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Study Unveils Xarelto Clinical Trial Misconduct

Xarelto bleeding complicationsXarelto bleeding complications may have been falsified, according to a recent report on clinical trial misconduct. The report suggests major issues with one early study on the drug, including signs that data regarding the safety of the anticoagulant may have been falsified and subsequently destroyed.

In early February, Jama Internal Medicine published a report by Charles Seife, of the Arthur L. Carter Institute of Journalism at New York University, revealing that the FDA frequently uncovers clinical trial misconduct and discrepancies in studies conducted by drug makers. However, this information is rarely reported to medical journals who publish the research.

Consequently, the studies are published in the medical journals, without any indication that the FDA found issues such as falsified data, unsafe practices and a complete disregard for scientific protocols. These instances are typically referred to as Official Action Indicated (OAI).

Throughout the course of his research, Seife found that most FDA clinical trial inspection records were filled with blacked out sections removing the name of the drugs, companies and researchers, making it difficult to see which clinical trials had major problems — with the exception of Xarelto.

RECORD 4 rebuked by FDA

According to the report, one of the Xarelto study reports — RECORD 4 — was conducted so poorly that the FDA rejected it entirely when deciding whether or not to approve the next-generation anticoagulant. However, the report was still published in The Lancet in May 2009. While the publication of the study states that Xarelto is safe and effective for the prevention of deep vein thrombosis and pulmonary embolism after knee replacement surgery, it fails to reveal the FDA knew researchers falsified some of the data and destroyed medical records, which was presumably done to cover up questionable practices.

In 2011, Xarelto received FDA approval for the prevention of strokes among patients with atrial fibrillation. The indication was later expanded to include the prevention of deep vein thrombosis and pulmonary embolism after knee and hip surgery, which is exactly what the four RECORD trials aimed to achieve.

“Eight of 16 FDA inspections of sites involved in a clinical trial of rivaroxaban, a novel anticoagulant, had been rated OAI. These inspections had uncovered evidence of various transgressions, such as ‘systemic discarding of medical records,’ unauthorized unblinding, falsification, and ‘concerns regarding improprieties in randomization’,” Seife wrote.

“Consequently, the entire study, RECORD 4 (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep-Venous Thrombosis and Pulmonary Embolism 4), was deemed unreliably by the FDA. These problems are not mentioned in the article describing the study’s results or in other publications associated with the trial.”

Xarelto bleeding complications

In 2011, the FDA refused to use the information contained in RECORD 4, claiming the data integrity was so poor it could not be considered in Xarelto’s approval process. The Agency noted that inspections at five clinical trial sites revealed that researchers did not report adverse effects experienced by patients, didn’t maintain adequate medical records, failed to acquire proper consent from subjects and didn’t report unanticipated risks to human test subjects.

“Inspection of Bayer Pharmaceuticals as the sponsor of the four RECORD 4 studies revealed that the sponsor failed to 1) ensure proper monitoring of the study, 2) ensure the study was conducted in accordance with the protocol and/or investigational plan, and 3) to ensure that FDA and all investigators were promptly informed of significant new adverse effects or risks,” FDA reviewers determined.

In addition to the unreliable data found in RECORD 4, the FDA also found issues with RECORD 2 and RECORD 3. The Xarelto website also sites only RECORDS 1-3, also eliminating the use of RECORD 4.

The findings come on the heels of mounting lawsuits involving uncontrolled Xarelto internal bleeding, for which there is no antidote. Plaintiffs claim that Xarelto manufacturers downplayed this major risk in an effort to boost sales.

  1. JAMA Internal Medicine, Research Misconduct Identified by the US Food and Drug Administration Out of Sight, Out of Mind, Out of the Peer-Reviewed Literature

  2. National Institutes of Health, Rivaroxaban Versus Enoxaparin for Thromboprophylaxis After Total Knee Arthroplasty (RECORD4): A Randomised Trial.

  3. U.S. Food and Drug Administration, Application Number: 022406Orig1s000 Summary Review