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Janssen Pharmaceuticals, a division of Johnson & Johnson, submitted an approval application for Xarelto to the U.S. Food & Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) in January 2011.
Although the FDA ultimately approved the drug for preventing deep vein thrombosis and pulmonary embolism during and after hip or knee arthroplasty, the agency expressed concern over the results of a series of clinical studies, known as the “ROCKET” trials, conducted by the company. Specifically, the FDA was unable to characterize the likelihood of liver toxicity based on the trial information provided in the application. The FDA also mentioned several problems with data integrity. 1
February 2015 Study of Xarelto ROCKET Trials
This concern with data integrity has been detailed in a study that appeared in Feb. 2015 in the Journal of the American Medical Association. It pointed out that a large number of FDA clinical trials have been cited for not following clinical protocols.
Some studies were also negligent in several other areas, including ensuring patient safety and other breaches of safety and trial protocols. Several studies also underreported adverse effects. In spite of these glaring problems and FDA regulatory inquiries and actions, many of these trial’s manufacturers and investigators never mentioned these problems in papers presenting trial results submitted and printed in medical journals.
The Xarelto Regulation of Coagulation in Orthopedic Surgery to Prevent Deep-Venous Thrombosis and Pulmonary Embolism (RECORD 4) trial was rated with the FDA’s most serious clinical trial citation, “official action required” due to serious clinical trial problems, including discarding medical records and falsifications. Because of these problems, the FDA determined the results from this study were unreliable. 2
As indicated in an editorial in the same issue, these problems call into question how valid the clinical trial results presented in medical journals really are, if disclosure of these serious violations is not required. 3
Black Box Warning Added to Xarelto Label
In 2014, the FDA required the makers of Xarelto to add new language to the anticoagulant’s warnings and precautions, including at least one update to the “black box” warning, the FDA’s strongest and most urgent type of warning. The additional verbiage notifies patients and caregivers about certain risks and potentially dangerous side effects of Xarelto, including the following:
- Uncertainty about the best timing for the application of Xarelto in relation to neuraxial procedures (regional anaesthetic techniques)
- A warning about the risks of using Xarelto with a epidural anesthesia and spinal puncture
- Results from a study of Xarelto on renal functionality
- Lack of an antidote to treat excessive bleeding due to the blood-thinning effects of Xarelto
- Caution against using Xarelto with combined P-gp and strong CYP3A4 inhibitors, such as ritonavir, itraconazole, ketoconazole, conivaptan, lopinavir/ritonavir, and indinavir
- Incomplete data with respect to Xarelto’s effects on who have heart valves
- Thrombotic events upon early discontinuation of the anticoagulant
These and other warnings are currently required to appear in Xarelto’s literature. 4
On June 6, 2013, the FDA sent a letter to Johnson & Johnson to inform the company that the agency had determined its print advertising in WebMD magazine earlier that year was misleading, as the advertizing downplayed the effects of the drug to potential patients.
Xarelto Advertising Requirements
On June 6, 2013, the FDA sent a letter to Johnson & Johnson to inform the company that the agency had determined its print advertising in WebMD magazine earlier that year was misleading, as the advertizing downplayed the effects of the drug to potential patients. In particular, the FDA claimed that the ads failed to properly draw readers’ attention to the effects of the drug, and the claims of efficacy appeared to be disassociated from the risks. Furthermore, the advertisement asserted that Xarelto has “no dosage adjustments,” which the FDA noted is inaccurate according to the product information’s sections on warnings and precautions as well as dosage and administration.
Because of these allegations, the FDA declared Johnson & Johnson to be in violation of U.S. laws and regulations that oversee drug marketing. 5
Expanding Blood Thinner Uses
In May 2012, the FDA Cardiovascular and Renal Drugs Advisory Committee met to discuss the possibility of extending the uses of Xarelto. During that meeting, the committee was divided on whether to allow the new uses, or wait for more information, since at least some of the committee members “could not rely on the evidence” presented by Johnson & Johnson’s Janssen Pharmaceuticals. Ultimately, the committee decided to refrain from approving the drug on a split vote of 4 – 6, with one member abstaining. 6
Nevertheless, in November 2012, the FDA approved Xarelto for several expanded uses. Although the agency still conveyed concerns about serious conditions, such as heavy bleeding, the agency’s press release indicates that three studies of almost 9,500 participants purportedly indicate Xarelto is safe for treatment of deep vein thrombosis and pulmonary embolism. The names of the studies are not revealed in the FDA’s announcement, which also noted bleeding was a “major side effect” of Xarelto. 7
FDA Postmarket Requirements
In July 2011, the manufacturers of Xarelto received three FDA postmarket requirements:
- To provide a low-dose option by creating a 5-mg tablet or a scored 10-mg tablet
- To determine potentially adverse risks affiliated with renal impairment by conducting a clinical study
- To track risk factors, clinical management and outcomes of all major bleeding episodes and report findings through a quarterly report for three years (from 2011 through 2014) and annually thereafter. 8
The FDA’s approval of Xarelto in November 2011 indicated use with nonvalvular atrial fibrillation (NVAF), a decision that came about only after copious discourse and review. The agency’s concerns suggested that, although the anticoagulant adequately fulfilled the criteria of an effective alternative upon the failure of other treatments, there was no indication that Xarelto might be superior to warfarin (another coagulant). In addition, the FDA communicated concern about:
- The low rate of people whose anticoagulation was adequately controlled in the warfarin study group during the ROCKET-AF clinical trial
- An increased rate of strokes in people taking Xarelto after the study’s conclusion
- No “rational basis” for Janssen’s trial dosing in the ROCKET-AF study
- The inability to ascertain whether Xarelto could achieve the same results of warfarin in most instances
- U.S. Food & Drug Administration. “Center for Drug and Evaluation Research: Application number: 022406Orig1s000.” (Jan. 4, 2011) FDA.gov. Accessed Oct. 27, 2014.
- Seife, Charles, “Research Misconduct Identified by the US Food and Drug Administration: http://archinte.jamanetwork.com/article.aspx?articleid=2109855. Accessed March 5, 2015.
- Steinbrook, Robert and Redberg, Rita F., ”Reporting Research Misconduct in the Medical Literature.” http://archinte.jamanetwork.com/article.aspx?articleid=2109848; Accessed March 5, 2015.
- U.S. Food & Drug Administration. “Xarelto (Rivaroxaban) Tablets. Boxed warning.” (March 2014.) FDA.gov. Accessed Oct. 27, 2014.
- U.S. Food & Drug Administration. “Letter to Roxanne McGregor-Beck, RE: NDA #202439.” (June 6, 2013) FDA.gov. Accessed Oct. 27, 2014.
- U.S. Food & Drug Administration. “Summary Minutes of the Cardiovascular and Renal Drugs Advisory Committee.” (May 23, 2012) FDA.gov. Accessed Oct. 24, 2014
- U.S. Food & Drug Administration. “FDA expands use of Xarelto to treat, reduce recurrence of blood clots.” (Nov. 8, 2012) FDA.gov. Accessed Oct. 25, 2014.
- U.S. Food & Drug Administration. “Center for Drug Evaluation and Research. Approval package for: Application # 022406Orig1s000.” (July 1, 2011) FDA.gov. Accessed Oct. 27, 2014.