Fool Me Twice? - Boehringer Ingelheim, Medtronic Settle Lawsuits Alleging Deceptive Marketing

It seems like it has been really quiet on the legal settlement front in the US, but maybe corporate executives wanted to wait until things calmed down after the unofficial start of summer to let out news that some people might not think reflected well on them.  So this week it was time to announce two new legal settlements of allegations of bad behavior by corporate health were announced, as we will list in alphabetical order....<br /><br /><b>Boehringer Ingelheim Settles Suits Alleging it Hid Data About Pradaxa Harms</b><br /><br />As <a href="http://www.bloomberg.com/news/2014-05-28/boehringer-pays-650-million-to-end-blood-thinner-cases.html">per Bloomberg</a>,<br /><br /><blockquote class="tr_bq">Boehringer Ingelheim GmbH, the German family-owned drugmaker,<i> agreed to pay $650 million to settle the majority of lawsuits filed over its blood thinner Pradaxa, which has been linked to more than 500 patient deaths.</i></blockquote><br />The major allegations were about deception,<br /><br /><blockquote class="tr_bq"> Patients and their families alleged<i> Boehringer executives knew Pradaxa posed a deadly risk to some consumers when they brought it to the U.S. market in October 2010.</i></blockquote><br />In particular, as we <a href="http://hcrenewal.blogspot.com/2014/02/cant-this-be-avoided-how-corporate.html">discussed</a> in more detail in February, 2014, <br /><br /><blockquote class="tr_bq">Documents made public as part of patients’ Pradaxa suits showed <i>Boehringer officials didn’t disclose to U.S. regulators a data analysis that indicated the blood-thinning drug may have caused more fatal bleeding</i> after it was cleared for sale than in a study used to win approval.  </blockquote><br /><a href="http://www.nytimes.com/2014/05/29/business/international/german-drug-company-to-pay-650-million-to-settle-blood-thinner-lawsuits.html">Per </a>the New York Times, Boehringer Ingelheim executives continued to maintain<br /><br /><blockquote class="tr_bq">that it stood behind the safety and efficacy of Pradaxa and continued to believe that the lawsuits lacked merit, but that settling the case <i>allowed the company to move on.</i> 'Time and again, the benefits and safety of Pradaxa have been confirmed,' said Desiree Ralls-Morrison, senior vice president and general counsel of Boehringer Ingelheim USA.</blockquote><br />This is typical of most legal settlements involving large health care organizations, whether they end lawsuits brought by private parties or by the US government.  The settlements often allow the parties to continue to disagree, do not establish guilt or innocence, but leave one to wonder why executives would pay so much of admittedly other peoples' money just to "move on" without upholding their or their companies' honor, especially when documents revealed and legal findings made in cases prior to settlement remain unchallenged.<br /><br />So this settlement also comes after December, 2013, as we discussed <a href="http://hcrenewal.blogspot.com/2013/12/a-second-order-cover-up-judge-finds.html">here</a>, December, when a judge<br /><br /><blockquote class="tr_bq">ordered Boehringer to pay a $931,000 fine in December for <i>failing to preserve 'countless' files on Pradaxa’s development and marketing. Patients’ lawyers say Boehringer should have placed an effective 'litigation hold' on the documents</i>, forcing employees to preserve them.</blockquote><br />(The above <a href="http://www.bloomberg.com/news/2014-05-28/boehringer-pays-650-million-to-end-blood-thinner-cases.html">per Bloomberg</a>.)  That finding, which the settlement does not dispute, does not fill one with confidence about the openness and transparency of Boehringer Ingelheim managers.<br /><br />Also the settlement does not refute documents released during this litigation which suggested that Boehringer Ingelheim personnel tried to influence, or manipulate a company sponsored research paper to prevent it from contradicting the company's official marketing message that Pradaxa administration does not require monitoring of patients with blood tests (as we discussed <a href="http://hcrenewal.blogspot.com/2014/02/cant-this-be-avoided-how-corporate.html">here</a>).     <br /><br />Note further that this case comes only a few years after a case in which Boehringer Ingelheim settled allegations of deceptive marketing of drugs other than Pradaxa, as we discussed <a href="http://hcrenewal.blogspot.com/2012/10/just-another-day-at-office-boehringer.html">here</a>. <br /><br /><b>Medtronic Settles Suit Alleging Kickbacks to Physicians</b><br /><br />The most extensive and colorful <a href="http://www.startribune.com/business/260978651.html">report</a> was in the Minneapolis Star-Tribune, <br /><br /><blockquote class="tr_bq"><i>Medtronic Inc. will pay the U.S. Justice Department $9.9 million to settle a whistleblower lawsuit that accused the company of paying kickbacks to doctors for using its defibrillators and pacemakers.</i><br /><br />The alleged kickbacks, according to the newly unsealed suit, included '<i>gifts of wine and alcohol</i>' and '<i>trips to strip clubs</i>' paid for by the Fridley-based company. The lawsuit also says Medtronic paid to fly doctors to events in San Francisco, Las Vegas, New Orleans, New York, Minneapolis and other cities that some physicians used as 'a free vacation.'</blockquote><br />More colorful details,<br /><br /><blockquote class="tr_bq">The lawsuit, whose details remained secret until Tuesday, describes Medtronic <i>business plans with names such as 'Project Wildfire' that had sales representatives offer 'cash payments, expensive trips and meals, expensive gifts and entertainment to physicians as kickbacks in exchange for the physicians’ agreement to implant Medtronic devices.'</i><br /><br />The lawsuit alleged that Medtronic '<i>funneled millions of dollars in unrestricted grant money to physicians</i>' to get them to encourage the use of Medtronic defibrillators and pacemakers in patients whose 'mild heart failure symptoms did not meet [Food and Drug Administration] criteria for an implantable device.'<br /><br />Those procedures were not only unnecessary, the suit alleged, but potentially dangerous.<br /><br />The suit describes <i>payments of thousands of dollars in speaking fees to doctors for attending dinners at which they spoke for only a few minutes</i>, if at all. In other cases, <i>Medtronic allegedly prepared entire presentations that physicians offered almost verbatim.</i><br /><br />The suit talks of a plan that 'instructed sales representatives to personally review patient charts in friendly doctor’s offices' and to flag those patients the sales representative 'felt should receive an implant.'</blockquote><br />Note that commercially supplied "unrestricted grant money" is now the lifeblood of many ostensibly academic continuing medical education (CME) programs, but this case suggests that corporate executives may believe they are paying such money to get doctors to use their products.  Note further that many physicians defend their receipt of money in payment of talks they have given on behalf of commercial firms as fair payment for providing unbiased education, but this case suggests that corporate executives may believe they are paying such money for marketing, and/or to get the supposedly unbiased physician speakers to use their products.  <br /><br />Once again, the settlement did not resolve the allegations. <br /><br /><blockquote class="tr_bq"> Medtronic said it <i>did not admit that any of its activities were improper or illegal</i> and that the settlement would bring to a close a long-running review of events dating from 2001 to 2009.</blockquote><br />Also,<br /><br /><blockquote class="tr_bq"> Asked to comment specifically on the strip club allegations and the accusation that it financially facilitated unnecessary implantations, Medtronic<i> reiterated that its $9.9 million payment was not an admission that it had done anything illegal or improper.</i></blockquote><br />See my comments above.  Why would executives with even the slightest ability to feel shame not contest such allegations if they were untrue?  But maybe many of today's corporate health care executives are not capable of feeling shame, and of course they get to pay off these lawsuits with other peoples' money.<br /><br />By the way, this is just one of many Medtronic settlements.  As Bloomberg <a href="http://www.bloomberg.com/news/2014-05-28/medtronic-settles-suit-over-heart-device-kickback-claims.html">summarized</a>,<br /><br /><blockquote class="tr_bq"> Medtronic agreed in 2007 to <i>pay about $130 million to settle consumer suits accusing the device maker of hiding defects in its defibrillators</i>. The company agreed to a <i>$268 million settlement of suits in 2010 over allegations that fractured wires in another line of defibrillators caused at least 13 patient deaths.</i></blockquote><br />In fact, Medtronic has provided our blog with <a href="http://hcrenewal.blogspot.com/search/label/Medtronic">lots of material</a>.  