Sarepta’s Exondys 51 Saga Continues as More Details About FDA’s Criticism Uncovered

August 22, 2017
By Mark Terry, BioSpace.com Breaking News Staff

In September 2016, after a tumultuous approval process, the U.S. Food and Drug Administration (FDA) approved Sarepta Therapeutics (SRPT)'s eteplirsen for Duchenne muscular dystrophy (DMD). But the drama never seems to end as more and more information is revealed about conflicts within the FDA over the decision. The drug is now on the market as Exondys 51 with a price tag of about $300,000 per year, based on a patient’s weight.

Now more details have been released about a retraction and/or correction of a paper about eteplirsen that was part of the basis for approval.

Ellis Unger, who led the FDA team that reviewed eteplirsen, indicated that one of the pivotal studies of the drug that was published in the Annals of Neurology, was “misleading” and based on “unreliable data.” In early November, Unger, with then-commissioner of the FDA, Robert Califf, wrote the editors of the journal to “urge that the paper be corrected or retracted.”

Recently released documents show that on November 9, 2016, Clifford Saper, the editor in chief of the Annals of Neurology, agreed to correct the article, writing to Califf and Unger, “[The paper’s authors] offer the attached draft as an Erratum that they are willing to submit for their paper….Would this satisfy your concerns?”

The paper’s lead author, Jerry Mendell, told Retraction Watch that “he characterized the draft as an attempt to provide a ‘comparison’ rather than an ‘erratum’ of his team’s analysis to the FDA’s via a new table. ‘There was not an error but a difference of methods.’”

Unger in November 14, 2016, noted that he didn’t find it satisfactory that they only replaced a single table with new data, but didn’t change the text of the paper or its conclusions. In his and Califf’s opinion, the authors needed to also revise the paper’s abstract, results, and conclusions. “We also note that the photomicrographs are exaggeratory and in no way ‘representative’ as claimed by the authors. The authors didn’t address that at all. These photomicrographs should be removed or replaced.”

The journal gave Unger and Califf a choice: accepted the proposed changes by Mendell or write a letter and publish it detailing their concerns. The first would place the issue in PubMed in the context of the original paper. The second would make it official, but no one would necessarily be made aware of it in the context of reading the original paper or its abstract on PubMed.

Unger published the letter, which appeared in the Annals on January 24, 2017. However, Clarivate Analytics’ Web of Science notes that the original paper has been cited 181 times since it was published in 2013, underscoring the problems with how peer review works and when there are problems with a paper.

Saper told Retraction Watch, “The point of this entire thing was to get the record straight….It is now in the literature. There is no point in publishing the same thing again. Or in discussing the same thing again, and again, and again, and again….”

Perhaps. But analyses of the internal discussions at the FDA are continuing and will likely be the subject of books and articles for some time. The drug was essentially approved on the basis of a clinical trial involving 12 boys, and two of them weren’t included in the final analysis.

There were at least three major opponents to the approval within the FDA. Ronald Farkas, clinical team leader, left the agency just prior to approval. The agency’s acting chief scientist, Luciana Borio, and Ellis Unger, director of the office of drug evaluation, strongly opposed approval, arguing that Sarepta did not provide substantial evidence of Exondys 51’s effectiveness.

But Janet Woodcock, director of the CDER, pushed it through, overruling her staff. The final decision then went to Robert Califf. Evidence suggests Califf had similar reservations as Borio and Unger, but sided with Woodcock.

As part of the approval, Sarepta will need to conduct a two-year, randomized controlled trial to verify the drug’s benefits. At its core, more data is needed to prove that the drug actually improves motor function. If that trial fails, FDA approval could be withdrawn.