Recently, the U.S. Food and Drug Administration (FDA) questioned the ROCKET-AF trial, the largest clinical trial that supposedly proved beyond a reasonable doubt that Xarelto is a safe and effective medication. It’s thanks to the results purported in the above trial that, in fact, the new blood thinner was approved in 2011 as a potential substitute of the older competitor Warfarin. However, today the American agency is investigating about a possible device malfunctioning that may have skewed the results of this trial, providing unreliable information about this drug’s alleged safety. Many lawyers brought to the attention of the court that Johnson & Johnson (J&J), the pharmaceutical company that manufactures the Novel Oral Anticoagulant (NOAC), knew that one of the devices used to monitor the drug’s effectiveness was, in fact, defective. As described in a recent New York Times article, a group of attorneys provided internal company documents as evidence, on behalf of plaintiffs who suffered personal injuries due to the uncontrolled bleedings caused by this medication .
The FDA questions Xarelto safety and effectiveness because of a defective device
Xarelto (rivaroxaban) gained much of its marketing success due to its superior ease of use over its competitor Warfarin. The older blood thinner did, in fact, require constant monitoring and several dietary restrictions, and it was often regarded as a not-so-much-safe drug with several side effects. However, side effects of the newer blood thinner did include the much dreaded uncontrolled bleeding accidents. If a patient suffered from one of these events, there was no effective antidote available to reverse Xarelto effects, leading to a scaringly high number of subjects who suffered from serious injuries, emergency hospitalizations and, in some instances, even death. Hundreds of patients filed a Xarelto lawsuit, whose number kept growing in the last few months up to a current total of over 2,800 litigations [2, 3].
The faulty device upon which the FDA is currently investigating is an instrument produced by Alere (the INRatio 2PT/INR Monitor System) to gauge patient’s international normalized ratio (INR), a parameter that helped physician know whether the subject was taking the right dose of Warfarin. The agency is questioning whether the device malfunctioning may have skewed the results negatively for the older anticoagulant, leading doctors to provide an inadequate dosage of the drug itself. An excessive dose may have as a consequence an increased number of Warfarin bleeding accidents, resulting in Xarelto gaining an unfair advantage in terms of purported safety over its older counterpart. Due to its malfunctioning, the device was later recalled by the FDA in January 2015 .
After a brief investigation, a panel from the European Medicine Agency (EMA) concluded that the faulty device results weren’t relevant enough to affect the outcome of the trial. However, the controversy did not end, as the researchers from Duke Clinical Research Institute, who conducted the original trial failed to mention that central laboratory tests that could be used to provide an estimate of the device’s accuracy were, in fact, ignored. To make the matter even more controversial, the EMA panel was composed of members from the companies itself, lacking the independence to assess adequately the trial’s reliability . The cardiologist Dr. Harlan M. Krumholz, head of the Yale University Open Data Access Project had an agreement with J&J to freely provide outside researchers with data from clinical trials performed by the company. However, when he asked Bayer to provide information about the device malfunctioning, the german Big Pharma refused to grant permission .
The INR devices malfunctioning and the FDA investigation
The FDA already questioned the INRatio device’s reliability in monitoring patients. Warning letters were sent to the previous manufacturers of HemoSense, as the devices produced “clinically significant” inaccuracies in gauging patient’s parameters. However, when Alere later acquired the device property, they did not investigate the complaints and ignored the matter until 2014, when they recalled the device [6, 7]. It was obvious that the instrument inaccuracy could raise several concerns during the ongoing 2006 ROCKET-AF trial. However, no words were ever spoken about this question until last December, when an article was published in the British Medical Journal . The article aptly called “Data on trial of anticoagulant is to be reanalyzed after discovery that investigators used faulty device,” reopened the old controversy, leading both the EMA and the FDA to inquiring about the Xarelto trial itself. And while the EMA decided that the device did not affect the trial’s outcome, the FDA keeps looking on this matter, especially asking questions about what kind of actions were taken by the company to minimize the effects of the faulty device. Evidence filed with Judge Eldon E. Fallon in the Eastern District of Louisiana in the Xarelto Multidistrict Litigation proves, in fact, that they were well aware of all the limitations of the INRatio monitoring.
Article written by: Dr. Claudio Butticè, Pharm.D.
- Katie Thomas. F.D.A. Asks If Faulty Blood Monitor Tainted Xarelto Approval. New York Times. FEB. 22, 2016
- FDA U.S. Food and Drug Administration Website. “MEDICATION GUIDE XARELTO® (zah-REL-toe) (rivaroxaban) tablets” Reference ID: 3688029 (Accessed June 2015).
- “Bleeding with dabigatran, rivaroxaban, apixaban. No antidote, and little clinical experience.”Prescrire Int. 2013 Jun;22(139):155-9.
- FDA U.S. Food and Drug Administration Website. Alere INRatio2 PT/INR Professional Test Strips: Recall – Higher INR when Performed by Central Laboratory. (Accessed February 2016)
- European Medicines Agency (EMA). EMA concludes defective device in ROCKET study does not impact Xarelto’s safety. 05/02/2016
- FDA U.S. Food and Drug Administration Website. Inspections, Compliance, Enforcement, and Criminal Investigations – HemoSense Corporation 04-Oct-05. (Accessed February 2016)
- FDA U.S. Food and Drug Administration Website. Inspections, Compliance, Enforcement, and Criminal Investigations – HemoSense, Inc. 29-Nov-06. (Accessed February 2016)
- Cohen Deborah. Data on trial of anticoagulant is to be reanalyzed after discovery that investigators used faulty device. BMJ 2015; 351 :h6431