Claims Made Regarding Manufacturer’s Study Results

Further questions regarding the safety of the anticoagulant Pradaxa (Dabigatran) have been raised in a new article in the British Medical Journal.

The drug’s manufacturers, Boehringer Ingelheim, recently settled 4000 lawsuits in the United States arising from episodes of major bleeding associated with the market leading drug for a total of $650million.

Now, the BMJ, relying on information released during the litigation and obtained in its own investigations, has queried the extent to which those injuries might have been avoided by full disclosure of the company's own internal studies and analyses.

The issue relates specifically to the requirement, or otherwise, for analysis of blood concentrations of the drug. The purpose of anticoagulants is to thin the blood, to reduce the risk of blood clotting either temporarily during surgery, or in the long term for patients at risk of stroke or deep vein thrombosis. However, an excessive dose can thin the blood to dangerous levels, and potentially cause severe internal bleeding. For that reason, patients on traditional blood thinners like Warfarin are regularly monitored to ensure that blood viscosity remains within safe limits.

Pradaxa's particular selling point has always been that the dose does not need to be adjusted to reflect patient characteristics; nor does blood viscosity need to be monitored after application. That represents a significant advantage over Warfarin, which does, and was a key factor in the regulatory approval process and Pradaxa's later market success.

According to the BMJ, Boehringer Ingelheim possessed study results as early as 2011 which identified a very wide variation in the response to Pradaxa between different patients provided with the same dose, leading its employees to question whether the drug was really suitable for use without monitoring.

The study found that the concentration of the drug in the blood was strongly influenced by kidney function and patient age, and recommended that dose adjustment and monitoring could reduce the incidence of major bleeds by 30-40% compared to Warfarin. It also identified a specific upper limit of blood concentration which should not be exceeded because of the risk of bleeding and recommended that a dose adjustment to reflect patient characteristics could be beneficial

However, the BMJ’s report discloses evidence of internal emails which suggest a conflict between the scientific advice and company policy. One email from a company official in October 2012 in relation to the 2011 study read: “The publication will [do] more harm than be useful for us, neither in the market but especially harmful in the discussions in the regulatory bodies.” Other emails referred to the difficulty which the release of the information would create for Pradaxa’s product placement as a “no monitoring” drug. Ultimately, the 2011 study was not published and the drug was licensed for use without mandatory monitoring or dose adjustment.

Since its licence was granted, Pradaxa has been one of the drugs most frequently associated with adverse incidents report to the US Food and Drugs Administration. The UK Health Regulator, the MHRA, has received 2,300 adverse incident reports for Pradaxa since 2009, of which 81 were fatal. The risk associated with any serious bleed is increased by the fact that, unlike Warfarin, the effects of Pradaxa cannot be reversed by an antidote.

Although concerns continue to exist within the medical community, Boehringer Ingelheim maintains that Pradaxa is safe for use without dose monitoring and that any information not released was either not relevant or not scientifically significant.

For the moment, the drug remains licensed for use in Europe as an anticoagulant, although the European regulator, the Europeans Medicines Agency has confirmed that if it is found that relevant information has been withheld, they will not hesitate to take action and to alter recommendations for use of the drug if appropriate.

Matthew Newbould, a lawyer at Irwin Mitchell who specialises in cases related to defective medical products including drugs, said: “Pradaxa presents an unusual legal situation because, in general terms, the scientific trial data does not really indicate that it performs significantly worse than competitors like Warfarin in terms of adverse bleeding, or in terms of its function as an anti-coagulant.

“Whilst concerns have been raised about the main source of the data – a trial carried out by Boehringer Ingelheim – these statistics would ordinarily mean that Pradaxa would be unlikely to be considered unsafe, or defective, and therefore legal action would not be likely to succeed in the event of an injury.

“However, if the BMJ is correct, the reality may be that although Pradaxa was a reasonable product, it was sold in an irresponsible way – with the result that it caused avoidable injury to some patients. If that is true, then injured patients may have rights of action against the manufacturer, or even the regulator, for deliberately or negligently withholding relevant information.

“While Boehringer Ingelheim denies that the studies were scientifically significant, the marketing principle of Pradaxa as a ‘one size fits all’ drug, seem to be at odds with at least some of the available facts.

Of more concern is the suggestion that internal documentation identified by the BMJ appears to suggest that Boehringer Ingelheim’s failure to release the information on dose monitoring was the result of a deliberate commercial strategy; in other words, that the need to sell drug drugs was prioritised over patient safety.

“Pradaxa has been associated with a number of adverse incident reports for major internal bleeds in the US and in the UK; how many of those cases could have been avoided by the effective use of dose monitoring and adjustments is a question which remains unanswered.

“For the moment, the facts are in dispute; however, there may well be rights to compensation for some patients who have suffered from internal bleeding through the use of this drug in the UK, particularly amongst older patients or those with pre-existing kidney function problems who might be less able to deal with the standard dose.”