Newly disclosed emails underscore the extent to which high-ranking US Food and Drug Administration officials were upset with the decision-making process used to approve a controversial Sarepta Therapeutics drug for combating Duchenne muscular dystrophy.

The Sept. 14 emails were written in response to a memo that Dr. Robert Califf, the FDA commissioner had drafted in which he sided with Dr. Janet Woodcock, the controversial head of the drug review division. She had pushed hard to approve the Sarepta medication over objections of key people on her staff, one of whom had filed an official scientific dispute over the approval, which occurred on Sept. 19.

The details of that dispute were released at the time the FDA approved the Sarepta drug. And the newly disclosed emails are no less pointed than the accusations contained in the official dispute. But the comments in the emails posted on the FDA web site this week underscore the level of concern some agency officials had that proper procedures were not followed and key data was downplayed.

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The most stinging remarks were written by Dr. Ellis Unger, who is acting director of one of two offices that evaluates drugs and reports to Woodcock. He firmly disagreed with the conclusions that Califf reached in his draft memo and argued that there was no scientific basis for Woodcock to pursued accelerated approval, a route to speed availability of drugs for unmet needs by using surrogate markers.

After reading the memo and an earlier note about the dispute, Unger wrote to Califf that “I do not agree with your conclusions that all applicable processes and procedures were followed; the appealing parties had ample opportunity to present their views; and the decision to grant accelerated approval was made following consideration of all relevant scientific evidence.” (Please go to page 22 of the 311-page document, which was first reported by Endpoints).

As an example, he cited a discrepancy in immunohistochemistry data that he maintained Woodcock did not know about at the time she filed her approval memo last July. Why? Unger wrote that he had not yet performed his own analyses.

“Her issuance of a decisional memorandum prior to careful consideration of my final review represents a critical deviation from protocol,” he charged. “It follows, therefore, 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.”

As we noted previously, the intensity of the dispute surrounding the Sarepta drug underscored the stakes that were involved in this episode. Beyond this one drug, the discord among FDA officials illuminated a wider debate about the pressures the agency faces to endorse medicines from an increasingly aggressive patient population seeking more drugs and faster approvals. There were also concerns that an FDA rejection would deter future investment.

Sarepta added to this pressure. In a June 2 email to Woodcock and Dr. Richard Moscicki, an FDA deputy director, Shamim Ruff, a Sarepta senior vice president for regulatory affairs, wrote that a process for assessing additional data requested by the agency had to begin right away. “There is no room for flexibility with this date due to our dire financial constraints as a result of the ongoing delays” in the approval process (see page 51).

Unger, meanwhile, also raised questions about methods used to determine whether the Sarepta drug produced sufficient levels of a protein called dystrophin, without which muscle fibers degenerate and voluntary movement becomes impossible. In his Sept. 14 email, he noted Sarepta was unable to reproduce its own findings and there was “no way to reach a rational conclusion” a “reasonably likely” clinical benefit could be predicted.

“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,” wrote Unger, who noted that “her decision was based on her 30 years of experience at FDA and her own ‘medical/scientific’ judgment.”

Unger then got even more pointed: “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.”

In another email, Dr. Luciana Borio, the FDA’s Acting Chief Scientist, who convened the board that reviewed the dispute, took Califf to task for appearing to “downplay the significance of the very small amount of dystrophin reported” by Sarepta in its new drug application, which was submitted in order to win regulatory approval.

“Instead, your draft decisional memo attributes the scientific disagreement to a lack of consensus on the appropriate threshold for clinical benefit both within (the agency) and in the scientific literature; and concerns regarding the correlation between dystrophin production and clinical outcomes” in Sarepta studies,” she wrote. “To me, the crux of the disagreement is not whether there is an appropriate threshold, but whether such a miniscule amount of dystrophin is reasonably likely to predict clinical benefit… 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.”

Ultimately, as we know, Califf swatted aside these arguments in his Sept. 16 memo. But the larger issue remains unanswered – whether the FDA really did lower the bar. This is a debate that will take a long time to be resolved.

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  • If you go on the website “Drugs at FDA” and look up any drugs and read the reviewer comments, most of the internal communications are dreadfully dull to read. This is the first time I’ve seen FDA air its dirty undies in public. Unger is in a foot race with Jim Comey for most unpopular Federal Employee.

  • It will be ‘a long time to resolve’ if Sarepta is taken as a standalone case. If one views it as a follow-on to the Sprout (‘pink viagra’) approval, then the question becomes – ‘is there a third example?’ If so, one can draw a trend line.

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