healthy4u: Neurontin

Justice Delayed is Justice Denied? - Another Neurontin Settlement by Pfizer 20 Years After the Alleged Events

We have argued repeatedly against the strategy used by US government authorities to address allegations of bad behavior in health care (and elsewhere) by pursuing monetary <a href="http://hcrenewal.blogspot.com/search/label/legal%20settlements">settlements</a> against the companies involved, rather than trying to impose penalties on the people who may have done wrong.  There are many apparent things wrong with this approach (which we will rant about again below), but one aspect that deserves more attention is its slowness. The Latest Pfizer Settlement For example, Bloomberg <a href="http://www.bloomberg.com/news/2014-06-02/pfizer-agrees-to-325-million-settlment-over-neurontin.html">reported</a> in early June about yet another settlement by Pfizer of allegations about the marketing of the drug Neurontin (gabapentin, made by its Parke-Davis subsidiary): <blockquote class="tr_bq">Pfizer Inc agreed to pay $325 million to settle a lawsuit brought by health-care benefit providers who claimed the drugmaker marketed the epilepsy drug Neurontin for unapproved uses. The settlement, which needs approval from a federal judge in Boston<a href="http://topics.bloomberg.com/boston/"></a>, would end a case over claims that the company’s Parke-Davis unit schemed to market the drug for unapproved conditions as early as 1994. </blockquote> Thus this settlement occurred 20 years after the first actions were alleged to have occurred. Officially, "Pfizer Didn't Admit Wrongdoing" Despite Allegations of Kickbacks Otherwise, this particular settlement appears unremarkable.  As is typical, the federal authorities and the judge allowed a settlement which obscures what really happened, because, <blockquote class="tr_bq">The Boston accord will resolve 'all third-party payer claims regarding off-label promotion' and state antitrust claims over Neurontin sales, Steve Danehy, a company spokesman, said in a statement. Pfizer didn’t admit wrongdoing, he said. </blockquote> Nonetheless, the allegations were about kickbacks to physicians, a behavior that ought to concern ethical health care professionals. <blockquote class="tr_bq">The companies alleged that Parke-Davis, part of Warner-Lambert Co., paid kickbacks to doctors to encourage them to prescribe the anti-seizure drug for unapproved uses such as bipolar and panic disorders. Pfizer acquired Warner-Lambert in 2000 and 'deliberately expanded the promotion of off-label uses,' lawyers for the benefits firms said in an amended complaint filed in 2011. </blockquote> So Why Pay $325 Million? So Pfizer appears to have paid another $325 million to allow the company to claim again that these allegations were never proven.  Yet if these allegations were really entirely false, one might think it would have cost the company less than that to take the case to trial? As Judge Rakoff noted in rejecting a settlement between the US Department of Justice and Citigroup of allegations of financial misbehavior (look <a href="http://hcrenewal.blogspot.com/2011/11/will-citigroup-ruling-challenge-health.html">here</a>), <blockquote class="tr_bq">As for common experience, a consent judgment that does not involve any admissions and that results in only very modest penalties is just as frequently viewed, particularly in the business community, as a cost of doing business imposed by having to maintain a working relationship with a regulatory agency, rather than as any indication of where the real truth lies.