The following is a guest blog post from one of our contributors, Susan Molchan, MD, a psychiatrist in the Washington, DC, area. She’s been closely following, and criticizing, NEJM’s stance on data-sharing and conflicts of interest.
Last week, many media outlets, including the New York Times, reported on concerns about the validity of a huge, and hugely important, clinical trial published in the New England Journal of Medicine (NEJM) involving a drug taken by millions to decrease their risk of stroke.
What’s at issue? Whether the object of the trial–the now best-selling blood thinner Xarelto (rivaroxaban)–really does have the advantage of being safer than the traditionally used blood-thinner Coumadin (warfarin). That’s now open to question, as the BMJ reported, because of a malfunctioning blood test device used in the trial. Those in the Coumadin group may have received higher doses of Coumadin than would have been optimal, leading to an increased risk of serious bleeding. Problems with the device were reported as far back as 2002, and it was recalled by the FDA in 2014.
How the problem could have been caught sooner
The Times’s coverage is tough, but there’s one point that they and other media outlets didn’t touch on here that’s important: Had the protocol and data from the trial been made available upon or shortly after publication of the trial, there’s a much better chance the problem would have been caught much sooner.
The editors of the NEJM and other journals that publish clinical trials now require that authors make their data publicly available within 6 months of publication. However, the data from this trial apparently aren’t going to see the light of day because study sponsor Bayer wants to keep them under wraps. While they’ve agreed to share data moving forward, Bayer told the BMJ that this policy applies only to “study reports for new medicines approved in the US and the EU after January 1, 2014.”
The Xarelto trial authors published a letter in the NEJM on February 25 to try to allay concerns about the blood test device used in the study. But surprisingly, they didn’t include blood test data that some scientists say may help clarify the comparison between the two drugs. The NEJM editors told the Times that they did not know such data existed at the time they published the letter, and — just as surprisingly — they didn’t seem put out by the fact that the Xarelto authors hadn’t shared the data. Dr. Jeffrey Drazen, the NEJM’s editor in chief, “disputed that the editors had been misled about the data,” according to the Times, “and said it was not relevant to the letter that was published.”
Not the first time for NEJM
This isn’t the first time the NEJM has been embroiled in controversy over missing data. The Times referenced a past situation where NEJM editors knew of missing heart attack data from a clinical trial and allowed the study to be published anyway. The drug that was studied, the painkiller Vioxx (rofecoxib), was eventually withdrawn from the market, but not before leading to an estimated 55,000 deaths, as well as thousands of heart attacks and strokes.
As I pointed out in January, the NEJM editors have recently made a case against transparency and data sharing, in opposition to the push for universal acceptance of these principles by many in the research community. After publicly raising concerns that data-sharing would benefit so-called “research parasites” who might have the temerity to use the data “to try to disprove what the original investigators had posited,” Dr. Drazen quickly clarified that his stance against data-sharing didn’t apply to clinical trials such as the Xarelto study. However, I think it’s fair to say that NEJM’s embrace of transparency is — as the Xarelto and Vioxx situations illustrate — both grudging and limited. It’s also fair to ask whether NEJM’s foot-dragging on this issue is connected to the journal’s cozy relations with industry, which the editors recently defended in a tone-deaf set of editorials.
Journals make money from big trials like these
The fact is, big successful industry-sponsored trials bring in hundreds of thousands if not millions of dollars in revenue for journals. In the case of Vioxx, the Wall Street Journal noted, the journal sold 900,000 reprints producing revenue of $697,000, most of them bought by the company selling the drug (Merck). In all likelihood the company selling Xarelto also bought plenty of reprints, although the amount is not made public by the journal. Scientists concerned with this obvious conflict of interest, and the publication bias that it can produce (i.e. the tendency of journals to publish studies with positive results while rejecting negative studies), have suggested that the number of reprints sold or revenue garnered from those sales be published with the articles, just as authors must disclose their conflicts of interest.
Instead of trying to guess who knew what and when in terms of device malfunctions and side effects in clinical trials, or waiting for people to be hurt or die with subsequent lawsuits being the only way for the information to come to light, wouldn’t it be better to just put the data out there from the beginning? All of it?
Update 3/10/16: Journalist Larry Husten, who has been following this story all along, pointed us to some of the early reporting on the faulty device — including from Deb Cohen at BMJ as well as David Hilzenrath and Charles Babcock at POGO — that sparked this story and gave it life.