As reported by the New York Times, the litigation is over allegations by thousands of patients and families that privately held Boehringer Ingelheim concealed the bleeding risks of the anticoagulant drug Pradaxa.
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.
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.
Internal Documents Show the Influence of Marketers on a Clinical Research Report
As summarized by the NY Times,
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 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.
A second NY Times article added more details,
In one email, from June 2012, an employee wonders about the implications of internal research showing that blood levels of Pradaxa could vary significantly in a single patient.
'This may not be a onetime test and could result in a more complex message (regular monitoring), and a weaker value proposition … vs. competitors,' wrote the employee, whose name was redacted in accordance with privacy laws in Germany, where the company is based.In another, an employee — whose name was also removed — asks about whether a newly available blood test in the United States might be useful for doctors treating patients with Pradaxa, which is also known as dabigatran. Another replies that such a test could be developed 'in-house,' but '2 years ago there was an informed decision NOT to develop this.' The employee continued, 'this would go against the ‘no monitoring’ idea/claim.'Employees also continued to question the merits of allowing a research paper to be published showing that some patients could benefit from monitoring of their blood. The paper was published on Tuesday but with some details removed.'This publication will more harm than be useful for us, neither in the market but be especially harmful in the discussions with regulatory bodies,' one email read. 'Can’t this be avoided?'
So, in summary, Pradaxa has been marketed basically on its convenience, as a drug whose dosage need not be customized according to frequent blood tests, in contrast to cheaper generic warfarin whose dosage may need adjustment according to frequent blood tests. Yet a clinical trail sponsored by Boehringer Ingelheim, the manufacturer of Pradaxa, seemingly showed that its risk of bleeding might be dependent on its blood level, and hence perhaps that its dosage should be varied according to blood test.
However, the manuscript reporting the results of this trial was apparently subject to vetting by multiple company managers whose specific concerns were whether the results of this research "undermined" the marketing message, and hence whether these results should be changed or suppressed to avoid contradicting the company's intended marketing message.
Let me try to add some context, based on my experiences in academic medicine writing research papers, commenting on colleagues' papers, and reviewing papers for journals. Considerable discussion among the researchers and clinicians involved in research projects about how manuscripts are worded is the norm. However, working a perhaps more innocent era, input from people with vested interests in the project producing a particular result was unheard of. Many health care professionals thus may still act based on the idealistic assumption that clinical research reports are all about science, and not about marketing.
Was the Manipulation Successful?
A Medscape article noted that the published version of the research article
found ischemic stroke and bleeding risks were correlated with plasma concentrations of the drug in 9183 patients treated with dabigatran 110 mg or 150 mg twice daily (the available European doses). In their logistic regression analysis, the risk of ischemic stroke was inversely associated with trough concentrations of dabigatran.
The researchers concluded that 'the magnitude of the effect of dabigatran plasma concentrations on outcomes in atrial-fibrillation patients in RE-LY depends strongly on demographic factors, most importantly increasing age.' However, the results also confirmed a wide therapeutic range among those treated with dabigatran, with a more than fivefold variation in plasma concentrations. The researchers concluded there might be a subset of patients who could improve their risk/benefit profile by tailoring the dose of dabigatran.
In the paper, there are no references to the optimal plasma concentration of dabigatran, although such statements were in various drafts that circulated throughout the company, according to the New York Times. When the paper was published online in October, Reilly told Reuters news that the 'there is no single plasma concentration range that provides optimal benefit-risk for all patients" and that "no monitoring is necessary.' [see relevant Medscape article here.]
So it does appear that the final version of the article included a discussion that was influenced by the marketers' wishes that the results would not appear to contradict the marketing party line.
A rigorous review of the article might have suggested that varying the dosage of the drug according to its blood level might reduce bleeding risk, and hence increase its benefits versus its harms. However, a casual reading might not have revealed that the data in the study undermined the marketing message that Pradaxa is a better drug than warfarin because it can be given at a fixed dose without the need for inconvenient blood tests. Thus, the efforts by the marketers to alter the dissemination of the clinical research to support marketing messages and increase sales of the drug and resulting revenues - never mind what the data showed - appeared to be successful.
This case study, only made possible by the public release of internal corporate documents in the course of litigation, suggests that in retrospect the dissemination of the results of one particular clinical trial were manipulated in a somewhat subtle way so that the data would not contradict a marketing message that now appears rather fictional.
In the absence of litigation, and of a judge willing to make public documents that one party to the litigation doubtless wanted to hide, the manipulation of this particular study might never have been apparent. Most clinical research is now sponsored by health care corporations with vested interests in how the research turns out. Much of this research could be manipulated by corporate marketers who wish it to support their marketing messages, the truth be damned. We (and others) have discussed many examples of apparent manipulation of clinical research,
However, it is unlikely that we, physicians, health care professionals, health care researchers and policy makers, and the public, will ever know for such which studies were manipulated. At best, very critical, skeptical, rigorous review can suggest which studies might have been manipulated. In the absence of such review, we are in danger of being swamped in a morass of manipulated research, and thus lead to make clinical decisions that are based mainly on hucksterism, not science.
Thus, I strongly advocate that those who author authoritative systematic reviews, meta-analyses, and clinical practice guidelines base their work on extremely rigorous, skeptical reviews that assume the likelihood that all commercially sponsored published clinical research has been manipulated (and that research that even post manipulation could not be twisted to support marketing many have been suppressed) Reviews, meta-analyses, and guidelines that were not so based on extremely critical review should also be viewed with a jaundiced eye.
Perhaps it is possible to devise legal and regulatory methods to at least make such manipulation more transparent. Maybe this case, however, should again suggest that clinical research, that is, research on human beings, should be completely separated from those with vested interests in selling products or services which could be better hyped were the research turn out in their favor.