</blockquote> Yet the latest Pfizer Neurontin settlement, occurring 20 years after the events in question, officially gives no indication of where the real truth lies. No Admitted Wrongdoing, Despite Past Evidence, Including a RICO Conviction These very late denials of admission of wrongdoing seem hollow when they are compared to the revelations that have appeared over the years from various legal actions about Neurontin marketing.  As we have discussed <a href="http://hcrenewal.blogspot.com/search/label/Neurontin">here</a>, documents revealed by previous Neurontin litigation have uncovered a catalog of deceptive marketing practices, including <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation of clinical research</a>, including its design and the analysis and dissemination of its results,  (look <a href="http://hcrenewal.blogspot.com/2012/10/when-clinical-trials-are-meant-for.html">here</a> and <a href="http://hcrenewal.blogspot.com/2009/11/editorial-that-wasnt-evidence-for.html">here</a>), the <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppression of clinical research</a> (look <a href="http://hcrenewal.blogspot.com/2008/10/did-pfizer-marketers-suppress-and.html">here</a>), and <a href="http://hcrenewal.blogspot.com/search/label/stealth%20marketing">stealth marketing campaigns</a>, including manipulation of <a href="http://hcrenewal.blogspot.com/search/label/CME">continuing medical education</a> through "unrestricted educational grants," captive speakers bureaus, docile and well-paid academics and physicians on advisory boards and consultants, the use of <a href="http://hcrenewal.blogspot.com/search/label/key%20opinion%20leaders">key opinion leaders</a> as marketers, and publications strategies including <a href="http://hcrenewal.blogspot.com/search/label/ghost%20writing">ghost writing</a> (look <a href="http://hcrenewal.blogspot.com/2006/08/stealth-marketing-of-neurontin.html">here</a>).   Note also that this is only the latest chapter in the long saga of Neurontin, for whose mismarketing Pfizer has already shelled out a lot of money (for the most recent example look <a href="http://hcrenewal.blogspot.com/2014/04/the-pervasiveness-of-health-care.html">here</a>, then see<a href="http://hcrenewal.blogspot.com/2006/08/stealth-marketing-of-neurontin.html"> this post</a>, and look <a href="http://hcrenewal.blogspot.com/search/label/Neurontin">here</a> for the collection).  Pfizer has an amazing record of bad behavior on view <a href="http://hcrenewal.blogspot.com/search/label/Pfizer">here</a>.  In fact, it has had a conviction as a Racketeering Influenced Corrupt Organization (RICO) on the basis of its previous marketing of Neurontin (look <a href="http://hcrenewal.blogspot.com/2013/12/blogscan-us-supreme-court-turns-down.html">here</a>), which was recently upheld on appeal (look <a href="http://hcrenewal.blogspot.com/2013/12/blogscan-us-supreme-court-turns-down.html">here</a>).   Yet Pfizer, convicted as a racketeering influenced corrupt organization, gets to officially deny wrong-doing once again.  And through all this, no Pfizer executive who authorized or directed any of this conduct, or who got a big bonus based on Neurontin revenues hiked by deception, has apparently had to suffer any negative consequences. Summary: the Usual Rant So here we go again,...  The failure of the current limp legal efforts against such corruption is evident by how many corporations have become ethical repeat offenders.  Pervasive bad behavior by large health care organizations has got to be a major cause of our ongoing health care dysfunction.  So, to really deter bad behavior, those who authorized, directed or implemented bad behavior must be held accountable. As long as they are not, expect the bad behavior to continue. True health care reform would include much more vigorous enforcement of existing laws to make sure health care organizations and their leaders actually put health, rather than personal enrichment, first.

