New questions have been raised about the validity and reliability of data in the ROCKET-AF trial, which serves as the backbone for the approval of rivaroxaban (Xarelto), according to an investigation published Wednesday by The BMJ. Rivaroxaban is a blockbuster drug for stroke prevention in atrial fibrillation (AF) that gained approval from both U.S. and European regulators.
The ROCKET-AF trial, published in the New England Journal of Medicine (NEJM) in 2011, compared rivaroxaban with the older anticoagluant drug warfarin (marketed as Coumadin, Jantoven). The U.S. FDA recommended that year rivaroxaban not be approved because of evidence that warfarin use in the trial’s control arm was not adequately performed. Although the advisory committee meeting was highly contentious, in the end, the committee voted to recommend approval of rivaroxaban.
Now, concerns about the trial results that were used to gain approval have resurfaced, including a major new concern: the portable device used to monitor and calibrate warfarin usage in the trial appears to have been seriously defective. The device — the Alere INRatio and INRatio2 PT/INR Monitor System — was recalled in December 2014 after giving falsely low test results. The recall was listed as a Class I recall, which according to the FDA, is “the most serious type of recall. They involve situations when it is likely that use of these devices will cause serious health problems or death.”
The BMJ’s Associate Editor, Dr. Deborah Cohen, says in a special report: “In terms of the trial results, it 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.”
Rivaroxaban, manufactured by Bayer and marketed in the U.S. by Janssen Pharmaceuticals, part of Johnson & Johnson, belongs to a class of drugs called ‘direct oral anticoagulants’ (DOACs). Unlike warfarin, rivaroxaban doesn’t require that patients undergo regular blood testing to ensure the dosage is correct.
Duke University’s Clinical Research Institute, who did the study on behalf of Bayer, published a letter Thursday in the New England Journal of Medicine stating that it has re-analyzed the trial’s results and stands by its conclusions. Problems with the device “did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial,” the researchers wrote.
The re-analysis findings “are in line with the sensitivity analyses conducted by Bayer and Janssen, which also affirm the results of the ROCKET-AF study and the positive benefit-risk profile of rivaroxaban (Xarelto) in patients with non-valvular atrial fibrillation,” said Janssen in a statement to Drug Discovery & Development.
In response to The BMJ report, doctors and scientists are calling for an independent investigation to determine if there are grounds for retraction, and access to the original data to clear up the drug’s benefits and harms.
In December, Duke University’s Clinical Research Institute said further analyses “are consistent with the results from the original trial and do not alter the conclusions of ROCKET-AF.” But a former FDA reviewer Dr. Thomas Marciniak, told The BMJ that he would not rely on re-analyses done by Duke, the affiliated pharmaceutical companies or the FDA. “The only solution that would lead to unbiased analyses” is to release the original data, he said.
The BMJ reports: The manufacturers of the INRatio device confirmed to the medical journal that problems with the device date back to 2002. Yet, they nor the FDA responded to “questions about why nothing had been done about the problem earlier.”
Update: Duke University’s Clinical Research Institute published a letter Thursday in the New England Journal of Medicine, and Janssen Pharmaceuticals made a statement, standing by its re-analysis findings.
Filed Under: Drug Discovery