Questions are reportedly being raised about a clinical drug trial that was part of the approval process for a top-selling blood clotting prevention drug.
The 2011 trial known as ROCKET-AF helped convince the U.S. Food Drug and Administration (FDA) and the European Medicines Agency (EMA) to approve the drug rivaroxaban for use as a blood thinner in the United States and Europe.
In an investigative story published today, The BMJ reported that doctors and scientists are calling for an independent investigation into the drug trial that pitted rivaroxaban against an older blood thinner called warfarin.
The drug trial was overseen by the Duke Clinical Research Institute (DCRI) and published in the New England Journal of Medicine.
Rivaroxaban is developed under the name Xarelto by Bayer and Janssen Global Services. Janssen is a part of Johnson & Johnson.
Officials from both Janssen and the DCRI said today they have conducted recent follow-up analyses that affirm the results from the drug trial.
Device Called Into Question
The 2011 drug trial involved 14,000 patients and found rivaroxaban to be “non-inferior to warfarin for preventing ischemic stroke or systematic embolism,” according to The BMJ article.
The trial also concluded there was no significant difference in the risk of major bleeding between the two drugs.
However, scientists told The BMJ that a defective point-of-care device was used in the warfarin portion of the trial. The device was used to measure international normalized ratio (INR) in patients.
The INR is a standardized number computed in a lab. It’s part of a test that measures the time it takes a person’s blood to clot.
The BMJ reported that this particular INF device could have produced faulty readings for patients using warfarin. That could have caused warfarin doses to be increased. That, in turn, could have produced a greater risk of bleeding in warfarin patients.
“[That] could make rivaroxaban seem safer than it was in terms of the risk of bleeding and throws doubt on outcomes used to support the use of the world’s best selling new oral anticoagulant,” The BMJ wrote.
Attempts by Healthline to get comment from Alere officials were unsuccessful.
Company officials told The BMJ they were aware of complaints about the device’s functionality as early as 2002, before the ROCKET-AF trial began.
The BMJ said neither Alere nor the FDA would comment on why those complaints weren’t investigated more fully.
In an editorial published today in the New England Journal of Medicine, DCRI officials said their follow-up analyses show the device shortcomings did not affect the overall results of the drug trial.
“These results are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial,” the DCRI officials wrote.
In addition, officials at Janssen Global Services said their separate analysis concluded the same thing.
“(The DCRI) findings are in line with the sensitivity analyses conducted by Bayer and Janssen, which also affirm the results of the ROCKET AF study and the positive benefit-risk profile of Xarelto,” Kristina Chang, director of product communication at Janssen, told Healthline in an email statement.
On Friday, the EMA released a statement saying the defect in the device did not change its conclusions on the overall safety of Xarelto.
What Happens Now?
The question now facing regulators is what to do when a device used in a drug trial is found to be faulty.
An official with the FDA told The BMJ it was aware of the concerns about the Alere device and was “reviewing relevant data.” The agency also announced it will hold a public workshop in March to examine the effectiveness of point-of-care INR devices.
That, however, is not alleviating the concerns of some scientists.
Harlan Krumholz, a professor of medicine at Yale University, told The BMJ that the New England Journal of Medicine should place an “immediate expression of concern” on the 2011 published study to alert the medical community.
“The study should be considered of uncertain validity until a more thorough review can be done,” Krumholz was quoted as saying. “[There should be] an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”
In addition, Dr. Thomas Marciniak, a former FDA reviewer, told The BMJ he wouldn’t rely on any analyses done by the DCRI, the FDA or Johnson & Johnson. He said the data from the trial needs to be released so “unbiased analyses” can be done.
Pulling rivaroxaban from the market could be difficult, though.
Former FDA clinical pharmacologist Bob Powell told The BMJ that once a drug is on the market, regulators lack a mandate to act unless safety concerns arise.