Boehringer Ingelheim accused of withholding safety information for Pradaxa

In a feature published in the British Medical Journal, investigations editor Deborah Cohen, MD, has accused Boehringer Ingelheim of withholding information regarding the potential benefit of plasma level monitoring of its drug dabigatran for the prevention of bleeding events, which the company strongly denies.

In her article, Cohen wrote that the risk for major or minor bleeding with the highly successful anticoagulant dabigatran (Pradaxa) was near that of warfarin (16.4% of patients per year on a higher dose of dabigatran vs. 18.15% of those on warfarin) and much higher in patients with impaired renal function in the RE-LY trial. However, according to Cohen, the company held information from the FDA and European Medicines Agency (EMA) related to the potential to reduce risk for major bleeds by 30% to 40% vs. controlled warfarin, without impacting risk for ischemic stroke, with measurement of plasma levels and subsequent dose adjustments. Once Pradaxa was approved, Cohen added, the company marketed the drug as an alternative to warfarin that did not require monitoring of plasma concentrations via blood test.

Additionally, safety concerns about an upper threshold dosage of 200 ng/L were also withheld, according to Cohen, who wrote that employees of Boehringer Ingelheim expressed concerns about the potential bleeding risks in company emails.

Boehringer Ingelheim denies the accusation, and stated in a press release that the British Medical Journal paper contained “misleading statements,” noting that the FDA issued results in May from an analysis of 134,000 patients aged 65 years or older and “reaffirmed the positive safety-efficacy profile” of the drug, without the need for monitoring.

The company wrote that clinical data did not support making dose decisions for dabigatran according to blood levels of the drug alone. “Preliminary, exploratory simulations with mathematical models” did not indicate a potential improvement to safety or efficacy resulting from dose adjustment according to plasma concentrations; consequently, the company stated, that information was not provided to regulators. They also noted that patient factors such as age, renal function and dabigatran use in combination with other medications are “critical factors” impacting risk for bleeding events.

Cohen cited a 2013 article published in the Journal of the American College of Cardiology that was coauthored by Boehringer Ingelheim employees, as well as researchers from universities, in which a fivefold variation in blood plasma concentration was observed with each dose. A draft of the article produced in Aug. 2011 indicated the potential for an optimal plasma concentration range for dabigatran, according to Cohen. The draft suggested that monitoring of plasma concentrations or antithrombotic activity would be necessary to identify at-risk patients, while a subsequent dose adjustment could improve risk-benefit ratio, Cohen wrote. Additional data – which Cohen noted were not included in the company’s March 2012 safety presentation to the EMA – indicated that suboptimal dosing of dabigatran was also possible, potentially leaving patients at an “appreciably higher” risk for stroke.

According to Cohen, internal company emails released during U.S. litigation suggest that some in the company were concerned these findings would negatively impact its no-monitor marketing strategy for the drug, with one employee seeming to recommend against publishing the paper altogether. Cohen also noted that the EMA discussed routine monitoring of anticoagulant activity during the March 2012 meeting, but the committee ultimately voted against the practice.

For more information:

Cohen D. BMJ. 2014; doi:10.1136/bmj.g4670.