Justice Delayed is Justice Denied? - Another Neurontin Settlement by Pfizer 20 Years After the Alleged Events

We have argued repeatedly against the strategy used by US government authorities to address allegations of bad behavior in health care (and elsewhere) by pursuing monetary settlements against the comp…

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16 Jun 2014

The Pervasiveness of Health Care Corruption as Shown by Another Roundup of Legal Settlements

Legal settlements are one way to document unethical and even corrupt behavior by large health care organizations, even if they may not deter bad behavior in the future.  It is time for another roundup of settlements by large pharmaceutical and device companies, presented in alphabetical order Abbott Laboratories This one goes back to late December, 2013.  As <a href="http://www.chattanoogan.com/2013/12/27/266328/Abbott-Laboratories-To-Pay-5.475.aspx">described</a> in the Chattanoogan (from Tennessee): <blockquote class="tr_bq">Abbott Laboratories, a global healthcare company, has agreed to pay $5.475 million to settle alleged violations of the False Claims Act, and other federal laws and regulations in connection with the operation of its medical device business which manufactures, markets and supplies carotid, biliary, and peripheral vascular products.</blockquote> The US Justice Department accused Abbott of kickbacks to physicians, <blockquote class="tr_bq"> As alleged in the settlement agreement, between 2005 and 2010, through its employees and a third party continuing medical education providers, Abbott offered physicians paid teaching and training assignments, consulting arrangements, speaking engagements, and/or sponsorship grants for physician conferences, for the purpose of inducing physicians to arrange for or recommend that the hospitals with which they were affiliated purchase or order Abbott’s carotid, biliary and peripheral vascular products.</blockquote> Note in particular that the kickbacks were disguised as payments for consulting or speaking.  As is usual in such cases, no individual seems to have paid any penalty or been subject to any punishment.  Because this was a legal settlement, the company did not admit wrongdoing. Abbott's previous issues are discussed <a href="http://hcrenewal.blogspot.com/search/label/Abbott">here</a>, including a <a href="http://hcrenewal.blogspot.com/2012/05/abbott-pleads-guilty-settles-for-16.html">$1.6 billion settlement in 2012</a>.  Baxter International This was <a href="http://www.modernhealthcare.com/article/20140421/INFO/304219992">reported</a> in April, 2014 by Modern Healthcare, <blockquote class="tr_bq"> Baxter International agreed to pay $64 million to settle a class-action lawsuit that alleged the Deerfield, Ill.-based company and some of its competitors colluded to raise prices of plasma-based therapies.</blockquote> Unlike the other cases above and below, this seemed to be a purely financial misadventure, although one that clearly increased health care costs, <blockquote class="tr_bq">Hospitals and drug distributors, saying they bought the plasma products at inflated prices, sued in 2009 Baxter; Victoria, Australia-based CSL; and the Plasma Protein Therapeutics Association, an Annapolis, Md.-based trade group.</blockquote> Once more, the company admitted no wrongdoing, and no individuals seemed to be subject to any negative consequences.   Baxter International's previous misadventures are <a href="http://hcrenewal.blogspot.com/search/label/Baxter">here</a>, including the <a href="http://hcrenewal.blogspot.com/2011/08/jama-article-begs-key-questions-about.html">striking case</a> of its marketing of contaminated and sometimes deadly heparin made from Chinese pigs.  Endo Health Solutions This one is from February, 2014, as<a href="http://www.bloomberg.com/news/2014-02-21/endo-to-pay-193-million-in-lidoderm-marketing-probe.html"> reported</a> by Bloomberg <blockquote class="tr_bq">Endo Health Solutions entered a deferred-prosecution agreement and will pay $193 million to settle whistle-blower claims that it marketed the shingles drug Lidoderm for unapproved purposes, the U.S. said. Endo will pay $20.8 million in forfeitures and $171.9 million in civil false claims settlements with the states and the U.S. government, the Justice Department said today in a statement. </blockquote> This one was all about marketing for uses not approved by the US Food an Drug Administration, <blockquote class="tr_bq">Between 2002 and 2006, Endo sales managers instructed some representatives on how to expand 'sales conversations' with doctors beyond the treatment of shingles-related pain, the U.S. said. Under the deferred-prosecution agreement, Endo admitted that it intended Lidoderm to be used for uses not approved by the U.S. Food and Drug Administration, the Justice Department said. </blockquote> Note that this case involves false claims, that is, fraud, because it is illegal to bill government programs for unapproved uses. Again, no individual suffered any consequences, and the company offered the usual kind of statement that admitted neither responsibility nor guilt, <blockquote class="tr_bq">'We are pleased to resolve this matter and are confident that we have robust programs in place to assist us in satisfying our legal and regulatory agreements,' Endo Chief Executive Officer Rajiv De Silva said in a statement.  </blockquote> One wonders, as usual, why a company would pay so much merely to avoid the legal expenses of a trial, unless of course the lawyers suspected the trail would not go well? Hospira This one was about hiding quality problems due to cost-cutting from investors, as<a href="http://www.reuters.com/article/2014/03/27/hospira-lawsuit-idUSL1N0MO2BS20140327"> reported</a> by Reuters in March, 2014.   <blockquote class="tr_bq">Hospira Inc has agreed to pay $60 million to resolve a class action lawsuit accusing the drug maker of misleading investors about quality control problems that undermined an initiative to improve the company's margins and operations.