Drama at FDA: 5 things to know about the Sarepta approval
While it isn't unusual for there to be dispute amongst U.S. Food and Drug Administration reviewers regarding clinical trial data and its interpretation – particularly in the case of rare disease drugs – the review of Sarepta's Duchenne muscular dystrophy (DMD) drug was high drama compared to a typical approval.
When the FDA granted conditional approval to Exondys 51 (eteplirsen) on Monday, it brought to a close a much-delayed review process, one characterized by vocal and sustained advocacy on the part of patients and lawmakers in favor of the drug.
Unusually, in deciding to approve eteplirsen, the FDA overruled an independent advisory panel which had recommended rejecting the drug. Documents released this week show the decision to do so divided FDA leadership, prompting an appeal to FDA Commissioner Robert Califf.
Some critics have questioned the role Janet Woodcock — director of the Center of Drug Evaluation and Research (CDER) — played in the approval decision, pointing to her early involvement in the process. Others worry about the precedent set, raising concerns about lower standards for approvability.
Here are 5 key takeaways from the documents released by the FDA:
1.) Approval of eteplirsen was driven by Woodcock's belief that the amount of dystrophin protein produced by eteplirsen in clinical testing was "reasonably likely" to predict a clinical benefit.
Eteplirsen was given a green light under the FDA's accelerated approval pathway, meaning approval was based on a surrogate endpoint rather than an easily seen and measured clinical benefit.
In the case of eteplirsen, Sarepta applied for approval based on the theory that increased levels of the dystrophin protein would be an indicator the drug works. DMD is characterized by a near or total lack of dystrophin in patients suffering from the muscle-wasting disease, due to a problem with the gene responsible for production of the protein.
While all of the principal FDA reviewers generally agreed dystrophin production was an acceptable surrogate endpoint, they had conflicting opinions about the levels needed for benefit to be reasonably likely, according to summary review documents for the drug.
In brief, Woodcock believed even low-level increases in dystrophin production were reasonably likely to predict a clinical benefit, citing existing literature and evidence from Sarepta's trials. Fellow reviewers Ellis Unger, director at CDER's Office of Drug Evaluation I, and Luciana Borio, acting chief scientist, strongly disagreed.
Unger, in particular concluded dystrophin levels would need to be in the range of 10% of normal levels to translate into a clinical benefit, much higher than the 0.93% seen in a FDA analysis of patient samples from one of Sarepta’s two trials.
Califf, arbitrating over the scientific dispute, deferred to Woodcock's judgment, upholding her decision to approve eteplirsen.
"Overruling the Center Director is exceedingly rare and, in my view, would be appropriate only if the Center Director’s decision could not be supported by the available data and information," Califf said. "In the present case, the scientific uncertainties lead to a situation in which the decision is a matter of reasoned expert opinion and judgment."
2.) Top FDA staff involved in the decision thought Woodcock had been too involved in the process, influencing staff decision making and "chilling" scientific debate within CDER.
In appealing to Califf, Unger asked the commissioner to review not only the scientific dispute between members of the review team and Woodcock, but also the degree to which Woodcock was involved in the approval process.
Unger flagged her early engagement in the review process, including from between six to 12 meetings with patient advocacy groups "very early on in the review process," according to a letter from Borio, who is head of the SDR board, to Califf regarding Unger’s appeal.
This concern continued through the advisory committee meeting for eterplirsen, at which Woodcock spoke at length and referred to the danger of rejecting a drug that might actually work. The SDR board also cited Woodcock’s initial (and internal) decision on May 4 to conditionally approved eteplirsen, some days before the review team finalized its position.
"We fear that those actions could have chilled scientific debate within CDER and reduced the level of participation by the review team during the final stages of the decision-making process," Borio’s letter reads.
Califf specifically reviewed Woodcock’s conduct, however, and concluded her level of engagement was not atypical given her well-known and established hands-on managerial style. He also referenced the agency’s evolving support for patient-centered drug development.
"I do not find that [Woodcock] deviated from her responsibilities as Center Director, nor do I find that she succumbed to pressure for the patient community, the public, the press, or others," Califf wrote.
3.) Members of the scientific dispute review board were concerned about Woodcock's apparent interest in Sarepta's financial capacity to fund development.
In reviewing Unger’s appeal, Califf made special note to address a suggestion in Borio’s letter that Sarepta’s financial well-being was a factor in Woodcock’s decision.
"Dr Woodcock cautioned that, if Sarepta did not receive accelerated approval for eteplirsen, it would have insufficient funding to continue to study eteplirsen and other similar drugs in its pipleine," Borio wrote. Woodcock apparently wondered whether a rejection for eterplirsen would have the broader effect of turning other drugmakers away from DMD development.
Califf indicated this statement "troubled" him, prompting him to raise the issue directly with Woodcock. His conclusion was Woodcock’s decision was wholly based on her "scientific evaluation of the evidence."
4.) Sarepta failed to follow advice from the FDA. Califf, Woodcock, Unger and Borio all criticized the drugmaker's conduct of its clinical trials.
While there was plenty of disagreement between senior FDA leadership over eteplirsen’s clinical evidence, most found agreement in their criticism of Sarepta’s handling of its new drug application.
Califf described "major flaws in both the design and conduct of the clinical trials [which] have made it impossible to use much of the trial data as reliable evidence in regulatory decision-making." Poor-quality biopsies and the failure of Sarepta to properly conduct assay validation made much of the data from the company’s trials unusable, according to Califf’s review.
The original analyses submitted by Sarepta for its Study 201 were "oversaturated, unreliable, and uninterpretable," Unger wrote.
With the FDA’s help, Sarepta again performed biopsies on 11 of the 12 patients in Study 201/202, producing usable samples. But baseline samples were available for only three of the 11 patients, forcing Sarepta to use stand-in samples from external patients.
5.) Some FDA staff felt approval for eteplirsen would set a dangerous precedent, although Califf believed the unique situation and context of accelerated approval would mitigate any impact.
The high-profile nature of Sarepta’s application has made the FDA a lightning rod for criticism. Approval for eteplirsen is a relief for the many patients and families who gave moving testimony to the drug’s apparent benefit. At the same time, approval has sparked worries the FDA has lowered its standards and set a dangerous precedent for other drugmakers.
"Approval of this NDA would send the signal that political pressure and even intimidation—not science—guides FDA decisions, with extremely negative consequences," wrote Unger in his appeal.
Unger further warns eteplirsen’s approval would lower the FDA’s evidentiary standards and harm future drug development. In a letter to Califf, Borio echoed some of Unger’s warnings as well.
While recognizing the dangers of lowering regulatory standards, Califf concluded the context of an accelerated approval charges the FDA with exercising additional flexibility in reviewing an application.