ROCKET-AF Investigators Seek To Calm Concerns About Trial Reliability

(Updated) In response to disturbing questions about the integrity and reliability of crucial data in the ROCKET AF trial, the executive committee of the trial has released a statement saying that they have “conducted a secondary analysis of the trial findings” and that “the findings from the analysis are consistent with the results from the original trial and do not alter the conclusions of ROCKET AF.”

The statement contains no details about the analysis except that the executive committee “intends to publish a full description of this analysis and results as rapidly as possible.”

By way of background, ROCKET AF was the pivotal trial that compared rivaroxaban to warfarin in patients with atrial fibrillation. The trial served as the basis for the use of rivaroxaban (Xarelto, Johnson & Johnson) for this indication– a huge and important market. The new questions about the trial 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 in December 2014. 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.”

Timeline Details

In an interview, Duke’s Manesh Patel, a member of the ROCKET AF executive committee, provided details about the timeline of recent events. Although the devices were recalled a year ago, Patel said that the ROCKET AF investigators first became aware of the problem only this past October. Prior to that time, he said, they had no reason to suspect a problem.

Patel said that the executive committee of the trial was immediately convened when they learned of the problem. The executive committee then performed a secondary analysis “in order to understand the effect the possible malfunctioning of the device might have had in specific patient groups,” according to the statement. Patel would not provide any details about the analysis, but the statement says that it confirms the finding of ROCKET AF that “rivaroxaban is a reasonable alternative to warfarin and is non-inferior for the prevention of stroke and systemic embolism with less intracranial hemorrhage and fatal bleeding.”

Patel declined to respond to my question about whether the analysis involved stored blood samples from patients taken during the course of the trial. But he did point out that in the trial lab samples were stored at one point in time while INRs were performed on multiple occasions.

Patel said the analysis is now under peer review and that it has also been made available to the FDA, the EMA, and the drug’s manufacturers, Janssen and Bayer. He said he was unable to estimate when the paper would be published. Patel said that permission to give open access to the study data would need to come from Janssen and Bayer. Janssen has previously stated that it would make the study available to outside researchers if Bayer also agrees.

 One reason for the attention paid to the story was the involvement of Rob Califf, who served as the co-chairman of the trial. Back in January of this year Califf moved to the FDA and has since been nominated by President Obama to be the next FDA commissioner.  Since going to the FDA earlier this year Califf has had no role in ROCKET-AF, according to Patel. Califf has not participated in any of the analyses performed since the investigators first became aware of the problem in October. I have asked Califf to clarify whether he has had any involvement in the FDA’s handling of this case. (Update: The FDA informs me that Califf “is recused from the matter.”)

 

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