Were Problems With the Point-of-Care Device Used in ROCKET AF Kept From the FDA? BMJ Says Yes

Soon after the ROCKET AF trial evaluating rivaroxaban began enrolling patients, study investigators started expressing concerns about the accuracy of the device that was being used to measure international normalized ratio (INR) values, eventually leading drug maker Janssen to initiate a safety program to check the readings, according to an investigation by the BMJ.

The problem is that Janssen did not reveal the existence of or results from that program—called the Covance recheck program—to the trial’s data and safety monitoring board, Bayer (co-developer of rivaroxaban), or the US Food and Drug Administration (FDA) before rivaroxaban was approved in July 2011, reports Deborah Cohen, associate editor of the BMJ. The European Medicines Agency (EMA) and Bayer didn’t know about the program until this year, she says, claiming, however, that Bayer knew about the concerns with the device.

Cohen notes that patients in the United States are now suing Janssen and Bayer for misleading consumers regarding the safety and efficacy of rivaroxaban and that “in legal testimony, a Bayer official has alleged that Janssen, which had responsibility for conducting and managing the trial, withheld the program from the company.”

When asked for comment by TCTMD, Bayer deferred to Janssen. In an emailed statement, a Janssen spokesperson said: “It is always our intent to provide all data that are relevant to analyzing the results of our clinical trials to health authorities, including the US FDA.  Janssen and our development partner Bayer will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials. The companies have disclosed safety data to regulators and the safety monitoring board of the ROCKET AF trial and deny the central premise of BMJ’s report.”

Likewise, in her story, Cohen quotes Bayer stating that it “expressly [disagrees] with the allegation that Bayer would have withheld safety data from drug regulators and the safety monitoring board of the ROCKET AF trial.”

Issue Precedes ROCKET AF

The device in question—the INRatio and INRatio2 PT/INR Monitoring System—was on the FDA’s radar as early as October 2005, when the agency told then-manufacturer HemoSense (Alere is the current manufacturer) that it had determined that the company knew about problems with the device giving incorrect values, a problem that could lead to inappropriate doses of warfarin and excess bleeding risks. That was followed by another warning letter in November 2006 that listed violations revealed during an FDA inspection.

The first patient was enrolled in ROCKET AF in December 2006. Cohen reports that just a few months later, in February 2007, several investigators, including members of the trial’s executive committee, expressed concerns about the accuracy of the device. Janssen eventually launched the recheck program in early 2008.

Results of the trial—showing rivaroxaban to be noninferior to warfarin at preventing stroke or systemic embolism in patients with nonvalvular A-fib without an increase in major or nonmajor clinically relevant bleeding—were presented at the American Heart Association Scientific Sessions in November 2010.

In March 2011, the FDA was reviewing rivaroxaban for approval when it asked Janssen for information about the performance of the INRatio device. The company responded but did not include data from the recheck program or tell the agency about investigators’ concerns, Cohen reports. Later that year, rivaroxaban was approved in both the United States and Europe.

Issues with the device came to the forefront again in December 2014, when Alere issued a medical device correction—through an FDA recall notice—for the INRatio and INRatio2 PT/INR Monitor System, warning that it should not be used in patients with certain conditions because of the possibility of getting INR results lower than would be expected with laboratory testing.

ROCKET AF trial leaders, who said that they only became aware of the recall in October 2015, have since performed multiple analyses—one published in February 2016 and another in July 2016—that show any issues with the device would not have influenced the results of the trial.

The FDA continues to review the issue, but the EMA conducted its own review and concluded that the benefit-risk balance with rivaroxaban remains unchanged.

The device, meanwhile, has been withdrawn from the market by Alere after discussions with the FDA.

Uncertainty Remains

Not everybody is convinced that the issue settled and that device issues did not skew the results of ROCKET AF, however.

Referring to Thomas Marciniak, MD, a former reviewer for the FDA, Cohen writes, “Marciniak described EMA’s review as a ‘whitewash,’ alleging that the regulator has ignored ‘the serious device inaccuracies that those analyses reveal.’”

Cohen says the investigation raises questions about the EMA’s review and the analyses published by the ROCKET AF investigators to address concerns.

In an accompanying editorial, Kamal Mahtani, MBBS, PhD, and Carl Heneghan, BMBCh, DPhil (University of Oxford’s Centre for Evidence-Based Medicine, England), call for a reevaluation of rivaroxaban, as well as dabigatran, citing uncertainty about the reliability of the pivotal trials of those two drugs.

“Although independent replication of trials, data transparency, and detailed analysis of clinical study reports will be arduous and costly, the concerns highlighted by recent investigations have shown how essential these approaches are to increase our confidence in new oral anticoagulants,” they say. “Meanwhile, patients and clinicians must, for now, live with the uncertainty left by the evidence currently available.”

Related Stories:

• FDA: No More Chances for Embattled Coagulation Monitoring System
• ROCKET AF Investigators Respond to New Questions About Point-of-Care Warfarin Monitoring Device
• ROCKET AF Investigators: Problems With Warfarin Monitoring Device Did Not Skew Results