</blockquote> The details included, <blockquote class="tr_bq">As Hospira was promising to address issues raised by the U.S. Food and Drug Administration following inspections, the plaintiffs said the company was 'making the problems worse by gutting quality control efforts through cost cutting aimed at boosting short-term profitability.' The lawsuit said those cost-cutting moves stemmed from a March 2009 initiative called 'Project Fuel' intended to increase shareholder value by eliminating underperforming and duplicative units and reducing its global workforce. Plaintiffs contended the cuts in the budget and workforce hurt Hospira's quality control efforts, particularly at Rocky Mount, the company's largest facility. An FDA inspection in January 2010 of the Rocky Mount facility found a number of problems with the company's quality control and drug validation processes, the lawsuit said, and the agency issued a warning letter that April.</blockquote> Note that this involved quality control problems presumably in drug or device production, possibly leading to safety risks for patients.  Yet it was investors who brought the lawsuit. Note also that this seemed to be a clear case in which cost-cutting measures meant to improve short-term corporate revenue lead to problems that could have caused such risks.   One interesting feature of this case was that company executives were named as defendant (presumably again because it was investors, not patients or law-enforcement officials who initiated the suit.) <blockquote class="tr_bq">The lawsuit ... also named executives including Chief Executive Officer Michael Ball as defendants,...</blockquote> I cannot find any information about whether these executives were personally liable for any payments, however.    Pfizer This is yet another settlement involving the marketing of Neurontin, as <a href="http://www.bloomberg.com/news/2014-04-22/pfizer-agrees-to-pay-190-million-to-settle-neurontin-case-1-.html">reported</a> by Bloomberg in April, 2014, <blockquote class="tr_bq">Pfizer Inc the world’s biggest drugmaker, agreed to pay $190 million to end a lawsuit claiming it violated federal antitrust laws by delaying generic versions of its Neurontin epilepsy drug.  </blockquote><blockquote>Pfizer agreed to settle the class-action litigation pending in federal court in Newark, New Jersey, according to a filing today. U.S. District Judge Faith Hochberg must approve the accord, which would cover purchasers of Neurontin from December 2002 to August 2008. </blockquote> Note that this settlement, like many others, is of matter from a long time ago.  When it comes to bad behavior by big health care corporations, any form of justice is not swift. Note also that this is only the latest chapter in the long saga of Neurontin, for whose mis-marketing Pfizer has already shelled out a lot of money (see<a href="http://hcrenewal.blogspot.com/2006/08/stealth-marketing-of-neurontin.html"> this post</a> to start, and <a href="http://hcrenewal.blogspot.com/search/label/Neurontin">here</a> for the collection).  Pfizer has an amazing record of bad behavior on view <a href="http://hcrenewal.blogspot.com/search/label/Pfizer">here</a>.  In fact, it has had a conviction as a Racketeering Influenced Corrupt Organization (RICO) on the basis of its previous marketing of Neurontin (look <a href="http://hcrenewal.blogspot.com/2013/12/blogscan-us-supreme-court-turns-down.html">here</a>). This particular bad behavior involved included, <blockquote class="tr_bq"> improperly listing certain patents with the U.S. Food and Drug Administration, engaging in illegal promotion and sales of Neurontin for unapproved uses, filing and maintaining sham litigations with respect to certain patents, and making misrepresentations to the patent courts,</blockquote> Note that while much of this was legalistic, illegal marketing was in there too. Once more, I found nothing about any negative consequences for individuals who authorized, directed, or implemented questionable actions. Summary So it is all drearily familiar.  Big health care organizations seem to repeatedly engage in deceptive marketing, providing kickbacks to health professionals, fraudulent billing, anti-competitive practices, etc, etc.  These practices increase health care costs, and may risk patients' health and safety.  Many of these practices are corrupt, at least according to the Transparency International definition of corruption, "abuse of entrusted power for private gain."  Drug and device companies, for example, are entrusted to provide safe and effective products.  Deceptive marketing, kickbacks to health professionals to encourage overuse, and cutting quality control to cut costs all seem to be examples of abuse of this entrusted power.  The private gain obviously goes to any managers and executives who score bigger bonuses due to the increases in revenue that result.  Yet there are very few examples of any individuals who gained ever being subject to any negative consequences.  Given that lack, and the lack of any requirement for corporate leaders to admit responsibility, much less guilt, is it any surprise that these practices go on and on.  The failure of current limp legal efforts against such corruption is evident by how many corporations have become ethical repeat offenders.   (Note that in fact, as noted above, one of the pharmaceutical companies above actually was convicted of being a RICO, racketeering influenced corrupt organization, yet that conviction seemed to have no real negative consequences for the organization or any of the people involved.) As I have said again and again, pervasive bad behavior by large health care organizations has got to be a major cause of our ongoing health care dysfunction. So, to really deter bad behavior, those who authorized, directed or implemented bad behavior must be held accountable. As long as they are not, expect the bad behavior to continue.

