Perspective on Pradaxa

Much of the information published this week in BMJ about the oral anticoagulant dabigatran has appeared piecemeal throughout the years. But putting individual events into a narrative paints a more comprehensive picture.

The journal BMJ published three pieces that in many ways overlapped. An analysis walked through the many stages of debate during the drug approval process for dabigatran (Pradaxa, Boehringer Ingelheim) in the U.S. and Europe. The authors addressed the different concerns and responses between regulators. The FDA seemed more intent on efficacy and the European Medicines Agency on safety.

The FDA takes a beating in the analysis. The authors recounted how the agency chose to not review use of a lower dosage, and in a move that is not seen often in advisory proceedings, the panel insisted on an unofficial vote to approve or reject the lower 110 mg dosage. They approved on a 6-4 vote. The analysis also highlights one panel member’s remarks about five-fold variability in blood plasma levels and the possible need for monitoring.

Reports of bleeding events, some fatal, surfaced after approval of the drug in many nations. The FDA published a post-approval evaluation of dabigatran with a focus on bleeding risk using its Mini-Sentinel system. The analysts concluded that the adverse event reports were the result of heightened awareness with a new drug, or “stimulated reporting.”

The FDA seems bull-headed and dismissive in the analysis. The authors chastise the agency for placing some patients at increased risk of bleeding events and recommend approval of the lower dose and blood level monitoring.

Manufacturer Boehringer Ingelheim, in the meantime, has faced thousands of lawsuits in the U.S. over bleeding risks in patients treated with dabigatran. The company announced in May that it set aside $650 million to settle claims.

The investigative feature focuses on the litigation and includes details on two fatal bleeding events in the pivotal RE-LY trial. The information came to light publicly in lawsuits filed against Boehringer Ingelheim.

Boehringer Ingelheim responded with a press release that calls the BMJ stories misleading and unbalanced. “Many of the allegations made by BMJ were reported months ago in the media and have been previously addressed in full by Boehringer Ingelheim,” according to the statement.

The company may be right, that much of what BMJ reported was old news. But viewing the larger picture may help identify missteps in the approval process and avoid controversies in the future.

Candace Stuart

Cardiovascular Business, editor