Documents Show How Contentious Woodcock’s Exondys Decision Was
New CDER review documents embedded in a just-released approval package for Sarepta’s controversial Duchenne drug Exondys 51 (eteplirsen) shows how contentious a dispute between director Janet Woodcock and Office of Drug Evaluation 1 director Ellis Unger had become in the final days before Woodcock overrode his decision to reject the drug’s approval (see earlier story). In response to a memo from FDA commissioner Robert Califf that ruled in Woodcock’s favor to approve eteplirsen, Unger complained that proper procedures were not followed because Woodcock failed to review all evidence and analyses before she rendered her decision, and that the 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.
Unger’s memo to Califf noted that late in the review, he dug deep into the “confusing nature of the immunohistochemistry results from Study 201/202. He said he discovered a disparity that had not been addressed adequately by the review team. “Importantly,” Unger wrote, “this discrepancy, raising important doubts about all of the immunohistochemistry data, was not known to Dr. Woodcock at the time she filed her approval memo on 7/14/16. (I had not performed these analyses until the evening of 7/15/16.) Her issuance of a decisional memorandum prior to careful consideration of my final review represents a critical deviation from protocol.”
Unger told Califf that Woodcock “provided no cogent rationale for her decision that the barely detectable amount of dystrophin produced is ‘reasonably likely to predict clinical benefit.’” He noted that she told an appeal board that her decision was based on her 30 years of experience at FDA and her own “medical/scientific judgment... 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.”
Unger was also particularly troubled that the approval could lower the standard for all rare disease drugs. He questioned whether any increase in a surrogate endpoint could be used to support approval for other drugs. “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,” he told Califf. “But in my opinion, this approach should receive broader public (and FDA) input before being implemented. Your decision seems to say that the ‘reasonably likely’ standard for accelerated approval need have no quantitative component at all. We all agree that making a reasonable amount of dystrophin would provide a sound basis for accelerated approval. But the amount here – a median value of one part in a thousand that is not perceptibly greater than none – fails to meet the ‘reasonably likely’ test.”