Two senior FDA officials mounted a vehement assault on Janet Woodcock’s decision to push through an approval of Sarepta’s Duchenne muscular dystrophy drug Exondys 51. New documents posted by the FDA, including a round of memos on the issue in September, warned FDA Commissioner Robert Califf that he was allowing an approval even though Woodcock had not considered all the analysis they had done to underscore the company’s weak case, adding that there was no scientific basis to conclude that the drug was reasonably likely to benefit patients.
The agency has already posted some of the memos offered up in the lead-up to the approval decision, along with Califf’s decision that he would defer to Woodcock, who overruled the agency’s reviewers as well as Luciano Borio and Ellis Unger, the acting chief scientist and director of the Office of Drug Evaluation at the FDA. But these memos from September hit hard on their conclusion that Woodcock was deviating widely from the agency’s standards for an approval in allowing Exondys 51 on the market after the biotech had provided only a “mere scintilla” of evidence of efficacy.
In a memo to Califf on September 14, Unger wrote that he had conducted an analysis of the evidence on dystrophin production, which Woodcock did not take into consideration before reaching her decision:
I think it will be important for the regulatory record to reflect that there was no scientific basis underlying the conclusion of “reasonably likely” in this case. This was simply a judgment call by Dr. Woodcock. (Dr. Woodcock might have also taken the position that, in this desperate patient population, any dystrophin production would suffice as a basis for accelerated approval, but she didn’t state this.)
In Unger’s opinion, the FDA also needed to more carefully consider the impact the decision on eteplirsen would have on other rare disease drug applications:
We all agree that each situation must be evaluated on its own merits; however, I fail to see how DMD differs intrinsically from other rare neurological diseases, e.g., Alexander disease, Canavan disease, Early infantile GM1 gangliosidosis, Krabbe disease, Metachromatic leukodystrophy, Niemann–Pick disease, Pelizaeus–Merzbacher disease, Pompe disease, Sandhoff disease, and X- linked adrenoleukodystrophy. Based on what you have written in your draft memo, it is not clear to me why a standard of any increase in the surrogate endpoint wouldn’t apply for these diseases.
“Perhaps granting accelerated approval to drugs that show a mere scintilla of an effect on a surrogate endpoint represents a stroke of brilliance – one that will stimulate investment in the development of drugs for these disorders. But in my opinion, this approach should receive broader public (and FDA) input before being implemented.
Unger also noted:
Her (Woodcock’s) issuance of a decisional memorandum prior to careful consideration of my final review represents a critical deviation from protocol….
Unaware of my final conclusions on this matter, Dr. Woodcock did not rebut the above reasoning. As I noted (and the SDR Board appeared to agree), she provided no cogent rationale for her decision that the barely detectable amount of dystrophin produced is “reasonably likely to predict clinical benefit.
Calif, though, had already made up his mind the day before:
I have concluded that although I believe that both views are rational and reflect extraordinary dedication to the topic, there is no basis upon which I should overrule Dr. Woodcock’s decision, and that additional external review is not indicated.
Luciano Boria, the acting chief scientist, also criticized Califf for failing to grapple with the “minuscule” amount of data that Sarepta had offered. In a memo dated September 14, Borio wrote Califf:
(Y)our draft decisional memo seems to downplay the significance of the very small amount of dystrophin reported in the eteplirsen NDA (see, e.g., pages 4-5 of your draft decisional memo). In fact, your draft decisional memo never once cites the 0.3% increase in dystrophin production shown by Study 301 (or the 0.93% detected in Studies 201/202). Instead, your draft decisional memo attributes the scientific disagreement to: (1) a lack of consensus on the appropriate threshold for clinical benefit both within CDER and in the scientific literature, and (2) concerns regarding the correlation between dystrophin production and clinical outcomes in Study 201/202. To me, the crux of the disagreement is not whether there is an appropriate threshold, but whether such a miniscule (sic) amount of dystrophin is reasonably likely to predict clinical benefit. Your draft decisional memo does not address that issue. In my view, it is not sufficient to say that no threshold has been established and that, therefore, any increase in dystrophin production is reasonably likely to predict clinical benefit.
In the months ahead of the showdown inside the FDA, regulators repeatedly expressed their willingness to help speed the work they asked for to provide additional evidence of dystrophin production, which provoked Sarepta’s Shamim Ruff, their head of regulatory affairs, to fret about the “dire financial constraints” the company was forced to deal with as a result of the delays at the FDA.
“We must start the process by June 6, 2016,” Ruff wrote.”There is no room for flexibility with this date due to our dire financial constraints as a result of the ongoing delays.”
Here’s a look at all the documents released by the FDA:
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