The documents keep coming from the FDA over the controversial September decision to approve Sarepta’s ($SRPT) Duchenne med Exondys 51 (eteplirsen), and this week amid 311 pages of fresh docs, we saw the pressure the biotech was under, and how this pressure was pushed onto the FDA to make a decision on the med.
In an email dated June 2 of this year from Sarepta’s head of regulatory affairs, Shamim Ruff, to the FDA’s Dr. Janet Woodcock and Dr. Richard Moscicki, Ruff said that, in order to grant the FDA’s request to produce new dystrophin analysis for its med, the FDA would have to agree that the process must start by June 6: “There is no room for flexibility with this date due to our dire financial constraints as a result of the ongoing delays.”
It also told the regulator, with the bold and underlining direct from the email: “FDA will confirm--by June 3, in writing, that Accelerated Approval will be granted by the end of June when an increase in dystrophin is demonstrated based on the assumptions above.”
In redacted documents released along with the approval back in September, it became clear that it was Dr. Woodcock who helped push the drug through to approval--despite internal protestations from Dr. Ellis Unger, a senior doc at the agency, to FDA Commissioner Dr. Robert Califf.
Dr. Unger, among others, had expressed concerns at the small study and its lack of clear efficacy, but Dr. Woodcock said the FDA must be “prepared to be flexible with respect to a devastating illness with no treatment options.”
The email from Sarepta about its “dire financial constraints” clearly had an impact on Dr. Woodcock, who said that Sarepta in particular “needed to be capitalized” and noted that the biotech’s stock had risen and fallen on a series of updates over the year.
In these documents, it recorded: “Dr. Woodcock cautioned that, if Sarepta did not receive accelerated approval for eteplirsen, it would have insufficient funding to continue to study eteplirsen and the other similar drugs in its pipeline. She stated that, without an approval in cases such as eteplirsen, patients would abandon all hope of approval for these types of products and would 'lapse into a position of' self-treatment.”
Dr. Califf said he would “defer” to Dr. Woodcock in this case and allow the green light.
In the latest tranche of emails from the FDA, more details of Dr. Unger’s protestations have also come to light. In an email dated Sept. 13, Dr. Califf sent a memo explaining that he would not overrule Dr. Woodcock’s wish for the drug to gain approval.
Dr. Unger said in reply that he had several “concerns” with the memo: “First, whether proper procedures were followed such that all evidence and analyses were reviewed by the Center Director before a decision was rendered, and second, whether this decision will set a general precedent--where accelerated approval could be provided for a rare disease based solely only on the medical and scientific judgment/opinion of the Center Director, as was clearly the case here.”
Dr. Unger said that in the case of this drug, he did not feel that “All applicable processes and procedures were not followed; I did not have the opportunity to present this highly relevant scientific evidence to Dr. Woodcock; and Dr. Woodcock’s decision to grant accelerated approval was made prior to consideration of all relevant scientific evidence.”
He said “there is no way to reach a rational conclusion that the dystrophin detected by the applicant, by either immunohistochemistry or Western blot, is 'reasonably likely to predict clinical benefit.'”
“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.'”
“Dr. Woodcock told the SDR Board that her decision was based on her 30 years of experience at FDA and her own “medical/scientific judgment.” (SDR Board Memo, page 16). 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. Unger also questioned why DMD should get a special pass: “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 Xlinked 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.”
He concluded: “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.”
A number of FDA experts have in the weeks after its approval come out against the drug’s approval. John Jenkins, who runs the FDA’s office for new meds, spelled out his problems with the approval in a presentation last month, saying that the “path taken by Sarepta NOT a good model for other development programs.”
This was followed by external FDA expert Aaron Kesselheim, who advised against the regulator approving Exondys 51 and used a JAMA article to hit out at the regulator’s processes and the biotech that led to its green light.