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Behind the Sarepta drug approval was intense FDA bickering

In the approval of Sarepta’s drug, the FDA’s commissioner, Dr. Robert Califf, deferred to the controversial head of the agency’s drug review division.Andrew Harnik/Associated Press/File 2016

The run-up to Monday’s approval of a Sarepta Therapeutics Inc. drug to treat Duchenne muscular dystrophy was marked by unusual bickering inside the Food and Drug Administration, where debate over a key scientific question was transformed into a formal dispute and the head of the drug review division was accused of being too intensely involved in the process for evaluating the medicine.

Ultimately, the decision to greenlight the drug fell to the FDA commissioner, Dr. Robert Califf. In a 12-page memo last Friday, he deferred to Dr. Janet Woodcock, the controversial head of the drug review division, who pushed hard to approve the Sarepta medication but clashed with other FDA officials along the way.


“The science is not in dispute beyond the usual types of disagreement that occur when experts review clinical evidence from different perspectives,” he wrote. “It is clear that Dr. Woodcock’s decision utilized the flexibility afforded under the relevant statutory provisions, including consideration of the life-threatening decisions of the disease and the lack of alternative treatments.”

Califf was compelled to chronicle his decision in response to a formal complaint over the dispute that was filed by Dr. Ellis Unger, who reports to Woodcock, and disagreed with her decision to approve the drug and the way she went about advocating for approval. The Califf memo was one of several internal FDA documents involving the dispute and the fate of the Sarepta drug that were released Monday.

There is frequently disagreement among FDA staff over the extent to which clinical trial data should support the approval of a medicine. But the intensity of the dispute surrounding the Sarepta drug underscores the stakes 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.


In his complaint, Unger identified four deviations from the usual typical decision-making process. He asserted Woodcock was involved in the early stages of the review; she had “extensive involvement” in planning and participating in an expert panel meeting last spring; she made an initial decision last May to approve the drug before the FDA review team completed a draft review memo; and she issued a final decision memo before Unger finalized his own memo.

Unger was not alone. In an Aug. 8 memo to Unger, Dr. Luciana Borio, the FDA acting chief scientist who convened the board that reviewed the dispute, wrote that “we fear that those actions could have chilled scientific debate within (the FDA Center for Drug Evaluation and Review) and reduced the level of participation by the review team during the final stages of the decision-making process.”

“Rather than ensuring that the scientific reviews started at the bottom of the chain of command, Dr. Woodcock made clear from her position at the top that she was pushing for a particular outcome from the very early stages,” Borio wrote. And she noted that at least two staffers were leaving or were about to leave in response to the decision-making process “and the pressures exerted by outside forces.”

Indeed, the dispute centered primarily on a disagreement over whether the Sarepta drug, known as eteplirsen, would produce enough of a protein called dystrophin to generate a clinically meaningful benefit. Boys suffering from Duchenne have a mutation and lack the protein. Sarepta argued that a very small clinical trial demonstrated the drug helped enough boys based on various measures, including a six-minute walking test.


According to the memos, Woodcock acknowledged some issues with trial data submitted by the company to win approval, but she disagreed with Unger and other FDA staff about the extent to which boys treated with the medicine would experience a meaningful clinical benefit.

Their disagreement, however, also reflected a more fundamental debate over the stance the agency should take toward the Sarepta drug. Until now, the FDA had not approved a drug to treat Duchenne, prompting parents and some lawmakers to argue for accelerated approval, a process that relies on predictions of a medical benefit instead of actual benefits to endorse a drug.

This has been a highly charged issue and has transformed the Sarepta drug into a litmus test for agency approval of medicines, notably for diseases with unmet medical needs. Seen through that prism, Unger maintained that approving the drug would be detrimental to the FDA approval process on a long-term basis.

“By allowing the marketing of an ineffective drug, essentially a scientifically elegant placebo, thousands of patients and their families would be given false hope in exchange for hardship and risk,” he wrote in a July 18 dispute report. “I argue that this would be unethical and counterproductive. There could also be significant and unjustified financial costs – if not to patients, to society.”


He added that approval “would send the signal that political pressure and even intimidation — not science — guide FDA decisions. ... A standard this low would undercut FDA’s ability to ensure that drugs that are approved are effective; it would call into question much of what we do. Lowering the bar to this level would be tantamount to rolling back the 1962 Kefauver-Harris Drug Amendments to the Federal Food, Drug and Cosmetic (FD&C) Act, which have served Americans well for some 54 years.”

According to Borio, both Unger and the members of the FDA review team told the dispute review board that Woodcock “seemed focused on the external pressures, from both patient advocacy groups and Congress, and that she frequently talked about the effects of a decision regarding eteplirsen in terms of overarching policy.”

Ultimately, the review board found that “Woodcock’s extensive, early involvement in the review process troubling. Indeed, her involvement here appears to have upended the typical review and decision-making process.”

Ed Silverman can be reached at ed.silverman@statnews.com. Follow Ed on Twitter @Pharmalot