An investigation released July 23 by The BMJ  raises new concerns about the anticoagulant dabigatran (Pradaxa) and the regulatory decisions that led to its approval. Dabigatran was approved by the U.S. Food and Drug Administration (FDA) in 2010 and by the European Medicines Agency (EMA) in 2011.

Additional Resources RE-LY Trial Summary Anticoagulation Initiative Anticoagulation Management Clinical Community

According to the investigation, company information about the benefits – specifically reductions in bleeding risk – associated with monitoring blood levels in patients taking the drug was not shared with regulators. The BMJ specifically points out that documents from 2011 revealed Boehringer Ingelheim worried about the need for monitoring and dose adjustment in high risk patients. In early 2012, the EMA asked Boehringer Ingelheim to give evidence to a specially convened expert safety committee, but the presentation did not reflect the company’s concerns. In June 2012, a company analysis of RE-LY data showed that measuring blood dabigatran levels and adjusting the dose accordingly could reduce major bleeding events by up to 30 – 40 percent compared to well controlled warfarin. However, The BMJ investigation suggests neither doctors nor regulators were made aware of these calculations.

In response to the report, Boehringer Ingelheim said its "scientists determined, and the FDA concurred, that the research does not support making dosage decisions based on plasma concentrations – a conclusion based solely on science and patient welfare." They added that the information about bleeding risks was not shared because the analysis did not provide a reliable prediction of patient outcomes.

Meanwhile, an accompanying analysis suggests the safety of dabigatran "can be substantially improved in both the U.S. and EU." The authors urge Boehringer Ingelheim, the FDA and EMA "to agree on a therapeutic range and recommend initial dose adjustment based on plasma measurements." They also recommend a blood test be available in the U.S. and that the FDA make available the lower 110 mg strength that is approved in the EU, Canada, New Zealand and Australia "to permit dose adjustment in high risk patients."

An accompanying editorial, by Blake Charlton and Rita Redberg, MD, FACC, also cautions that society "must consider the trade-offs of an accelerated drug approval in terms of assurance of safety and effectiveness." They recommend "a more transparent process of data collection and review that would make important clinical data available without waiting for litigation and subpoenas."

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