We first <a href="http://hcrenewal.blogspot.com/2006/01/medtronics-payments-to-doctors-too.html">discussed</a> detailed and vivid allegations that Medtronic had been paying off doctors starting in 2003 here in 2006.  Medtronic has been involved in other lawsuits alleging various kinds of deception. <br />-  In 2011, it settled for $23.5 million two other federal lawsuits alleging it paid kickbacks to encourage physicians to implant its devices (look <a href="http://hcrenewal.blogspot.com/2011/12/medtronic-settles-yet-again.html">here</a>).   <br />- In 2008, Medtronic subsidiary Kyphon settled a suit for $75 million and signed a corporate integrity agreement for allegations that it defrauded Medicare through a scheme that lead to excessive hospitalization for patients who received the company's spine surgery device (link <a href="http://hcrenewal.blogspot.com/2008/05/corporate-integrity-agreement-for.html">here</a>)<br />- In 2006, Medtronic subsidiary Sofamor Danek settled for $40 million allegations that it gave kickbacks to doctors in the form of sham consulting fees and lavish trips (look <a href="http://hcrenewal.blogspot.com/2011/12/medtronic-settles-yet-again.html">here</a>). <br /><br />Yet we are now writing at the end of May, 2014, and Medtronic is still settling lawsuits involving vivid allegations of payoffs to physicians, and its executives are still saying nothing to see here, move on.<br /><br /><b>Summary</b><br /><br />These sorts of cases provide evidence that large health care corporations, including not just pharmaceutical companies, but biotechnology and medical device companies, commonly use deceptive and unethical practices to market their products.  Such marketing lets them charge high, even outrageous prices and sometimes results in patients getting expensive treatments that do them no good, or worse, that do more harm than good.  Some of the executives of these companies doubtless got large bonuses, and may have gotten millions in compensation partially because of the sales generated by these practices.  However, they get to walk away from such lawsuits without any personal accountability, just by paying out a few millions, or billions, of the company's, that is, other peoples' money.  They get do pay that money without any other explanation that it eliminates distractions and allows them to move on (with whatever they have already made).<br /><br />The more this goes on, the more health care dysfunction continues, and the more the health care oligarchy prospers.  As we have written many times,<br /><br /><blockquote class="tr_bq">penalties that only appear to be (relatively small) costs of doing business are unlikely to deter future bad behavior. Until the people who actually authorized, directed and implemented the bad behavior have to suffer some negative consequences, expect the bad behavior to continue.  Note that each of the companies discussed above have had their previous ethical lapses discussed in previous Health Care Renewal posts. <br /><br />The continuing march of <a href="http://hcrenewal.blogspot.com/search/label/legal%20settlements">settlements</a>, and sometimes <a href="http://hcrenewal.blogspot.com/search/label/crime">criminal</a> convictions involving major health care organizations should be regarded merely as providing a floor to estimates of the extent of bad behavior by large health care organizations. Bad behavior may not be reported, or lead to legal action, and legal action may not lead to settlements or convictions. However, it is amazing how many organizations that were once regarded as exemplary have had to settle, or plead guilty, or been convicted.<br /><br />When it comes to health care's leadership, society seems to have acceded to defining deviancy down. Until we start holding health care leaders to high standards, expect their organizations not to uphold high standards.</blockquote><br />(That version was from 2010, posted <a href="http://hcrenewal.blogspot.com/2010/10/last-weeks-scandals.html">here</a> re Medtronic's 2010 settlement. You heard it here first.  Medtronic is still settling, and according to its <a href="http://phx.corporate-ir.net/phoenix.zhtml?c=76126&p=IROL-secToc&TOC=aHR0cDovL2FwaS50ZW5rd2l6YXJkLmNvbS9vdXRsaW5lLnhtbD9yZXBvPXRlbmsmaXBhZ2U9OTAwMDI5NiZzdWJzaWQ9NTc%3d&ListAll=1">most recent proxy</a>, from 2013, the annual total compensation of its CEO was last reported to be <b><i>$8,975,886</i></b>.) <br /><br /><br />

