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Leaders of Xarelto Clinical Trial Reaffirm Conclusions

The blood thinner Xarelto remains “a reasonable alternative” to the decades-old drug warfarin, according to a committee of researchers that years ago led a clinical trial comparing the two and more recently reassessed their findings in light of newly raised questions about the study.

The findings of the new analysis “are consistent with the results from the original trial and do not alter the conclusions,” the executive committee said in a statement.

The committee was co-chaired by Robert Califf, a former Duke University researcher who is now a deputy commissioner of the FDA and President Obama’s nominee to head the agency. The Duke Clinical Research Institute (DCRI), which Califf founded and formerly led, coordinated the trial.

DCRI disclosed that it was reassessing the trial in a November 19 statement to the Project On Government Oversight. That was in response to an inquiry by POGO noting that the trial used a brand of blood-testing device that was the subject of FDA warning letters in 2005 and 2006, before the trial began, and an FDA recall notice in 2014, after the trial ended.

The recall said that the “INRatio” devices could deliver false test results which in turn could cause fatal dosing errors. In the Xarelto trial, the devices were used periodically to measure blood clotting rates of test subjects on warfarin and to help doctors adjust their doses. If the measurements were off, and if they led to test subjects being given too much or too little warfarin, they had the potential to cause worse outcomes in the trial’s control group and skew the comparison of Xarelto to warfarin.

Based on the clinical trial, the FDA in 2011 approved Xarelto to prevent blood clots and strokes in patients with atrial fibrillation, a heart condition estimated to affect millions of people in the United States. The drug, which has also been approved elsewhere and for other uses, reportedly generated global sales of $3.7 billion in 2014.

In a statement posted Monday on the DCRI website, the clinical trial’s executive committee gave a one-sentence summary of what it found when it reviewed the trial. Among other things, the summary said Xarelto is “non-inferior” to warfarin “for the prevention of stroke and systemic embolism with less intracranial hemorrhage and fatal bleeding.” Systemic embolisms involve the blockage of blood vessels, as by a clot; intracranial hemorrhages are a form of stroke that involves bleeding in the brain.

The executive committee “intends to publish a full description of this analysis and results as rapidly as possible,” the statement said.

POGO asked DCRI spokeswoman Susan Landis if the review found anything inconsistent with any data that was gathered during the clinical trial. POGO also asked how the review was done. Landis did not respond.

Landis had previously described the review as “an independent analysis.” However, DCRI and the executive committee were reassessing a study in which they played key roles.

As POGO reported in November, the European Medicines Agency (EMA), a foreign counterpart to the FDA, has been investigating whether defective devices affected the trial. “Due to the defect, it is now thought that the INR device may have impacted the clotting results in some patients in the warfarin group,” EMA spokeswoman Rebecca Harding said in an email to POGO Friday.

FDA spokeswoman Katie Conover said by email Tuesday that the FDA “is aware of concerns regarding the INRatio device and its use” in the Xarelto trial “and is reviewing relevant data.”

Spokeswomen for the marketers of Xarelto, Bayer and Johnson & Johnson subsidiary Janssen, said by email that they “are working closely with health authorities to address any questions they may have.” The companies “have conducted a number of sensitivity analyses, which confirm the results” of the clinical trial “and the positive benefit-risk profile of Xarelto (rivaroxaban) in patients with non-valvular atrial fibrillation.”

Sidney Wolfe, senior adviser at the Public Citizen Health Research Group, a consumer advocacy organization, said the statement issued by DCRI does not put questions about the Xarelto trial to rest.

“You don’t know what analysis they did,” he said.

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