The Pervasiveness of Health Care Corruption as Shown by Another Roundup of Legal Settlements

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30 Apr 2014

BLOGSCAN - US Supreme Court Turns Down Pfizer Appeal of RICO Conviction

Pfizer Inc, which boasts of being the world's largest research based pharmaceutical company, also seems to be one of the world's largest examples of health care corporations that have withstood an amazing number of settlements, fines, and at times convictions for misbehavior without major apologies, significant changes in leadership or corporate culture, or bankruptcy.  (Look <a href="http://hcrenewal.blogspot.com/2013/07/pfizers-umpteenth-settlement-for-491.html">here</a> for a list of the cases, and <a href="http://hcrenewal.blogspot.com/search/label/Pfizer">here</a> for all we have written about Pfizer).   Pfizer, amazingly, has the malodorous distinction of having been convicted by a US jury as a RICO - a racketeering influenced corrupt organization in 2010 (look <a href="http://hcrenewal.blogspot.com/2010/03/settlement-and-conviction-round-up.html">here</a>).  Pfizer executives, of course, kept their office of counsel busy by appealing the conviction, all the way up to the US Supreme Court. As <a href="http://1boringoldman.com/index.php/2013/12/11/r-i-c-o/">discussed</a> on the 1BoringOldMan blog, the court has now turned down the appeal and let the conviction, which had been affirmed by lower federal court, stand.   So Pfizer is now officially a racketeering influenced corrupt organization.   Yet although the description of the RICO statute that 1BoringOldMan quoted notes the law can be used to go after the leaders of organized crime, no individual at Pfizer who authorized, directed, or implemented the relevant misbehavior, which was in this case the promotion of Neurontin for off-label uses, for which its benefits were at best unproven, at worse nonexistent, even if its harms are well-documented.  Thus even this RICO conviction has not affected the impunity of top health care corporate leaders.  As we have said endlessly, true health care reform will not occur until the leaders of large health care organizations are made accountable for their actions, and are prevented from becoming amazingly rich while their organizations repeatedly commit unethical or illegal acts that harm patients' and the public's health.    ADDENDUM (14 December,2013) - The <a href="http://hcrenewal.blogspot.com/2013/12/blogscan-us-supreme-court-turns-down.html">followup post</a> at 1BoringOldMan on this topic includes some optimism that now that the validity of the RICO concept applied to a large health care corporation has been affirmed, more stringent law enforcement may follow.   Roy M. Poses MD for Health Care Renewal

BLOGSCAN - US Supreme Court Turns Down Pfizer Appeal of RICO Conviction

Pfizer Inc, which boasts of being the world's largest research based pharmaceutical company, also seems to be one of the world's largest examples of health care corporations that have withstood an ama…