Fool Me Twice? - Boehringer Ingelheim, Medtronic Settle Lawsuits Alleging Deceptive Marketing

It seems like it has been really quiet on the legal settlement front in the US, but maybe corporate executives wanted to wait until things c...

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Clinical Trial Prestidigitation - Making Old Data Look Worse So New Data Looks Better

Prestidigitation, also known as <a href="http://en.wikipedia.org/wiki/Sleight_of_hand">sleight of hand</a> or legerdemain, is a form of stage magic which uses dextrous manipulation and misdirection to distract the viewer from seeing it. <br /><br />The example, <a href="http://www.bloomberg.com/news/2014-02-25/boehringer-kept-pradaxa-analysis-from-fda-records-show.html">reported</a> by Bloomberg on 26 February, 2014, is discussed late because the nature of the trick meant it took me a while before I understood how it was done.<br /><br /><b>Background</b><br /><br />Pradaxa, a new anticoagulant, was approved by the US Food and Drug Administration (FDA) in 2010 for use by patients with atrial fibrillation to prevent strokes.  We <a href="http://hcrenewal.blogspot.com/2014/02/cant-this-be-avoided-how-corporate.html">discussed</a> previously the release of documents during litigation that showed how marketers from its manufacturer, Boehringer - Ingelheim, attempted to manipulate the results of a clinical study of the drug.  The study results initially seemed to suggest that blood tests should be used to monitor therapy with it.  However, that would have contradicted a key marketing message, that Pradaxa was more convenient than warfarin because it did not require blood tests for monitoring.<br /><br />Litigation by patients alleging that Boehringer-Ingelheim concealed the severity of the bleeding risks caused by the drug<br />continues.  The Bloomberg <a href="http://www.bloomberg.com/news/2014-02-25/boehringer-kept-pradaxa-analysis-from-fda-records-show.html">report</a> dealt with how the company responded to requests by the FDA for data about these risks.   <br />  <br /><b>The Question from the FDA</b><br /><br />As per Bloomberg,<br /><br /><blockquote class="tr_bq">In the Pradaxa case, the regulators asked Boehringer to compare fatal bleeding reports received by the FDA against the number of patients using the drug in order to establish a death rate. The request was made to allow the FDA to 'evaluate the need for modifications to the Pradaxa label or future study,' according to a letter made public as part of the court files.<br /><br /> The company reported back that 6.1 of every 10,000 patients who used the drug after approval developed fatal bleeding, the court documents showed. The regulators also asked Boehringer to reanalyze results from an earlier study used to gain approval to see how that rate compared. </blockquote><br />So, in other words, the FDA wanted to assess the rate of bleeding reflected by reports received after the drug had gone on the market (that is, the FDA was evaluating data from post-marketing surveillance.)  To do so, it wanted to calculate the proportion of patients who took the drug who developed fatal bleeding.  Then it wanted to compare this rate to the rate of fatal bleeding found in the previous controlled trials of the drug done by the manufacturer to secure drug approval.  Note that these trials are also considered the major source of clinical research evidence about the benefits and harms of the drug.<br /><br />The major source of clinical evidence about Pradaxa (dabigatran) was the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), sponsored by Boehringer-Ingelheim, published in the New England Journal of Medicine [Connolly SJ, Ezekowitz MD, Yusuf S et al.  Dabigatran versus warfarin in patients with atrial fibrillation.  N Engl J Med  <span class="citation">2009; 361:1139-1151.  Link <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa0905561">here</a>.]   The trial reported that the rates of life-threatening bleeding were 1.8% per year for warfarin, 1.45% for high dose dabigatran, and the rates of major bleeding of 3.36% versus 2.21%.  However, the trial report did not include rates of fatal bleeding per se, nor the rates of patients with major bleeding who then died.   </span><br /><br /><b>Presto Chango</b><br /><br />According to Bloomberg, here is how Boehringer-Ingelheim responded to the question from the FDA about the rate of fatal bleeding.<br /><br /><blockquote class="tr_bq"><i>That effort produced two separate analyses</i> by the company, according to the unsealed court documents. One, looking only at <i>people whose primary cause of death was bleeding, found 5.8 of 10,000 patients died per year</i>. The other, which included anyone who <i>had a major bleeding event and died for any reason, found a rate of 19.5 fatal events per 10,000 patients per year,</i> the documents show.