Nicholas Malfitano Jul. 5, 2016, 2:09pm


PHILADELPHIA – The quality and depth of clinical trials of the blood-thinner Xarelto could be a key issue when the first trials over the drug begin in Philadelphia courtrooms.

With the first trial of more than 800 lawsuits expected to begin next year, attorneys representing those claiming to have been injured by the drug disagree with its manufacturers over trials conducted prior to the drug's approval by the Food and Drug Administration for the U.S. market four years ago.

Xarelto follows in the footsteps of drugs such as Coumadin, often taken by patients suffering from nonvalvular atrial fibrillation, an abnormal heart rhythm, to decrease the risk of a stroke. Plaintiffs claim they experienced a risk of bleeding events after taking Xarelto.

One Philadelphia medical malpractice attorney who represents Xarelto users even called one of the drug trials "a total mess" and likened it to a school science fair project.

Where Coumadin required regular medical monitoring to ensure safe administration and possessed an antidote, newer drugs such as Xarelto were allegedly marketed as not needing such monitoring or to be taken as frequently, and did not have an antidote.

Now, Xarelto's manufacturers (Bayer and Janssen Pharmaceuticals) are faced with a similar situation as Boehringer Ingelheim's Pradaxa before it – with litigants charging they failed to warn patients that Xarelto use presented increased risks for cranial and gastrointestinal bleeding when only taken once daily.

Risks which, allegedly, would be greatly decreased if the drug was taken twice daily and monitored properly.

Philadelphia attorney Max Kennerly of Kennerly & Loutey says he expects the first Philadelphia trial to begin next summer, at the earliest, and a Feb. 6 start-date has been set for the first trial in the Xarelto federal multi-district litigation proceeding. 

Kennerly claims studies show business interests were favored over patient health.

“Regarding the clinical trials, once-a-day (dosing) is better for marketing, but marketing doesn’t trump basic biology. Two of the Phase II studies, ODIXa-DVT and EINSTEIN DVT, showed that once-a-day dosing created higher maximum plasma concentrations and lower trough plasma concentration,” Kennerly said. 

“It’s not hard to see how those kinds of fluctuations can both increase the risk of bleeding when concentrations are high and make the drug less effective for preventing clots when the concentrations are low.”

Kennerly stated one Xarelto Phase III study, “ATLAS ACT 2 - TIMI 51," did in fact compare once-a-day dosing with twice-a-day, but termed the trial results “a total mess.”

“An article in the Journal of the American College of Cardiology pointed out a host of problems, including ‘an unanticipated high rate of missing data,' a ‘lack of an expected dose response,’ a ‘divergent impact’ between the cardiovascular risks of the low dose and the high dose, a ‘lack of supportive external evidence’ for novel anticoagulants over standard dual antiplatelet therapy, and a ‘lack of a statistically persuasive efficacy benefit,’" Kennerly said.

"They might as well have turned in an elementary school science fair project."

The attorney added the FDA inquired about these same issues during Xarelto’s approval process.

“In terms of the litigation, I think this is a big problem for the makers of Xarelto. If they try to rely on the ATLAS trial, they're just going to raise doubts about the legitimacy of all of their clinical trials,” Kennerly said. 

“Conversely, if they try to claim that no study has shown conclusively that twice-a-day dosing is safer, the response is obvious: that’s because they chose not to do one.”

William Foster, spokesperson for Janssen Pharmaceuticals, Inc., provided an official statement on behalf of the company which contrasted sharply with Kennerly's point of view.

“Xarelto (rivaroxaban) is an important anticoagulant used to treat and reduce the risk of life-threatening blood clots. After more than four years on the U.S. market, and more than 3 million patients prescribed in the U.S. to date, the benefit-risk profile of Xarelto remains favorable and consistent with clinical trials,” Foster said.

Foster stated Janssen Pharmaceuticals has “always” made sure to warn of bleeding risks associated with Xarelto.

“All anticoagulants, or blood thinners, carry the risk of bleeding, and the prescribing information for Xarelto has always warned of these risks," he said.

"We continuously assess the benefit-risk profile of Xarelto, and the occurrences of bleeding observed since the medicine was approved are generally consistent with those seen in Phase III clinical trials completed across more than 64,000 patients."

Foster says Xarelto was studied as both a once-daily and twice-daily medication in its early clinical development, and once-daily dosing was shown to be appropriate for most indications.

“We observed a consistent coagulation effect across a wide range of patients of varying age, gender and weight. As once-daily medications are also associated with very high patient compliance, Xarelto was brought into Phase 3 trials in patients with non-valvular atrial fibrillation as once-daily,” Foster said.   

“As demonstrated by the pivotal ROCKET AF trial, Xarelto works as dosed and was approved by health authorities around the world. Continuing surveillance and real-world evidence confirms the positive benefit-risk profile of Xarelto that was observed in our Phase III clinical trials completed across more than 64,000 patients."

Foster indicated Janssen will proceed in vigorously contesting the allegations. Boehringer Ingelheim ultimately settled about 4,000 Pradaxa claims for approximately $650 million.

“Blood-thinners are important and potentially life-saving medicines that should be taken by patients as prescribed and should not be discontinued without a discussion with a physician. We will continue to defend against the claims raised in this litigation,” Foster stated.    

In addition to a grouping of Xarelto claims being processed in a Louisiana federal court, more than 800 lawsuits - most from out-of-state plaintiffs - will be handled in Philadelphia's Complex Litigation Center. 

The CLC has several mass tort programs, including cases over asbestos and Risperdal, and the percentage of claims belonging to out-of-state plaintiffs is typically in the high-80s.

About 840 cases have been filed in the Xarelto program at the CLC, overseen by Judge Arnold New. The first cases were filed in February 2014.

The federal Xarelto MDL is headquartered in U.S. District Court for the Eastern District of Louisiana as Case No. 2592, with Judge Eldon E. Fallon presiding.

From the Pennsylvania Record: Reach Courts Reporter Nicholas Malfitano at nickpennrecord@gmail.com

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