Janssen's Blood Thinner Safe Despite Faulty Device in Study: FDA

Stay ahead of developments in federal and state health care law, regulation and transactions with timely, expert news and analysis.

By Jeannie Baumann

Oct. 12 — A faulty device used in a clinical trial of Janssen Pharmaceutical Co.'s Xarelto doesn't change the FDA's conclusion that the blood thinner is an acceptable alternative to warfarin.

The Food and Drug Administration released a report Oct. 11 on the impact on the trial outcome of using Alere's INRatio, a device used to calibrate and monitor doses of the blood thinner warfarin.

The analysis came after years of questions about the accuracy of INRatio test results, for which the FDA initiated recalls in 2014. Alere voluntarily withdrew INRatio in July “due to the potential to generate inaccurate results,” the FDA said. The Waltham, Mass.-based device maker also has been fighting a class action lawsuit over allegations that INRatio provides misleading results (10 LSLR 18, 9/16/16).

“Because of the concern about the Alere INRatio device, the FDA has completed a variety of analyses to assess the impact that this faulty monitoring device had on the ROCKET-AF study results. The Agency has determined that effects on strokes or bleeding, including bleeding in the head, were minimal,” the FDA said in an Oct. 11 statement about the report titled ROCKET AF Reanalysis Reviews. “The FDA concludes that Xarelto is a safe and effective alternative to warfarin in patients with atrial fibrillation.” Janssen is a subsidiary of Johnson & Johnson.

The clinical trial that used the InRatio device, ROCKET AF, compared the then-experimental Xarelto (rivaroxaban) with warfarin, a blood thinner that has been on the market since 1954. Investigators in the ROCKET AF study found rivaroxaban was “noninferior”—or not worse than—warfarin, and the FDA approved Xarelto in 2011 based on that study. ROCKET AF is short for Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.

Califf Led Study While at Duke

FDA Commissioner Robert Califf, who was a cardiologist at Duke University before joining the agency, helped lead the study. He presented the study's results to an FDA advisory committee meeting in 2011, before he joined the agency in 2015.

Advocacy group Public Citizen has flagged Califf's role in the clinical trial and called on the FDA in a December 2015 letter to “further investigate the potentially dangerous situation involving a drug approval and the role of FDA Commissioner nominee Dr. Robert Califf, then Co-Chairman of the industry Steering Committee advising Johnson and Johnson on the study, especially his role in choosing the poorly-performing measuring device that was central to interpreting the study.”

Sidney M. Wolfe, founder and senior adviser of Public Citizen's Health Research Group, again noted Califf's role in the ROCKET AF clinical trial in an Oct. 12 interview with Bloomberg BNA.

“The larger issue is how many people died or were seriously injured or paralyzed” from the time it was “crystal clear” that the INRatio device was defective until it came off the market in July, Wolfe said. In March, Wolfe said during a presentation to the FDA that the ROCKET AF study and INRatio case highlights two overarching problems:

  •  the inadequacy of the FDA's low legal standard under Section 510(k) for determining that a device is substantially equivalent to already-approved devices that monitor life-threatening conditions; and
  •  the “dangerous failure of parties involved,” including the FDA's drug and device centers, the ROCKET AF investigators, Janssen and INRatio manufacturers.

Wolfe called on the FDA “to promptly investigate, communicate serious device warnings to all other parties and take appropriate, necessary actions.”

“The report that the FDA put out is narrowly focused” on whether using the defective InRatio device would have affected the agency's interpretation of the ROCKET AF study, Wolfe told Bloomberg BNA Oct. 12. But he said the agency made its conclusions “without enough data to really conclude as firmly as they have.”

Xarelto Decision Defended

FDA spokeswoman Sandy Walsh told Bloomberg BNA in an Oct. 12 e-mail that “The FDA conducted a thorough review and concluded that Xarelto is a safe and effective alternative to warfarin in patients with atrial fibrillation.” She also noted that “Dr. Califf was recused from this matter.”

In an Oct. 12 statement to Bloomberg BNA, Janssen spokeswoman Sarah Freeman said, “We’re pleased to see that the FDA’s reanalysis of the ROCKET-AF trial data confirms that the benefit-risk profile of XARELTO® (rivaroxaban) remains positive for reducing the risk of stroke in patients with non-valvular atrial fibrillation.”

“This conclusion comes directly after, and is in line with, the European Medicines Agency’s (EMA) recent review, which confirmed their original assessment, and with the independent reanalysis published in the New England Journal of Medicine,” Freeman said.

“Importantly,” she said, “the real-world performance of XARELTO® further supports these assessments. Since its approval in 2011, more than 23 million patients have been prescribed the medicine worldwide and one real-world study after another across its six approved indications continues to confirm XARELTO® is performing as expected.”

Alere spokeswoman Jackie Lustig declined to comment in an Oct. 12 e-mail to Bloomberg BNA.

To contact the reporter on this story: Jeannie Baumann in Washington at jbaumann@bna.com

To contact the editor responsible for this story: Randy Kubetin at rkubetin@bna.com

For More Information

The FDA report is at http://src.bna.com/jkz.

Copyright © 2016 The Bureau of National Affairs, Inc. All Rights Reserved.

Request Health Care on Bloomberg Law