An investigation by The BMJ has called into question the validity of the ROCKET AF trial, which was used to support approval for the direct oral anticoagulant rivaroxaban (Xarelto) in the US and European Union (EU).
For this trial, which was published in NEJM in 2011, researchers compared rivaroxaban to warfarin in patients with nonvalvular atrial fibrillation.
Results suggested rivaroxaban was noninferior to warfarin for preventing stroke or systemic embolism.
And there was no significant difference between the treatment arms with regard to major or nonmajor clinically relevant bleeding.
However, The BMJ article questions these results because the Alere INRatio Monitor System (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips), which was used to measure patients’ international
normalized ratios (INRs) during the trial, was recalled in December 2014 after giving falsely low test results.
“In terms of the trial results, [the defect with the system] could make rivaroxaban seem safer than it was with respect to the risk of bleeding and throws doubt onto outcomes used to support the use of the world’s best-selling new oral anticoagulant,” said Deborah Cohen, The BMJ’s associate editor and author of the article.
In November 2015, the European Medicines Agency told The BMJ they were investigating the potential implications of the issue with the INRatio system. And the US Food and Drug Administration (FDA) said they were “aware of concerns regarding the INRatio device and its use in the ROCKET AF trial and [were] reviewing relevant data.”
The makers of the INRatio system (Alere) confirmed that the fault dates back to 2002. However, neither they nor the FDA responded to questions about why nothing had been done about the problem earlier.
In the meantime, Harlan Krumholz, MD, of Yale University in New Haven, Connecticut, said NEJM should place an “immediate Expression of Concern” on the paper describing ROCKET AF to notify the medical community, and there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”
In December, Duke University’s Clinical Research Institute, which carried out the trial on behalf of Johnson and Johnson and Bayer Healthcare, said analyses conducted after the ROCKET AF trial was first published “are consistent with the results from the original trial and do not alter the conclusions of ROCKET AF.”
But former FDA reviewer Thomas Marciniak, MD, told The BMJ he would not rely on any re-analyses done by Duke, Johnson and Johnson, or the FDA. He added that public release of the data is “the only solution that would lead to unbiased analyses.”
However, Bayer told The BMJ the company has only signed up to share information on “study reports for new medicines approved in the US and the EU after January 1, 2014.”
According to former FDA clinical pharmacologist Bob Powell, PharmD, once a drug is on the market, the regulators lack a mandate to act without a safety signal.
“It is this lack of safety signal that appears to be hindering the FDA in their desire to pursue tailored dosing for [direct oral anticoagulants],” he said. “If it turns out that the issue with the INRatio device changes the safety profile of rivaroxaban, this very well may constitute the safety signal necessary for the FDA to act in this regard.”
