Credit: CDC
A series of papers published in The BMJ have raised concerns about the anticoagulant dabigatran (Pradaxa).
The papers claim the company developing dabigatran has underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.
The company, Boehringer Ingelheim (BI), has denied these allegations.
“During the course of litigation involving Pradaxa, specifically hand-picked fragments of our robust internal discussions were made available to the media by external parties, which resulted in a gross distortion of the facts about Pradaxa and Boehringer Ingelheim,” said John Smith, a regional medical director at BI.
“As a result, some media reports have wrongfully suggested that BI purposefully suppressed data and have questioned the company’s ethics in efforts to alert regulators, healthcare professionals, and patients of the risks associated with Pradaxa. Some reports have even accused BI of improper trial conduct. All of these allegations are absolutely false . . . .”
Concerns about the RE-LY trial
One of the papers published in The BMJ, “Concerns over data in key dabigatran trial,” said the design and oversight of the RE-LY trial were poor.
The trial compared dabigatran at 110 mg or 150 mg twice daily to dose-adjusted warfarin in patients with atrial fibrillation. Results suggested dabigatran was noninferior, and in some cases superior, to warfarin.
The BMJ article said the open-label design of this trial allowed for bias. And events—such as bleeding and myocardial infarctions—have been misreported.
The article also suggested that reviews by BI have failed to uncover all of the inaccuracies in the trial data, and all of the information has not been released—either to regulators or the public.
BI refuted these claims, saying regulators found RE-LY’s design “robust and valid.” And although reviews have uncovered inaccuracies, the results have not affected the trial’s conclusions.
In fact, the US Food and Drug Administration (FDA) “reaffirmed the positive efficacy-safety profile of Pradaxa” when it reviewed data from more than 134,000 patients.
BI also said it has provided the FDA and the European Medicines Agency (EMA) with the complete data set, and both regulators have affirmed the conclusions of the trial.
Allegations of withheld data
Another article in The BMJ, “Dabigatran: how the drug company withheld important analyses,” suggested BI withheld information indicating that monitoring and dose adjustment could improve the safety of dabigatran.
The article said the company did not provide regulators with data showing a 5.5-fold variation in plasma levels among dabigatran-treated patients. And the company withheld data garnered from analyses calculating how many major bleeds could be prevented by dose adjustment.
The analyses suggested that monitoring and dose adjustment could reduce major bleeds by 30% to 40% compared with well-controlled warfarin. And the adjustment would have little or no effect on the risk of ischemic stroke.
BI conceded that, in 2012, company scientists performed exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of dabigatran.
However, the initial hypothesis “could not be supported when applied to the actual clinical data from the RE-LY population.” So the company did not supply the data to the FDA or EMA.
Furthermore, “the totality of scientific evidence does not support dosing decisions for Pradaxa based solely on blood levels.” Instead, the company said that patient characteristics such as age, kidney function, and certain medications are the critical factors that contribute to the risk of bleeding.
The role of regulators, physicians, and patients
A third article in The BMJ, “Dabigatran, bleeding, and the regulators,” investigated the role the FDA and the EMA have played in all this.
The author said the EMA has made information, tests, and varying strengths of dabigatran available to promote safer use of the drug.
The FDA, on the other hand, has focused on efficacy rather than reducing the risk of bleeding. The agency approved only the 150-mg dose of the drug and has not approved a plasma-level diagnostic test.
The BMJ also published an editorial titled “The trouble with dabigatran.” It suggested that doctors and patients should “tread carefully” due to emerging risks associated with the drug.