<br /><br /> The report sent to the FDA, though, <i>contained only the analysis indicating the death rate from the earlier research was much higher than the numbers seen after approval,</i> according to the court filings. Potentially, such a finding <i>could head off any after-market action by the FDA because the data showed the drug was safer after it was approved and widely used.   </i></blockquote><br />So, to recapitulate, Boehringer-Ingelheim used results from the RE-LY trial to persuade the FDA that its new drug was safe and effective.  However, the company did not include, at least in the results reported publicly, any measure of fatal bleeding in patients given the drug.  It now appears that the rate of major bleeding in patients who subsequently died was high, perhaps high enough to have raised questions about the safety of the drug prior to approval, had it been revealed.<br /><br />However, after the drug had been approved, when the question was about rates of severe bleeding after the drug had been marketed, the company furnished an analysis of data from the clinical trial that now showed a very high bleeding rate. That was the major misdirection, the sleight of hand.. It would make the rate of fatal bleeding in the post-marketing surveillance data appear low.  <br /><br />But apparently this data also kept the eyes of the FDA focused on the question of bleeding in the post-marketing period.  Did no one in the FDA notice that while this high rate of bad bleeding in the trial made the post-marketing surveillance look good, it also raised questions about whether the drug should have been thought to have been safe enough to be approved in the first place?   <br /><br /><br />By the way, Bloomberg also reported that Boehringer-Ingelheim performed a trick for European regulators,  <br /><br /><blockquote class="tr_bq"><i>Selective disclosure of Pradaxa information may have camouflaged a serious safety signal</i>, according to an assessment report from <a href="http://www.ema.europa.eu/ema/" rel="external" title="Open Web Site">European Medicines Agency’</a>s Committee for Medicinal Products for Human Use in August 2012. That agency is the European Union’s drug regulator.<br /><br />Boehringer also didn’t give the EMA the figures showing that real-world bleeding rates were higher when the committee conducted a similar review and published a report in August 2012. The panel’s analysis, which concurred with Boehringer’s, concluded that Pradaxa’s bleeding risks among the general population were 'substantially less' than the rates seen in the study the drugmaker used as the basis for approval. It didn’t have the analysis showing the risk was higher using a different approach, according to the unsealed files. <br /> <br />'If the reporting rate in the post-marketing phase had been higher than in' Boehringer’s study, 'there would clearly have been a safety concern,' agency officials wrote. </blockquote><br /><b>Summary</b><br /><br />We have discussed a variety of ways that companies that sell health care goods (like drugs or devices) and services may <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulate clinical research</a> to make their products look better than they may actually be.  It appears that these companies may hire very clever people who are very knowledgeable about the design of clinical research to game the system to aid marketing, but meanwhile obfuscate the clinical research data that clinicians and patients rely on to make clinical decisions in the best interests of patients, and that policy makers rely on to make decisions in the best interests of the public.  So far, the hands of the corporate marketers seem to be quicker than the eyes of the clinicians, patients, and policy makers. <br /><br />I wonder, though, how those very clever people sleep well at night knowing that their talents for legerdemain are being used to increase revenues and make corporate insiders rich, at the expense of patients, and of patients' health? <br /><br />As I have said before, and most recently in the context of <a href="http://hcrenewal.blogspot.com/2014/02/cant-this-be-avoided-how-corporate.html">discussing</a> the previous example of manipulation of clinical research to support Pradaxa marketing,  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 <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppressed</a>)  Reviews, meta-analyses, and guidelines that were not so based on extremely critical review should also be viewed with a jaundiced eye.  <br /><br />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. <br /><br />Hat tip to <a href="http://1boringoldman.com/index.php/2014/02/26/foot-in-mouth-disease/">1BoringOldMan</a>.

