Concerns about a leading blood thinning drug – and the regulatory decisions leading to its approval – have been raised in a new investigation by the BMJ.
The BMJ describes dabigatran (Pradaxa) as being a “blockbuster anticoagulant,” which is one of a new generation of drugs for stroke prevention in patients with non-valvular atrial fibrillation.
These new drugs have been recommended as part of US, UK, European and Canadian stroke guidelines, partly because – unlike older treatments, such as warfarin – it is not necessary when prescribing the drug to monitor plasma levels and anticoagulant activity and to have to adjust the dosage accordingly.
The BMJ‘s investigation was prompted by the disclosure of previously confidential internal documents belonging to dabigatran’s manufacturer, Boehringer Ingelheim, which were released during litigation in the US.
They showed that the company had failed to share information with the regulators on the benefits of monitoring anticoagulant activity and adjusting dosage to ensure efficacy and safety.
Also, the journal reports, Boehringer Ingelheim failed to share analyses on how many major bleeds could be prevented by adjusting the dose. The manufacturer claims that this information was withheld because these analyses were not reliable.
The BMJ found that a single clinical trial, called RE-LY, provided evidence to the regulators for the main benefits of dabigatran.
However, documents obtained under freedom of information show that the regulators expressed concerns with the manufacturer about the design and oversight of this trial. The BMJ found that it took three reviews of the data to calculate the number of major and fatal bleeds among trial participants.
Even now, says the journal’s investigations editor, Dr. Deborah Cohen, there is some doubt over whether all of these events among trial participants were properly accounted for.
Approved by the Food and Drug Administration (FDA) in 2010, dabigatran was a financial success. By the end of 2011, though, the disclosed documents reveal that the company had become worried about fatal bleeds and whether high-risk patients should have the drug levels in their blood monitored.
These concerns were not made public when, in early 2012, Boehringer Ingelheim were required by the European Medicines Agency (EMA) to give evidence to a specially convened expert safety committee.
In June 2012, an internal review of the RE-LY data showed that measuring blood levels of dabigatran and adjusting the dose as necessary could reduce major bleeding events by 30-40%, compared with well-controlled warfarin.
When the journal asked Boehringer Ingelheim to respond to the release of this evidence, the manufacturer insisted that the data was not reliable and that anti-clotting activity and blood levels of dabigatran do not need to be monitored.
A company spokesperson told BMJ:
“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.”
In an analysis published alongside the investigation, Thomas J. Moore, senior scientist at the Institute for Safe Medication Practices in Alexandria, VA, says that the FDA and EMA must “agree on a therapeutic range and recommend initial dose adjustment based on plasma measurements” to improve the safety of dabigatran.
A related editorial by Prof. Rita Redberg of the University of California – San Francisco, states that the investigation “illuminates a lack of transparency about the safety of unmonitored dabigatran.” The professor also calls for “a more transparent process of data collection and review that would make important clinical data available without waiting for litigation and subpoenas.”
“More methodological rigor prior to regulatory approval,” she says, “and careful and accessible post-marketing surveillance can better inform patient care and allow us to recognize a truly novel therapy.”