Researchers Question Results of Clinical Trial Used to Approve Xarelto

The FDA first approved Xarelto (rivaroxaban) on July 1, 2011. A few months later, Thomas M. Burton, writing for the Wall Street Journal, noted that though the drug had been approved, it was despite the fact that FDA staff had found flaws in the clinical studies submitted by the manufacturer.

The FDA often establishes expert panels to submit recommendations on drug approvals. In the case of Xarelto, the panel voted 9-2 in favor, with one abstention, despite the administration’s concerns. According to Burton, the FDA often agrees with its expert panels, but “Xarelto is an unusual case because a strong majority of the panel disagreed with the FDA staff’s conclusions.”

In fact, one FDA staff reviewer stated that in the clinical trials, warfarin—the leading anticoagulant for decades—wasn’t skillfully used, which could have swayed the results to make Xarelto look better.

New information suggests that the expert panel made a mistake in not taking the FDA staff’s concerns about Xarelto more seriously. According to a recent report published in the British Medical Journal, researchers warn that a defective blood clotting test device used during the Xarelto clinical trials may have affected the results, and the European Medicines Agency (EMA) is now investigating the issue.

Defective Device Could Have Skewed Results

The question is whether the defective device may have impacted the clotting results in some patients during a part of the study that compared Xarelto with warfarin. So far, manufacturers have been advertising Xarelto as a superior alternative to warfarin, with similar effectiveness and risk, yet more convenience. Plaintiffs who have filed Xarelto lawsuits claim the warning labels were inadequate, particularly when it comes to the risk of excessive bleeding.

The device is called INRatio (international normalized ratio), and measures how quickly blood starts clotting. Researchers reviewed the results, and then adjusted how much medication patients were receiving accordingly. If the blood was clotting too quickly, the patients needed more; if the blood was too “thin,” they needed less.

This particular INRatio is manufactured by Alere. The device was recalled back in December 2014 after reports indicated it was giving falsely low results. The FDA also sent two warning letters to Alere in 2006 about the device before the Xarelto study began.

The clinical study under examination is the ROCKET-AF study, which concluded that Xarelto and warfarin had comparable effectiveness, and comparable rates of excessive bleeding. If the INRatio was giving false results, however, it could be that patients in the clinical trial were given too much warfarin, which would mean that the drugs were not compared equally.

“Relative to warfarin, which would have more bleeding than it should, [Xarelto] would look better in terms of intracranial hemorrhage,” said Sidney Wolfe of the consumer advocacy group Public Citizen.

Bayer Defends Xarelto Clinical Trial Outcomes

The possibility that the results of the INRatio test used could be faulty, yet was used in a clinical trial that was instrumental in the drugs approval has many concerned, because it could mean that some patients are more at risk of Xarelto bleeding than was previously understood. The Project on Government Oversight (POGO) states that the Duke Clinical Research Institute is conducting an independent analysis of the trial data to check for any potential effect the defective test may have had on the study results, and on certain population groups.

A member of the FDA advisory panel that reviewed Xarelto in 2011 stated that he was not aware of the FDA warning letters sent to Alere concerning the device, and that the panel should have had access to that information.

Manufacturer Bayer has defended the results of its clinical trial and stated that it conducted analyses that confirmed the results of ROCKET-AF, which showed that Xarelto was similar in effectiveness to warfarin, without significantly increasing risk of bleeding.