Thursday, 6 February 2014

Study of Drug for Blood Clots Caused a Stir, Records Show

The makers of the blood-thinning drug Pradaxa were so worried that an internal research paper would damage drug sales that some employees not only pressured the author to revise it, but suggested it should be quashed altogether, according to newly unsealed legal documents.
The documents were made public last week by a federal judge in Illinois who is overseeing thousands of lawsuits filed by patients and their families, who say that Pradaxa’s manufacturer, the German company Boehringer Ingelheim, failed to properly warn them about the risks of taking the drug.
Since its approval in 2010, the drug, which can cause fatal bleeding, has brought in more than $2 billion in sales in the United States, according to the research firm IMS Health.
It has been prescribed to 850,000 patients, but has also been linked to more than 1,000 deaths.
Boehringer Ingelheim has stood by the drug, noting that the Food and Drug Administration has upheld its safety and that its value has been proved in clinical trials.
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Documents show that some of Pradaxa’s employees openly fretted about the marketing implications of the study.
Many of the documents released by Chief Judge David R. Herndon of the United States District Court in East St. Louis, which included emails, memos and internal presentations, centered on whether a coming research paper would undercut one of Pradaxa’s main selling points: that it does not require regular blood tests to ensure it is working.
The issue has been hotly debated among heart and stroke specialists, in part because not all people — especially older patients — metabolize the drug the same way, and because there are fewer dose options as well as no tests available for Pradaxa in the United States to monitor those who might be most at risk. An additional dose and a test are available in Europe.
Testing is a critical issue because Pradaxa and two other recently approved drugs, Xarelto and Eliquis, are in a race to gain market share from warfarin, a generic drug that for decades has been the standard treatment for preventing blood clots and strokes. 

Many patients viewed the older warfarin as a nuisance because it requires frequent blood tests and careful attention to diet and other drugs.
The new drugs do not require such monitoring, yet claim to be as good, or better, at preventing strokes and blood clots in patients with a heart-rhythm disorder known as atrial fibrillation.
The documents show that Boehringer Ingelheim employees openly fretted when it appeared that the results of the research paper, written by Paul A. Reilly, a clinical program director at the company, indicated that some patients could benefit from monitoring of their blood. A certain segment of patients, the paper found, absorb too little of the drug to effectively prevent strokes, while another group absorbs so much that they are at a higher risk for bleeding.
In a draft version of the paper included in the court records, Dr. Reilly and his co-authors detailed specific levels of how much Pradaxa should be in a patient’s bloodstream, and said that keeping some patients within that range would help prevent strokes and bleeding.
As Dr. Reilly’s draft paper circulated within the company, some employees questioned what the marketing implications of such a conclusion would be.
One company supervisor, Dr. Jutta Heinrich-Nols, wrote in an email to other employees that she could not believe the company was planning to publish research that would negate a decade’s worth of work proving that patients taking Pradaxa would not need regular tests.
Publishing the research results, she warned, could make it “extremely difficult” for the company to defend its long-held position to regulators that Pradaxa did not require testing.
And, Dr. Heinrich-Nols added in the email, the research, if known, would “undermine” the company’s efforts to compete with other new anticoagulants, such as Xarelto and Eliquis.
“I would like to ask you to check again whether this is really wanted,” she wrote about publishing the research.
Another company leader, Dr. Andreas Clemens, questioned whether legal repercussions would arise if Dr. Reilly’s paper detailed a specific range where the drug worked best. “Maybe I am phobic, but I am not happy with the conclusion,” he wrote.
Still, some of the same employees acknowledged that Dr. Reilly’s paper addressed serious concerns that doctors were raising outside the company. “The world is crying for this information — but the tricky part is that we have to tailor the messages smart,” Dr. Clemens wrote in a separate email.
In emails, Dr. Reilly defended his conclusions, saying the research showed that a minority of patients might benefit from blood testing. “I think we just need to make the message clear,” he said. Dr. Reilly declined to comment, referring questions to the company’s public relations department.
The documents highlight how much information about drug safety is in the hands of people with a financial interest in the outcome, some drug industry observers said.
“With these drugs, this is a really tough call,” said Dr. Lisa M. Schwartz, a professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice.
“In these situations, where the stakes are really high, how crazy is it that it’s in the hands of people who are so conflicted?” she asked.
Dr. Reilly’s paper was published Tuesday in the Journal of the American College of Cardiology, and although many of the conclusions in the draft version remained, references to a patient’s optimal blood-level range no longer appear in the article.
In a statement, representatives for Boehringer Ingelheim said the recently unsealed documents “represent small fragments of the robust discussion and debate that is a vital component in all scientific inquiry, and in the research and development of any important medication such as Pradaxa.” The company said the changes to the manuscript were made as the scientists’ thinking evolved, and they ultimately concluded that no single blood-level range is ideal for all patients.
Lawyers for the plaintiffs declined to comment.
Pradaxa is approved in a 150-milligram dose, as well as a lower 75-milligram dose for patients with low kidney function. But unlike European regulators, the F.D.A. did not approve a 110-milligram dose because the agency felt the lower dose would not benefit most patients.
Boehringer Ingelheim continued to pursue the approval of the 110-milligram dose even after the higher dose was approved, but the company said it abandoned the effort after concluding that a proposed study and other analyses were not feasible.
Some doctors applauded Boehringer Ingelheim for finally addressing an area of intense interest among cardiologists. Dr. Hugo ten Cate, a professor of medicine at Maastricht University Medical Center in the Netherlands who has called for more monitoring of patients on the new blood thinners, said there had been a “lively discussion” about this issue.
“The company was initially reluctant to recommend anything about monitoring, because they were claiming you no longer have to monitor anymore,” said Dr. ten Cate, who said he had received payments from Boehringer Ingelheim and other companies to speak on such issues, and who also heads a Dutch association of warfarin-testing clinics. “But now, they’ve gradually come back a little bit.”
Others said the newly released documents show that drug makers and regulators had been too eager to approve such powerful drugs without more careful monitoring.
“The one-size-fits-all was a mistake for a drug with this kind of risk,” said Thomas J. Moore, a senior scientist at the Institute for Safe Medication Practices, which keeps track of safety reports submitted to the F.D.A. He rated anticoagulants — including warfarin and Pradaxa — as the most serious safety problem in 2011 and 2012. He said Pradaxa has been cited in more than 1,000 deaths reported to the agency through the end of 2012.