Boehringer Ingelheim withheld safety analyses on new anticoagulant, The BMJ investigation findsBMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4756 (Published 24 July 2014) Cite this as: BMJ 2014;349:g4756
The drug company Boehringer Ingelheim withheld from doctors and drug regulators the fact that monitoring the blood level of its new anticoagulant stroke drug and adjusting the dose could substantially reduce major bleeds associated with it, an investigation by The BMJ has found.1
Dabigatran (marketed as Pradaxa) was licensed for stroke prevention in patients with non-valvular atrial fibrillation by the US Food and Drug Administration in 2010 and by the European Medicines Agency a year later. It is one of a new generation of oral anticoagulants that have been marketed as being more convenient than the traditional anticoagulant warfarin because patients do not need regular tests to check concentrations of drug in their blood.
This unique selling point has been used prominently by Boehringer Ingelheim. Dabigatran did not require “regular blood tests to see if your blood-thinning level is in the right range,” said advertisements to US patients.
After its launch dabigatran became a rapid success, reaching blockbuster status by April 2012, with over $1bn in global turnover. But by the end of 2011 concerns about fatal bleeds began to emerge. In 2011 the FDA received reports of 542 deaths and 2367 cases of haemorrhage linked to use of dabigatran.
Documents obtained by The BMJ under freedom of information legislation and released as part of the litigation in the US by families of patients who took part in a key clinical trial of dabigatran show that the safety of the drug could be improved if blood concentrations were monitored and doses adjusted.
Analyses conducted by Boehringer Ingelheim showed that in August 2011the company had calculated that there was an optimal plasma concentration range of the drug. In June 2012 another analysis showed that measuring blood dabigatran concentrations and changing the dose as needed could reduce major bleeds by 30-40% in comparison with well controlled warfarin.
The analyses concluded: “Optimally used (=titrated) dabigatran has the potential to provide patients an even better efficacy and safety profile than fixed dose dabigatran and also a better safety and efficacy profile than a matched warfarin group.”
But regulatory authorities were not made aware of these findings. And emails showed that Boehringer Ingelheim employees were reluctant to release the information as it could affect sales.
The European Medicines Agency confirmed that it did not know about the analyses. It added, “If we discover that the company withheld any relevant information, we will not hesitate to take necessary action” and would make “changes to the current recommendation.”
However, Boehringer Ingelheim maintains that blood concentrations of dabigatran do not need to be monitored. “Our 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,” a spokesperson told The BMJ.
The spokesperson added that the FDA reached the same conclusion that “monitoring is not necessary and that the increased benefit to patients in stroke reduction (even at the highest levels of plasma concentration) outweighed the marginal increase in bleeding risk.”
But in an accompanying analysis in The BMJ Thomas Moore, senior scientist at the US Institute for Safe Medication Practices, and colleagues said that the safety of dabigatran “can be substantially improved in both the US and EU.”2 They said that regulators should recommend plasma concentration testing in all new patients and eliminate the recommendation that dabigatran “does not in general require routine anticoagulant monitoring.”
In an editorial Rita Redberg and Blake Charlton of the Department of Medicine of the University of California at San Francisco said that bringing new drugs to market promptly can benefit patients but that there are tradeoffs in terms of safety and effectiveness.3 They called for “a more transparent process of data collection and review that would make important clinical data available without waiting for litigation and subpoenas.”
They concluded that “more methodological rigor prior to regulatory approval and careful and accessible post marketing surveillance can better inform patient care and allow us to recognise a truly novel therapy.”
Cite this as: BMJ 2014;349:g4756