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Drug company staff fretted when in-house paper’s conclusion clashed with marketing claims

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g1505 (Published 18 February 2014) Cite this as: BMJ 2014;348:g1505
  1. Michael McCarthy
  1. 1Seattle

When employees at the German drug firm Boehringer Ingelheim learnt that the conclusions of a company study clashed with a marketing claim that its new anticoagulant did not need monitoring, they sought to have the paper revised and even questioned whether it should be published at all, internal company documents released by a US court indicate.

In an email one employee, whose name was redacted, complained that the paper would harm the company’s marketing efforts and make discussions with regulatory agencies more difficult. “Can’t this be avoided?” the employee asked.

Another employee, Andreas Clemens, a medical team leader for the drug, wrote that he believed that the findings were important and should be published but with revision. “The world is crying for this information—but the tricky part is that we have to tailor the messages smart.”

In another email Clemens expressed concern that the paper “could be a liability issue” for the company.

The study involved dabigatran etexilate (marketed as Pradaxa), a thrombin inhibitor that is approved in the United States and Europe for the prevention of stroke and embolic events in patients with atrial fibrillation.

One of the drug’s main marketing claims is that, unlike the oral vitamin K antagonist warfarin, dabigatran does not require close monitoring of plasma concentrations to ensure that the patient’s dosage is in a safe and therapeutic range.

However, shortly after its introduction to the market, hundreds of adverse events involving hemorrhages began to be reported, and in 2012 dabigatran was the most frequently cited drug in direct reports of adverse events to the US Food and Drug Administration, second only to warfarin.

With both drugs hemorrhage was the most commonly cited side effect, but, unlike warfarin, whose effect can be reversed with vitamin K, dabigatran has no antidote.

Boehringer Ingelheim is now battling thousands of lawsuits filed by patients and their families who have claimed that the company did not adequately warn of the bleeding risk.

It was in connection to a class action lawsuit involving such claims that chief judge David Herndon of the US District Court in East St Louis, Illinois, ordered the release of the Boehringer Ingelheim documents.

The manuscript that alarmed the company’s employees described a pre-specified analysis of a pivotal study of the drug, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, which found dabigatran to be superior to warfarin in reducing the incidence of stroke and systemic embolism among patients with non-valvular atrial fibrillation.1

The analysis found considerable variation in plasma concentrations of the drug among patients, with lower levels being associated with a significantly increased risk of ischaemic stroke and higher levels with a significantly increased risk of “major bleeding.”

The manuscript concluded, “While a fixed dose of dabigatran has significant advantages in both safety and efficacy compared to warfarin, adjusting the dose at steady-state to attain an optimal plasma concentration range may further improve the benefit-risk ratio.”

This suggestion that monitoring the drug’s plasma concentration might be of benefit undercut an essential element of Boehringer Ingelheim’s marketing point that monitoring was unnecessary, wrote Jutta Heinrich-Nols, an international project manager for the company. She added in an email that it would “undermine our efforts to compete” with other novel oral anticoagulants competing for market share.

She wrote that “I cannot believe” that the company would release the paper after spending a decade developing a drug with the “clearly defined target of no monitoring needs.” She added, “This will make any defense of no monitoring to HA [health authorities] extremely difficult . . . and undermine our efforts to compete with other NOACs [novel oral anticoagulants].”

She concluded, “As I am not empowered to release or stop any publications I would like to ask you to check once again whether this is really wanted.”

Charles de Wet, medical director of Boehringer Ingelheim UK and Ireland, said in a statement to the BMJ, “We believe that the evidence shows that we have acted appropriately and responsibly and in the best interests of patients. We are ready to demonstrate the safety of our medicine and vigorously defend it against all associated product liability lawsuits.

“Our company discovered, developed, and launched this medicine because it brings an important benefit to patients. Its efficacy and safety were established in one of the largest stroke prevention trials, the RE-LY trial, which enrolled more than 18 000 patients.

“Our medicine is approved in over 100 countries worldwide. Both the US Food and Drug Administration and European Medicines Agency have stated the positive risk-benefit profile of Pradaxa, reaffirming that the treatment provides important health benefits for patients when used as directed to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.”

The revised paper was published online late last year in the Journal of the American College of Cardiology.2 It reports that safety and efficacy outcomes were correlated with plasma concentrations, with the patient’s age being the most important covariate.

It concluded, “There is no single plasma concentration range that provides optimal benefit-risk for all patients. The balance between stroke risk and bleed risk varied with concentration, suggesting that there is a subset of AF [atrial fibrillation] patients who may improve their benefit-risk balance with DE [dabigatran etexilate] by a tailoring of the dose in relation to patient characteristics.”

The BMJ asked for a statement from Heinrich-Nols. Duncan Cantor, a spokesman for Boehringer Ingelheim, said that this would not be possible because the lawsuit was ongoing. He said, “Unfortunately, as the documents and named individual are part of the ongoing process, I’m sure you can understand that we can’t provide an interview or further comment from [her].”

Notes

Cite this as: BMJ 2014;348:g1505

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