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A government watchdog group says that federal regulators approved the controversial anticoagulant Pradaxa despite information that clearly suggested the clinical trials conducted by the drug maker were biased and that users would face a potential bleeding risks from Pradaxa, with no tested means of reversing the blood thinning effects of the drug in emergency situations.
Since Boehringer Ingelheim’s novel anticoagulant Pradaxa was released in 2010, thousands of patients have suffered severe and uncontrollable bleeds, often resulting in death when doctors were unable to stop the bleeding.
The manufacturer has already paid hundreds of millions of dollars to individuals who suffered severe bleeding injuries and to family members of those who died through Pradaxa lawsuits filed over the failure to adequately warn about lack of an approved reversal agent.
In a report released by the Project on Government Oversight (POGO) on October 15, titled “Drug Problems: Dangerous Decision-Making at the FDA” (PDF), the federal regulatory agency is accused of being too lax and permissive with Boehringer Ingelheim in approving the drug.
“The result was to accommodate a pharmaceutical company by easing a drug’s passage to market and then deflecting questions about its safety once the product had won approval,” the report concludes. “The issues ranged from what standards to demand from the manufacturer-sponsored clinical trial used to secure the drug’s approval to what warnings to give patients about potential hazards and what claims to allow in ads for the product.”
The report was compiled using interviews with key participants and researchers, and accessing numerous public records, with some obtained through the Freedom of Information Act.
Researchers found that just two years after Pradaxa (dabigatran) was released, it was the most frequently named drug in adverse event reports submitted to the FDA. They also found that by September 2012, it had been identified as the primary suspect in nearly 2,000 patient deaths.
Only in the last few days did the agency approve Praxbind, a reversal agent to stop the blood thinning effects of Pradaxa bleeding events. Before that, doctors were on their own to figure out how to stop patients on the drug from bleeding out.
Praxbind comes too late for many individuals who suffered uncontrollable bleeding, and lawsuits alleged that Boehringer Ingelheim never should have introduced the drug without an available reversal agent.
Following several years of litigation, Boehringer Ingelheim ultimately agreed to pay $650 million in Pradaxa settlements last year, with an average of about $150,000 per claim. However, the drug maker continues to face new Pradaxa claims brought by individuals who have experienced Pradaxa emergency bleeding problems since the settlement.
“While the litigation was playing out, the federal judge presiding over it…found that the company had been withholding or failing to preserve records sought by plaintiffs,” the report notes. “He fined boehringer Ingelheim $931,500 and accused the company of acting in ‘bad faith.'”
FDA’s Questionable Decisions
The focus of the report is on decisions made by the FDA before and after the drug’s approval. The report calls those decisions a “troubling pattern.”
According to POGO, in addition to approving the drug without a reversal agent, despite knowing some patients would almost certainly bleed to death without one, the FDA defended Pradaxa in a number of statements made after the reports of patient deaths started being reported in large numbers.
POGO said experts criticized statements and studies made by the FDA in defense of Pradaxa, with Columbia University Professor of Statistics David Madigan calling the FDA’s Pradaxa study “junk” and Professor Jerry Avorn of Harvard Medical School calling an FDA analysis of Pradaxa “unsuitable for informing the care of patients.”
The report notes that the FDA did not call for a black box warning on Pradaxa due to bleeding risks, and approved the drug on an unblinded clinical trial where the researchers knew which patients were getting the actual drug and, according to one reviewer, treated those patients differently, making bias in the results more likely.
“When patients in the study showed signs of trouble, those on Pradaxa were more likely to have their treatment discontinued, an FDA review found,” the study revealed. “As a result, adverse events such as hemorrhagic strokes that might have occurred had they continued taking Pradaxa would have been averted.”
In some Pradaxa lawsuits, McMaster University and Hamilton Health Sciences were named as defendants. They run the Population Health Research Institute (PHRI) that was involved in those trials, known as RE-LY.
Independent medical experts have not only questioned the veracity of RE-LY, but some have suggested the study was so poorly done and so questionable that it should not only be investigated for accuracy, but for ethical violations as well.
RE-LY was originally published in September 2009, and has been amended twice, with one of the amendments included data on bleeding events the company admits were left out of the original findings.
In November 2010, the researchers issued a correction, admitting they had left out some bleeding events and other complications that had been overlooked. As many as 81 complications affecting 80 patients, including bleeding events, blood clots, heart attacks and at least one stroke, were found to have been omitted even before the recent revelation by Boehringer Ingelheim.
In October 2011, the results of RE-LY were questioned yet again by researchers from the University of British Columbia, who wrote a letter to Therapeutics Initiative, warning that the RE-LY was fundamentally flawed. They concluded that Pradaxa was prematurely approved and that it is unsafe to use for many patients.
Researchers also determined that an independent audit of the RE-LY clinical trials needs to be done to look at irregularities in the conduct, bias and RE-LY’s findings.
“The agency’s own inspection documented regulatory violations by Boehringer Ingelheim, according to an FDA memo,” the POGO report notes. “When the company originally submitted its application for approval of Pradaxa, the agency refused to even consider it because it was riddled with errors and numbers the FDA described as ‘highly implausible.'”
Pradaxa is part of a new-generation of blood thinners introduced in recent years as a replacement for warfarin, or Coumadin. Known as novel oral anticoagulants, other drugs in the same class are marketed under the brand names Xarelto and Eliquis.
While the medications have been promoted as superior alternatives to warfarin for prevention of blood clots among patients with atrial fibrillation, and following hip and knee replacement surgery for at-risk populations, the medications have been linked to a large number of reported emergency bleeding problems, where doctors were unable to control hemorrhages, often resulting in serious injury or death.
Although all blood thinners carry a risk of bleeding events, users of warfarin can be given a dose of vitamin K to reduce the blood-thinning effects. There are still no reversal agents for Xarelto or Eliquis, but both are in development.