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13 Dec 2013

When Clinical Trials are Meant for Marketing, not Science

The development of the randomized controlled clinical trial (RCT) was one of the major scientific advances in clinical medicine.  RCTs provide a major part of the evidence underlying evidence based medicine.  RCTs provide a major source of data used by the US Food and Drug Administration, and similar agencies in other countries, to decide whether to approve drugs or devices to manage particular clinical problems.  Unfortunately, with the rise of the RCT came a rise in attempts to <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppress</a> and <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulate</a> clinical trials by those with vested interests, often in selling the products and services the trials can evaluate. Many of the examples we have discussed were of attempts at manipulation or suppression of clinical trials originally done to provide evidence for product approval, or even ostensibly to advance clinical science.  Yet a relatively new article covering evidence revealed from litigation about the drug gabapentin (Neurontin) originally made by Parke-Davis, first a part of Warner Lambert, now part of Pfizer suggests that many clinical trials may not be done to advance science, or even just to provide data to regulators, but only to market products. The article is Vedula SS, Goldman PS, Rona IJ, Greene TM, and Dickersin K. Implementation of a publication strategy in the context of reporting biases: a case study based on new documents from the Neurontin litigation.  Trials 2012; 13: 136.  Link<a href="http://www.trialsjournal.com/content/13/1/136"> here</a>. Methods Summary The article described a case study based on documents revealed in 2008 litigation.  The purpose of the study was: <blockquote class="tr_bq">to describe the implementation of a publication strategy for off-label marketing of gabapentin, within the context of reporting biases and spin of Pfizer and Parke-Davis’s clinical trial findings, for four off-label uses: migraine prophylaxis, treatment of bipolar disorders, neuropathic pain, and nociceptive pain. </blockquote> The study examined documents revealed through the 2008 litigation.  It concentrated on documents relating to the marketing of Neurontin for four off-label indications, that is, for four potential reasons to use the drug which had not yet been approved by the US FDA.  It focused on documents discussing strategies for marketing for these indications, and then documents about particular company sponsored RCTs done for these indications. Strategies to Sell Drugs The documents examined by the investigators showed that Parke-Davis prepared "marketing assessments" for four possible indications for Neurontin.  The assessments discussed two possible strategies.  The "indication strategy" would be to conduct trials for the purposes of providing data to the FDA in the hope that the FDA would then approve the new indication for the drug.  The "marketing strategy" would be, in the words of an internal company memo quoted in the study, to conduct clinical trials and <blockquote class="tr_bq">to disseminate the information as widely as possible through the world’s medical literature</blockquote> In other words, the publication strategy involved using RCTs first for marketing, rather than scientific or regulatory purposes. How the Trials were Controlled by Marketers  The publication strategy involved not simply doing trials and publicizing their results, but controlling the messages conveyed by the trials to make sure they primarily supported marketing.  This was done by having the company's marketing department control the content of the trial reports. <blockquote class="tr_bq"> A Neurontin Publications Subcommittee (NTN PSC) was formed within Pfizer and Parke-Davis to implement a publication plan. Minutes from meetings between the NTN PSC and Medical Action Communications (MAC), a medical writing company, indicate that a list of key messages, guiding the content of published reports related to the trials of gabapentin for off-label indications, was developed based on a branding guide </blockquote>Thus it appeared to be that marketers, not physicians or scientists were in control of supposedly scholarly research publications appearing in medical journals. The marketers controlled content by controlling those who wrote it. <blockquote class="tr_bq"> A standard operating procedure related to publication of affiliate-driven manuscripts was identified in internal company documents dated October 16, 2002, and it sheds further light on the publication planning process (see Figure 3<a href="http://www.trialsjournal.com/content/13/1/136/figure/F3"></a>). (The term affiliate in this context refers to Pfizer’s foreign affiliates, that is, corporations related to Pfizer by either shareholdings or other means of control, including subsidiary, parent, or sibling corporations). According to the internal company documents, 'affiliate-driven manuscripts' were written for Pfizer and Parke-Davis by MAC and sent to the authors for approval. Each article was coordinated by a manuscript team, consisting of representatives from the medical and marketing divisions of the company. The documents also indicate that all affiliate-driven manuscripts should be forwarded to the NTN PSC for review. One of the objectives of manuscripts being reviewed by the NTN PSC was to ‘ensure that they are in-line with current product messages and areas of interest’</blockquote>Manipulating the Dissemination (and Analysis) of Research Results Note that the control of publication by marketers describe above involved ghost-writing of articles by medical education and communications companies (MECCs).  