Disturbing questions are being raised about the integrity and reliability of crucial data in the ROCKET AF trial. The investigation could have important implications on several fronts. First, the trial serves as the basis for the use of the blockbuster drug rivaroxaban (Xarelto, Johnson & Johnson) for stroke prevention in atrial fibrillation. Second, the trial co-chairman, Robert Califf, has been nominated by President Obama to be the next FDA Commissioner.
ROCKET AF compared rivaroxaban to warfarin in patients with atrial fibrillation. As in any controlled trial, the results are only as good as the quality of treatment in the control arm. In 2011, FDA reviewers raised serious questions— and recommended that the drug not be approved– because of evidence that warfarin use in the control arm was not performed skillfully. The subsequent FDA advisory committee meeting was highly contentious, but ultimately the committee voted to recommend approval of the drug.
The new questions go beyond the FDA reviewers original concerns and are based on the fact that the portable device used to monitor and calibrate warfarin usage in the trial appears to have been seriously defective. The device– the Alere INRatio and INRatio2 PT/INR Monitor System– was the subject of a broad class 1 FDA recall one year ago. At that time, the FDA said that the devices “may provide an INR result that is lower than expected result obtained using a laboratory INR method.”
Class I recalls, according to the FDA, “are the most serious type of recall. They involve situations when it is likely that use of these devices will cause serious health problems or death.”
News about the recall was first reported by POGO (Project on Government Oversight)– though I am aware that other reporters have been pursuing this story. POGO said that it had asked Califf, the Duke Clinical Research Institute (DCRI), the FDA, European regulator EMA, the makers of Xarelto, and others for comment. DCRI told POGO that 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.”
POGO subsequently reported that the European Medicines Agency (EMA) said that 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.”
Sanjay Kaul (Cedars-Sinai Medical Center), who served on the FDA advisory panel that evaluated ROCKET AF, told me that “the key issue is whether there was any malfeasance with regards to INR assessment (or data ascertainment). EMA has asked for information from the sponsors and it deserves to be given some time to scrutinize it. Until the results of this investigation come out, we should not prejudge the issue.”
Johnson & Johnson and ROCKET AF co-chair Keith AA Fox have responded to my request for further information, but I’m afraid they have not shed any new light on this situation.
Fox said that “to the best of our knowledge the impact of this is trivial.” I asked Fox for more details. He said that “a detailed statement will be released when all the checks are complete.”
A J&J spokesperson said: “We are aware of this matter and are currently assessing the situation. We stand by the conclusions of the ROCKET AF study and the positive risk/benefit profile of XARELTO®(rivaroxaban) in patients with non-valvular atrial fibrillation.”