Clinical Trial Prestidigitation - Making Old Data Look Worse So New Data Looks Better

Prestidigitation, also known as sleight of hand or legerdemain, is a form of stage magic which uses dextrous manipulation and misdirection ...

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"Can't This be Avoided?" - How Corporate Marketers Manipulated a Clinical Research Report to Avoid "Undermining" Marketing Messages

Documents newly made public in the course of litigation about the drug Pradaxa show granular details about how clinical research may be manipulated by corporate research sponsors intent on marketing their products.<br /><br /><b>Background</b><br /><br />As <a href="http://www.nytimes.com/2014/02/06/business/study-of-blood-clot-drug-pradaxa-unnerved-its-maker-documents-suggest.html">reported</a> 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.  <br /><br /><blockquote class="tr_bq">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.<br /><br /><div class="story-body-text story-content" data-para-count="190" data-total-count="2310" itemprop="articleBody">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.</div></blockquote><div class="story-body-text story-content" data-para-count="190" data-total-count="2310" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="190" data-total-count="2310" itemprop="articleBody">However,</div><div class="story-body-text story-content" data-para-count="190" data-total-count="2310" itemprop="articleBody"></div><div class="story-body-text story-content" data-para-count="190" data-total-count="2310" itemprop="articleBody"> </div><blockquote class="tr_bq"><div class="story-body-text story-content" data-para-count="180" data-total-count="747" itemprop="articleBody">Since its approval in 2010, the drug, <a href="http://www.nytimes.com/2012/11/03/business/a-rising-anti-stroke-drug-is-tied-to-risk-of-bleeding-deaths.html" title="From the archives.">which can cause fatal bleeding</a>, has brought in more than $2 billion in sales in the United States, according to the research firm IMS Health. </div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody">It has been prescribed to 850,000 patients, but has also been linked to more than 1,000 deaths. </div></blockquote><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"><b>Internal Documents Show the Influence of Marketers on a Clinical Research Report</b></div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody">As summarized by the NY Times, </div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"><br /></div><blockquote class="tr_bq"><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"> 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.</div></blockquote><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody">In particular,</div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="96" data-total-count="843" itemprop="articleBody"> </div><blockquote class="tr_bq"><div class="story-body-text story-content" data-para-count="463" data-total-count="2773" itemprop="articleBody">The documents show that Boehringer Ingelheim employees <i>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</i>. 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.</div><div class="story-body-text story-content" data-para-count="463" data-total-count="2773" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="272" data-total-count="3045" itemprop="articleBody"><i>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.</i></div><div class="story-body-text story-content" data-para-count="149" data-total-count="3194" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="149" data-total-count="3194" itemprop="articleBody">As Dr. Reilly’s draft paper circulated within the company, some employees <i>questioned what the marketing implications</i> of such a conclusion would be.</div><div class="story-body-text story-content" data-para-count="269" data-total-count="3463" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="269" data-total-count="3463" itemprop="articleBody">One company supervisor, Dr. Jutta Heinrich-Nols, wrote in an email to other employees that <i>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.</i></div><div class="story-body-text story-content" data-para-count="185" data-total-count="3648" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="185" data-total-count="3648" itemprop="articleBody">Publishing the research results, she warned, could <i>make it 'extremely difficult' for the company to defend its long-held position to regulators that Pradaxa did not require testing</i>.</div><div class="story-body-text story-content" data-para-count="183" data-total-count="3831" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="183" data-total-count="3831" itemprop="articleBody">And, Dr. Heinrich-Nols added in the email, the research, if known, would <i>'undermine' the company’s efforts to compete with other new anticoagulants, such as Xarelto and Eliquis.</i></div><div class="story-body-text story-content" data-para-count="183" data-total-count="3831" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"> 'I would like to ask you to <i>check again whether this is really wanted</i>,' she wrote about publishing the research.</div></blockquote><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody">A second NY Times <a href="http://www.nytimes.com/2014/02/08/business/new-emails-in-pradaxa-case-show-concern-over-profit.html">article</a> added more details,</div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"></div><div class="story-body-text story-content" data-para-count="176" data-total-count="2486" itemprop="articleBody">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.</div><div class="story-body-text story-content" data-para-count="269" data-total-count="2755" itemprop="articleBody"><br /></div><blockquote class="tr_bq"><div class="story-body-text story-content" data-para-count="269" data-total-count="2755" itemprop="articleBody">'This may not be a onetime test and could result in <i>a more complex message (regular monitoring), and a weaker value proposition … vs. competitors,</i>' wrote the employee, whose name was redacted in accordance with privacy laws in Germany, where the company is based.</div><div class="story-body-text story-content" data-para-count="269" data-total-count="2755" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="453" data-total-count="3208" itemprop="articleBody">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 <i>there was an informed decision NOT to develop this</i>.' The employee continued, '<i>this would go against the ‘no monitoring’ idea/claim.'</i></div><div class="story-body-text story-content" data-para-count="453" data-total-count="3208" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="231" data-total-count="3439" itemprop="articleBody">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 <a href="https://content.onlinejacc.org/article.aspx?articleid=1748241&resultClick=24">published on Tuesday</a> but with some details removed.</div><div class="story-body-text story-content" data-para-count="231" data-total-count="3439" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="198" data-total-count="3637" itemprop="articleBody">'This publication will <i>more harm than be useful for us, neither in the market but be especially harmful in the discussions with regulatory bodies</i>,' one email read. '<i>Can’t this be avoided</i>?'</div></blockquote><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"> </div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody">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 <i>should</i> be varied according to blood test.  </div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody">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.   </div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody">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. </div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"><b>Was the Manipulation Successful?</b></div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"><br /></div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody">A Medscape <a href="http://www.medscape.com/viewarticle/820324">article</a> noted that the published version of the research article </div><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody"><br /></div><blockquote class="tr_bq"><div class="story-body-text story-content" data-para-count="116" data-total-count="3947" itemprop="articleBody">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. </div><br />The researchers concluded that 'the magnitude of the effect of dabigatran plasma concentrations on outcomes in atrial-fibrillation patients in <b> <a href="http://www.medscape.com/viewarticle/708133" target="_blank">RE-LY</a> </b> 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. </blockquote><br />However,<br /><br /><blockquote class="tr_bq">In the paper, <i>there are no references to the optimal plasma concentration of dabigatran,</i> 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 <a href="http://www.medscape.com/viewarticle/812871">here</a>.]</blockquote><br />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. <br /><br />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. <br /><br /><b>Conclusions</b><br /><br />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.<br /><br />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 <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">examples of apparent manipulation of clinical research</a>, <br /><br />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.<br /><br />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 <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppressed</a>)  Reviews, meta-analyses, and guidelines that were not so based on extremely critical review should also be viewed with a jaundiced eye.  <br /><br />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. 

