Earlier this year, a raging controversy regarding a new drug spilled into the pages of a leading medical journal: the head of the U.S. Food and Drug Administration and another official publicly called for the retraction or correction of a peer-reviewed article about the drug. They didn’t get their wish. Now, documents released by the FDA via a lawsuit shed light on the attempt — and show how tricky it can be to correct the official record.
The controversy surrounds the approval of eteplirsen, a drug approved last September to treat Duchenne Muscular Dystrophy, a rare but invariably fatal disease that strikes (mostly) young boys. Eteplirsen was approved over the objections of the FDA team that reviewed the drug, which determined that there was insufficient evidence to approve the drug.
But the controversy didn’t end within the walls of the FDA complex. Ellis Unger, who led the review team, believed that one of the principal studies of the drug, published in the Annals of Neurology, was “misleading” because it was based on “unreliable data.” So in early November, Unger, joined by the then-head of the FDA, Robert Califf, took the extremely rare move of writing to the editor of the journal to “urge that the paper be corrected or retracted….”
According to the documents, the authors of the Annals article did, in fact, agree to correct the article.
On November 9, 2016, Clifford Saper, Annals‘ editor in chief, wrote 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?
Jerry Mendell, the lead author of the paper, told us 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.”
Whether or not the attached document was truly an erratum, it didn’t satisfy Unger. On November 14, 2016, he wrote:
In essence, their view is that they only need to replace the table with the new data from the reread, without changing the text of the paper or its conclusion….In our view, they need to replace not only the table (figure 2a), but also the graph (figure 2b). They also need to revise the paper’s abstract, results, and conclusions. We also noted 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.
But Unger and Califf were faced with a dilemma. Unger and Califf could either accept the proposed “erratum” as it was and, as Saper told us, “get this on the record in a way that will be attached in PubMed to the original paper.” Or they could reject the proposal and publish a letter detailing all their concerns — meaning that there would be no formal erratum or retraction, no “mark” on the article or in its listing in PubMed that would flag the concerns raised by the FDA.
Unger chose to publish the letter, which appeared in the Annals on January 24, 2017. And the original article, which has been cited 181 times since it was published in 2013, according to Clarivate Analytics’ Web of Science, has no mark or other indication of any dispute. Not even the Annals‘ own “Related Content” listings for the article makes mention of the letter, nor of Mendell’s response disputing Unger and Califf’s characterization, also published January 24.
In Saper’s view, the matter is closed. He told us:
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….
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Thanks to RW for highlighting the released FDA docs.
This case is very instructional for would-be whistleblowers, even though the FDA scientists may not exactly fit the whistleblower category.
A key exchange in the released docs between concerned FDA scientist Unger and the Editor of Ann Neurol follows:
From the Editor of Ann Neurol to Dr. Unger (Friday, November 04, 2016 2:08 PM):
“Before I act on this request, I need to know whether you are accusing the authors of scientific misconduct in this paper, or just sloppy science.”
The response (Friday, November 04, 2016 3:01 PM):
“I think this represents sloppy science – not scientific misconduct. Thanks, Ellis Unger, MD”
The editor also went on to state that the journal would publish a Statement of Concern and turn the case over to the institution only IF there was a charge of [potential] misconduct.
Absent an actual accusation of scientific misconduct, my experience is that Editors are very reluctant to correct, let alone retract, a paper that they have published.
If the charge is limited to sloppy science, a published letter like the FDA scientists got is the best a whistleblower [or concerned scientist] can hope for.
It is worrisome that Mendell’s response to Unger and Califf’s critique does not address major points from that critique, specifically that the “representative” micrographs were not consistent with the raw data seen by the FDA, and that the person reading the micrographs was not blinded to their sequence.