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An investigation published by the BMJ this week has raised new concerns about the validity of a trial that was used to gain approval for Xarelto from the U.S. and European regulators.
An investigation published by The BMJ this week has raised new concerns about the validity of a pivotal trial, known as the ROCKET-AF trial, that was used to gain approval for the anti-clotting drug rivaroxaban (Xarelto) from the U.S. and European regulators.
The trial, published in the New England Journal of Medicine (NEJM) in 2011, compared rivaroxaban with the older anti-clotting drug warfarin for preventing strokes in patients with irregular atrial fibrillation. BMJ claims that the blood-clotting test device used during the trial had since been recalled in December 2014 after giving falsely low test results.
“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," noted BMJ’s Associate Editor Dr. Deborah Cohen.
Rivaroxaban, manufactured by Bayer and marketed in the U.S. by Johnson and Johnson, is a ‘direct oral anticoagulant’ (DOAC). It works by preventing blood from clotting and is marketed as a better alternative to warfarin because patients don’t need regular tests to check if they have the right amount of drug in their bloodstream.
In November 2015, the European Medicines Agency (EMA) reportedly told the BMJ they were investigating, while Food and Drug Administration (FDA) said it was “aware of concerns regarding the INRatio device and its use in the ROCKET-AF trial and is reviewing relevant data.” The maker of the INRatio device confirmed to BMJ that the fault dates back to 2002, but neither the company nor the FDA responded to questions about why nothing had been done about the problem earlier.
In December, Duke University’s Clinical Research Institute, who carried out the trial on behalf of the manufacturer, said further analyses “are consistent with the results from the original trial and do not alter the conclusions of ROCKET-AF.” But former FDA reviewer, Dr. Thomas Marciniak, told the BMJ that he would not rely on any re-analyses done by Duke, Johnson and Johnson or the FDA. He added that the data need to be released as “the only solution that would lead to unbiased analyses.”
According to former FDA clinical pharmacologist, Bob Powell, 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 DOACs. 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,” he told The BMJ.
The BMJ investigation also exposes flaws in the U.S. device regulation system that allows manufacturers only to show that their devices are “substantially equivalent,” or similar, to one already on the market, according to the article. The system has been criticized by the Institute of Medicine for not providing enough evidence that a device is safe and effective. Johnson and Johnson, however, has lobbied against tightening up this aspect of device regulation and the need to provide more evidence.