"Can't This be Avoided?" - How Corporate Marketers Manipulated a Clinical Research Report to Avoid "Undermining" Marketing Messages

Documents newly made public in the course of litigation about the drug Pradaxa show granular details about how clinical research may be mani...

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A Second Order Cover Up? - Judge Finds Boehringer Ingelheim Allowed Destruction of Records Bearing on Allegations of Cover Up of Drug Adverse Effects

This case generated little coverage, a story in Bloomberg, and a <a href="http://www.pharmalive.com/boehringer-is-fined-nearly-1m-for-disappearing-documents">post</a> on PharmaLot, but perhaps should have received more attention.<br /><br /><b>Background - the Pradaxa Case </b><br /><br />The background, per Bloomberg, is that<br /><br /><blockquote class="tr_bq">Boehringer [Ingelheim BmbH] is preparing to face the first federal court trial of <i>claims that it hid Pradaxa’s bleeding risks. </i></blockquote>Pradaxa is dabigatran, a new anti-coagulant drug that can be used without frequent monitoring of blood tests, as is required when using the older drug warfarin.  However, unlike warfarin, the effects of dabigatran cannot be quickly reversed should a patient on the drug start to bleed. <br /><br />The reason for the trial is that<br /><br /><br /><blockquote class="tr_bq">Patients and their families <i>alleged that Boehringer executives knew Pradaxa posed a deadly risk to some consumers </i>when they brought the drug to the U.S. market in October 2010. Unlike older blood thinners, researchers said, Pradaxa has no antidote to reverse its effects, which can lead to so-called bleed-out deaths. <br /><br />Pradaxa has <i>generated more than $1 billion in sales worldwide</i> for Boehringer, the world’s biggest family-owned drugmaker. Researchers have found it more effective at preventing strokes than older competitors, including Bristol-Myers Squibb Co.’s Coumadin. <br /><br />Consumers’ lawyers contend that Boehringer officials marketed the drug as superior to existing blood thinners when they knew its performance was not better than similar medicines. <br /><br /><i>Pradaxa has been linked to more than 500 U.S. deaths over a two-year period</i>, and Boehringer faces claims that it sold the drug knowing the medicine could cause bleed-outs among some patients, according to a federal panel that tracks consolidated cases. </blockquote><br /><b>The Judge Found that by Letting Documents Vanish, the Company Committed "Egregious Wrongs" </b><br /><br />The trial has not yet begun, and the allegations by the plaintiffs are unproven.  However, Boehringer Ingelheim already is the subject of a finding by the judge,<br /><br /><blockquote class="tr_bq"><i>Boehringer Ingelheim GmbH  GmbH, the German family-owned drugmaker, withheld or failed to preserve 'countless' files sought by patients suing over the company’s blood thinner Pradaxa and must pay a fine of almost $1 million, a judge ruled. </i><br /><br />U.S. District Judge David Herndon in East St. Louis, Illinois, who’s overseeing more than 1,700 consolidated lawsuits over claims that Pradaxa caused excessive and sometimes fatal bleeding, <i>concluded that Boehringer executives acted 'in bad faith' by failing to ensure that documents and files about the drug’s development and marketing were preserved.</i> <br /><br /><b><i>'The wrongs here are egregious,</i></b>' Herndon said in yesterday’s ruling. 