Saga Continues for Sarepta as FDA Head Calls for Retraction of 'Misleading' 2013 Study

Saga Continues for Sarepta as FDA Head Calls for Retraction of 'Misleading' 2013 Study September 23, 2016
By Mark Terry, BioSpace.com Breaking News Staff

The months-long drama involving Sarepta Therapeutics ’s eteplilrsen for Duchenne Muscular Dystrophy (DMD) and the U.S. Food and Drug Administration (FDA) is not over, despite the drug’s accelerated approval earlier this week.

The biggest part of the drug’s controversy began in January when the FDA postponed a hearing until April. At the April meeting, 52 public commentators, including DMD children and their families, urged the FDA to approve the drug, despite significant skepticism on the part of the FDA. Congress weighed in earlier, urging that any DMD drug be approved, and 36 DMD experts wrote a public letter, arguing that the drug should be approved.

It finally received accelerated approval, despite being based on a 12-patient clinical trial, and significant disagreement within the FDA itself.

Now, Robert Califf, the commissioner of the FDA, in a 13-page memo, responds to an appeal of the approval made by Ellis Unger, Director of the Office of Drug Evaluation I. Basically, Unger appealed the decision to approve the drug that seemed to be forced through by Janet Woodcock, director of the CDER. Califf then reviewed the materials.

The latest controversy involves the inclusion of a 2013 study of the drug published in Annals of Neurology. It was conducted at the Nationwide Children’s Hospital in Columbus, Ohio.

Califf, in his memo, noted, “In view of the scientific deficiencies identified in this analysis, I believe it would be appropriate to initiate a dialogue that would lead to a formal correction or retraction (as appropriate) of the published report.”

In 2014, an inspection team for the FDA visited Nationwide Children’s Hospital, and in his appeal, Unger wrote, “We found the analytical procedures to be typical of an academic research center, seemingly appropriate for what was simply an exploratory Phase I/II study, but not suitable for an adequate and well-controlled study aimed to serve as the basis for a regulatory action. The procedures and controls that one would expect to see in support of a Phase III registrational trial were not in evidence.”

Luciana Borio, who was the FDA’s acting chief scientists, and the agency member who convened the board reviewing the dispute, called the study “misleading” and he was sorry it “has never been retracted.”

STAT contacted the study’s lead author, Jerry Mendell, a pediatrics and neurology professor at Ohio State University who heads the Gene Therapy Center at Nationwide Children’s Hospital, but he did not respond. STAT then contacted Clifford Saper, the editor of the Annals of Neurology. He also heads the Department of Neurology at Beth Israel Deaconess Medical Center, and it seems clear that he does not appreciate the controversy.

“It takes more than a call by a politician for a retraction of a paper,” Saper responded. “It takes actual evidence. It is the policy of Annals of Neurology, and every other responsible journal, to consider scientific evidence that one of its papers may be inaccurate.

“If the FDA commissioner has, or knows of someone who has, evidence for an error in a paper published in Annals of Neurology, I encourage him to send that evidence to me and a copy to the authors of the article, for their reply. At that point we will engage in a scientific review of the evidence and make appropriate responses.”

He also goes on to point out that the FDA report written by Califf “was the results of internal political squabbling within the FDA” and that the FDA did actually approve the drug.

In terms of Califf’s memo and review, he declined to overturn the FDA’s decision to approve eteplirsen, writing, “Both Dr. Unger and Dr. Woodcock have drawn upon a deep level of knowledge and practical experience in deriving their conclusions, and their documents reflect strong convictions and profound concern both for the well-being of the patients and families with DMD and for the preservation of the FDA’s mission to protect and promote public health. That said, the history of the FDA includes a consistent precedent of final decision-making about medical products at the Center level. Overruling the Center Director is exceedingly rare and, in my view, would be appropriate only if the Center Director’s decision could not be supported by the available data and information. In the present case, the scientific uncertainties lead to a situation in which the decision is a matter of reasoned expert opinion and judgement.”

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