Drug Problems: European Regulator Investigating Trial Led by FDA Nominee

A European regulator is investigating the soundness of the clinical trial that four years ago led the FDA to approve the blood thinner Xarelto for use in heart patients.

As the Project On Government Oversight has reported, the clinical trial, known as ROCKET AF, used a line of blood testing devices that was the subject of two FDA warning letters before the trial began and an FDA recall notice after the trial ended. The recall notice said certain devices in the “INRatio” product line could deliver false test results and that use of those devices may “cause severe or life-threatening injuries, including death.”

In response to recent inquiries by POGO, the European Medicines Agency (EMA), which is the European counterpart to the FDA, said it “is currently investigating whether the data generated from the INRatio device could have had any impact on the Rocket trial results and the extent of this impact, if applicable.”

Robert Califf, who is President Obama’s nominee to head the FDA, helped design and oversee the trial.

Based on the trial, the FDA and the European Commission, the executive arm of the European Union, approved Xarelto in 2011 to prevent blood clots and strokes in patients with a heart condition called atrial fibrillation. The drug has been approved for other uses on the basis of other studies.

Almost a year has passed since the FDA issued the December 2014 recall notice about INRatio testing devices.

The EMA plans to complete its probe in early 2016 and in the meantime can provide “no information on this issue,” EMA spokeswoman Rebecca Harding told POGO by email.

Califf, a deputy commissioner at the FDA, founded the Duke Clinical Research Institute (DCRI), which runs clinical trials for drug companies and coordinated the Xarelto trial. Califf co-chaired the ROCKET AF executive committee, which was responsible for designing and overseeing the trial. The committee was also responsible “for the accuracy and completeness of data analyses,” according to a medical journal article Califf co-authored presenting the results of the Xarelto trial.

POGO also has asked the FDA about the matter, including what if anything the agency has done to check the accuracy of INRatio test readings in the Xarelto trial. The FDA has provided no answers. Instead, Kevin Griffis, assistant secretary for public affairs at the Department of Health and Human Services, of which the FDA is a part, referred POGO to a researcher at Duke University.

The FDA’s silence raises questions as to how it would handle regulatory matters involving Califf, the clinical studies in which he participated before joining the FDA this year, his former clients in the pharmaceutical industry, and the Duke institute he formerly led.

Critics such as the consumer advocacy group Public Citizen have said Califf is too close to the pharmaceutical industry, which he would oversee as FDA commissioner. However, if his confirmation hearing was any indication, his nomination has strong bipartisan support.

Califf has not responded directly to POGO’s requests for comment.

In a statement to POGO on November 19, DCRI said it “is conducting an independent analysis of the trial data to understand what effect, if any, the potential device malfunction might have had in subpopulations and specific patient groups.”

Susan P. Landis, head of strategic communications at DCRI, would not say when or why DCRI began that review.

Landis said by email that DCRI’s statement also spoke for the Xarelto trial’s executive committee.

Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, markets the drug in the United States, and Bayer HealthCare markets it elsewhere. In 2014, Xarelto generated global sales of $3.7 billion, according to GlobalData information published by the industry news site PMLiVE.

The EMA said it has been in contact with Bayer. The drug maker “has a legal obligation to provide satisfactory answers to any question raised in relation to their product and the Rocket trial,” the EMA spokeswoman told POGO.

Spokesmen for Bayer and Janssen have not responded to POGO’s questions related to the testing devices. “Thank you for your inquiry. We are looking into it,” Bayer spokeswoman Stephanie Prate said by email on November 19.

Read our report, “Drug Problems: Dangerous Decision-Making at the FDA”

Read more articles in the “Drug Problems” series