'The gross inadequacy' of the company’s efforts to safeguard the documents justified a sanction of more than $931,000 against Boehringer, the judge said. </blockquote><br />The ruling apparently affirmed allegations made by the plaintiffs' lawyers,<br /><br /><blockquote class="tr_bq">The company can’t produce files of a high-level scientist involved in developing Prada’s or documents by consultants who worked on the marketing plan, patients’ lawyers alleged in court filings. The company also failed to order employees to save phone messages about their work on the medicine, they added. </blockquote><br />Of course, Boehringer Ingelheim contended otherwise,<br /><br /><blockquote class="tr_bq"> Boehringer said it has made 32 million pages of material about the drug available to the plaintiffs and has been bombarded with 'overly burdensome' document requests by patients’ lawyers, according to court filings. The company also argued that many of the documents sought by the plaintiffs’ attorneys are not relevant to the claims at issue. </blockquote><br />The judge vigorously disagreed,<br /><br /><br /><blockquote class="tr_bq">In his 51-page ruling, Herndon said he was forced to deal with claims that Boehringer was improperly withholding documents from the inception of the case consolidation in 2012. Pradaxa suits filed in federal court across the country were gathered before Herndon for pretrial information exchanges.<br /><br /><i>Boehringer officials 'made misrepresentations' about their efforts to preserve documents and failed to take obvious steps to preserve files and other records, the judge said. </i><br /><br />Boehringer executives 'failed to ensure the auto-delete feature of their employee cellphones, company owned and personal, was disengaged for the purpose of preserving text messages,'  Herndon said. This move <i>'allowed countless records to be destroyed.'</i> </blockquote><br /><b>Summary</b><br /><br />We have now discussed numerous examples of what appears to be organized <a href="http://hcrenewal.blogspot.com/search/label/deception">deception</a> by health care organizations about their products or their conduct.  Recent examples included a settlement by Johnson and Johnson of a case alleging its subsidiary had hid evidence about problems with a device for sterilization of endoscopes (look <a href="http://hcrenewal.blogspot.com/2013/12/how-many-straws-johnson-and-johnson.html">here</a>), and just before that a settlement in cases in which the same company was alleged to have hidden evidence about problems with a prosthetic hip device, and the drug Topamax (look <a href="http://hcrenewal.blogspot.com/2013/11/there-they-go-again-again-johnson-and.html">here</a>).<br /><br />The current case is an example of a second order deception, covering up an alleged cover up of a drug's adverse effects.  <br /><br />It appears that a culture of deception has taken hold in many of the world's most important health care organizations.  Deception and dishonesty may be seen as acceptable if it increases revenue, and hence the enrichment of top company insiders.  This seems to be the natural result of the belief that revenue is the only important goal, a product of the <a href="http://hcrenewal.blogspot.com/search/label/financialization">financialization</a> of the world produced by the <a href="http://hcrenewal.blogspot.com/2012/04/health-care-dysfunction-explained-by.html">shareholder value ideology</a> that dominates most Western business schools.  Pope Francis had a <a href="http://world.time.com/2013/11/26/pope-francis-denounces-idolatry-of-money-and-tyranny-of-capitalism/">more incisive description</a> of it, "the idolatry of money."<br /><br />Without vigorous efforts to discover and counteract the countless deceptions that big health care organizations use to make more money and make their executives richer, we will continue to pay ever more for ever poorer results for patients' and the public's health.<br /><br />Roy M. Poses MD for Health Care Renewal

A Second Order Cover Up? - Judge Finds Boehringer Ingelheim Allowed Destruction of Records Bearing on Allegations of Cover Up of Drug Adverse Effects

This case generated little coverage, a story in Bloomberg, and a post on PharmaLot, but perhaps should have received more attention. Backgr...

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