representative of the real-world scenario. Current treatment guidelines, they wrote in an open letter to the FDA published in August 2025, “show multiple treatment pathways in both the adjuvant and advanced disease setting funneling to the point of IGNYTE eligibility.”
That such a diverse group of experts disagreed so fervently on a critical factor of the study’s design speaks to just how complicated it can be to develop a new therapy while also ensuring it is as effective as advertised.
Predictability please
That isn’t to say that the FDA isn’t committed to bringing rare disease drugs to patients. This week, the agency took a step toward balancing safety with rigor when it published new draft guidance for gene editors. The safety guidance is intended to standardize methods for assessing the safety of gene editing therapies in order to bring them to market faster, according to the agency’s April 14 press release. Standardizing methods of safety assessment make it easier for FDA to approve these products—many of which are for rare diseases.
FDA might do well to provide—or at least further clarify—this type of guidance across the board.
Another issue the Replimune decision exposed is a lack of consistency in the agency’s decision-making, according to Peter Pitts, former FDA associate commissioner for external relations and current president and co-founder of the Center for Medicine in the Public Interest.
“The central issue is not whether the FDA should apply rigorous standards—it must,” Pitts wrote in RealClearHealth on Tuesday. “Rather, it is whether those standards are being applied consistently, transparently, and in a manner that allows sponsors to design development programs with confidence that regulatory expectations will remain stable over time.”
In addition, Pitts wrote, “the reemergence of concerns regarding trial heterogeneity and the absence of randomized controls—issues that were not clearly determinative during earlier stages of review—suggests a continued lack of alignment between the agency’s guidance and its final decision-making.”
In my coverage over the past year, I’ve pointed to this phenomenon time and time again—for example, when the FDA’s final (or late-stage) decision-making regarding rare disease candidates from Capricor Therapeutics and uniQure failed to line up with previous guidance.
In clinical trials, RP1 generated an overall response rate of around 33% and a complete response rate of 15%, according to Pitts, “outcomes that compare favorably to historical experience with PD-1 monotherapy in this setting.”
“When regulatory expectations evolve late in the process or are applied in ways that diverge from established precedent, the result is not greater scientific rigor. It is diminished predictability,” he wrote.
Consistency is particularly important when it comes to clinical trial design—it’s the very foundation upon which approvals are built. The challenge? Aspects of trial design can be exceedingly complicated.
Last year, the FDA issued guidance indicating support for—and even encouraging—cell and gene therapy developers to use innovative clinical trial designs, including externally-controlled trials. However, “it’s incredibly complex to determine whether an external control is appropriate,” Harpreet Singh, chief medical officer at Precision for Medicine, told BioSpace earlier this month. The final acceptability of an external control—including historical or real-world data—really can’t be determined until the review process is complete,” said Singh, a former division director of Oncology at the FDA.
So what’s a sponsor to do? If you accept Singh’s perspective—and she has years of experience both inside the FDA and with clinical trial design—adopting the FDA’s current guidance surrounding external controls would appear to be a dicey proposition.
During last month’s BioSpace webinar, which focused on aligning with the FDA on a regulatory pathway to avoid decision day surprises, Gupta acknowledged that “institutional transitions create policy ambiguity, even when the intent is aligned.” The current challenge, he continued, is “translating that FDA daily direction into actual, predictable and operational guidance for sponsors.”
I’d like to applaud the FDA on a positive first step with its safety guidance for gene editing therapies—but there’s more work to be done.
