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n an unusual development, US Food and Drug Administration Commissioner Dr. Robert Califf indicated that a study about a newly approved Duchenne muscular dystrophy drug was “misleading” and should be retracted.

The drug, which was developed by Sarepta Therapeutics, is the first to be approved for the rare genetic disease, which causes steady muscle deterioration, eventually confining boys to wheelchairs and condemning them to an early death. And the medicine was approved despite a rancorous, behind-the-scenes dispute among top FDA officials over the extent to which the drug can actually benefit patients.

Factoring into this dispute was a study published in 2013 that explored whether the drug, which is called eteplirsen, can sufficiently produce needed levels of a protein called dystrophin. Without this protein, muscle fibers degenerate and voluntary movement becomes impossible. And the study – which was funded by Sarepta, four of whose employees co-authored the study – determined the medicine produced enough of the protein to help boys walk.

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However, Califf agreed with two FDA officials who also maintained the study, which appeared in the Annals of Neurology, should be yanked.

“The publication, now known to be misleading, should probably be retracted by its authors,” he wrote in a 13-page memo in which he reviewed the internal dispute. “… 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,” he added in a footnote.

The dispute was prompted by the various moves made by Dr. Janet Woodcock, the controversial head of the FDA drug review division, to push hard to approve the Sarepta medication. While Woodcock reportedly had concerns about the study, she clashed with other agency officials, who disagreed with her decision to approve the drug and the way she went about advocating for approval.

The dispute was filed by Dr. Ellis Unger, an agency official who reports to Woodcock and oversaw the drug review. In his review memo, however, he wrote that the study “should probably be retracted by its authors.” Similarly, Dr. Luciana Borio, the FDA acting chief scientist who convened the board that reviewed the dispute, described the study as “misleading” and lamented that it “has never been retracted.”

Borio added that, “as determined by the review team, and as acknowledged by Dr. Woodcock, the article’s scientific findings — with respect to the demonstrated effect of eteplirsen on both surrogate and clinical endpoints — do not withstand proper and objective analyses of the data. … It is very disappointing that the findings did not hold up to careful review.” Their comments, along with Califf’s remarks, were first reported by Retraction Watch.

So where to from here? The lead author of the study, Dr. Jerry Mendell, an Ohio State University pediatrics and neurology professor who also heads the Gene Therapy Center at Nationwide Children’s Hospital, did not respond to questions.

However, Dr. Clifford Saper, the journal editor, who also heads the Department of Neurology at Beth Israel Deaconess Medical Center, offered a pointed reply.

“It takes more than a call by a politician for retraction of a paper. 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.

“If you read the FDA report, you will quickly realize that it was the result of internal political squabbling within the FDA, and that despite the comments you note (which were given without adequate scientific evidence in the public FDA document), the FDA actually approved the drug.

At this point, because I am neither a politician or a drug company representative, I have no opinion on the matter. I will wait for someone who is responsible to send me evidence of a problem, so that I can, if need be, investigate further.”

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Whether any evidence will be offered is unclear. And while the episode is unusual, the study itself does not appear to have been a factor in the approval, anyway, according to Washington Analysis’s Ira Loss, who tracks the intersection between Wall Street investing and regulatory policy.

“I don’t think anyone at the FDA relied on this study,” he told us. “The real issue came down to whether the drug produced dystrophin, and at the end of the day, that was the point of disagreement.”

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  • Robert Califf should call on the FDA to retract its own flawed risk classification of dental amalgam as only Class Ii with special controls, requiring warning labels only from manufacturers to dentists, and none to patients. He should call upon the Obama Administration to release the FDA’s own draft 2012 patient safety communication on mercury health risks from dental amalgam. Time to follow the growing number of other nations who protect patient health over dental industry denial of the four retractions of amalgam safety by James S Woods et al published since 2011 after reanalysis of the data by gender and gene type. He should call for retraction of the original article, on which FDA based its claim of safety for widespread use of a potent neurotoxin in the general public without knowledge of its contents, or the basic human and medical right of informed written consent.

  • The medicine absolutely helps an unmet need. All data show patients are benefiting with no side effects. The medicine makes their lives better. You guys should stop this sort of nonsense, calling this medicine poison. Stop it!!

  • Who is Saper kidding? He is INDEED a drug company representative – and a very well-paid one at that. His ilk are no better than the dine-and-dash drug reps out in the field. You can read that study and on its face see that the “conclusions” do not match the data – not even close. The question remains: how could the FDA possibly approve this possible poison, with nothing but junk science behind it?

    • It’s strikes me as odd that nobody is discussing how this approval was made two weeks before the pediatric priority review voucher program is set to expire. The approx $300 million that Sarepta will receive for selling it should fund the phase IV trials. I doubt we’ll see the patient advocates screaming for that.

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