Later the article explained that these ghost writers were "not appropriately acknowledged" in the resulting published articles. The Vedula et al study article provided examples of "spin" in the writing of again supposedly scholarly research publications used in fact to support marketing, and controlled if not composed by marketers. <blockquote class="tr_bq"> We identified spin in publications related to 8/12 trials included in our analysis.... We classified the following as spin: emphasis in the published report on outcomes that were not specified in the study protocol (Study 879–201) ...; conclusions that did not match study findings described in the internal company research report (Study 945–220) <a href="http://www.blogger.com/blogger.g?blogID=9551150" name="d7865e503"></a>...; extensive rationale to explain away statistically non-significant (unfavorable to the sponsor) findings (Study 945–209; 945–291; No study number - Gorson) <a href="http://www.blogger.com/blogger.g?blogID=9551150" name="d7865e508"></a><a href="http://www.blogger.com/blogger.g?blogID=9551150" name="d7865e510"></a><a href="http://www.blogger.com/blogger.g?blogID=9551150" name="d7865e512"></a>...; conclusion of treatment effectiveness from an uncontrolled study (Study 945–250) ...; emphasis on statistically significant secondary outcomes despite negative findings for the primary outcome (Study 945–271) ...; and an explicit description of an attempt to spin study findings (as described in internal company emails) (Study 945–306).</blockquote> Note that while most of these examples of spin involved manipulation of the dissemination of study results, that is, doubtful, biased or fallacious arguments based on apparently unbiased data, they also involved manipulation of the analyses (in italics).  The article also described manipulation of dissemination involving the timing of publication, including delaying publication of an article despite the wishes of the study's investigators because the results were not statistically significant, and hence not favorable for marketing.  Summary Documents revealed by litigation about Neurontin in 2004 provided insights about how pharmaceutical and presumably other kinds of health care corporations may conduct systematic, deceptive stealth marketing campaigns to promote their products and services (look<a href="http://hcrenewal.blogspot.com/2006/08/stealth-marketing-of-neurontin.html"> here</a>).  We noted that initial media coverage of documents revealed in the 2008 litigation also suggested the existence of a systematic "publication strategy" to control dissemination of results of particular trials, while suppressing trials whose results could not easily be spun to provide support of marketing objectives (look <a href="http://hcrenewal.blogspot.com/2008/10/did-pfizer-marketers-suppress-and.html">here</a>). Now the new paper by Verdula et al fill out our knowledge of this case.  The paper suggests that randomized controlled clinical trials may be done not to advance science, or even convince regulators, but primarily to market their sponsors' products.  Thus some significant proportion of the clinical research literature, the literature that physicians and other health professionals have relied upon to make evidence-based decisions for their patients, may exist mainly for marketing purposes.  Even the most rigorous methods used by clinical epidemiologists to review research are meant to discover problems that arose from human error or the inevitable trade-offs made when research is done in the real world, but not deliberately introduced biases and defects meant to promote vested interests.  Thus it is not clear that even the most "evidence-based" medical decisions are based on real scientific evidence rather than the spinning of marketers. Thus health care professionals, policy makers, researchers, and the interested public need to be even more skeptical about arguments made to promote innovative treatments and other clinical interventions.  However, it is not clear that even rigorous skepticism can defend the integrity of evidence based medicine from marketing disguised as clinical research. Going forward, we must consider erecting an impregnable barrier between clinical research and those whose primary interest is to make money by selling health care goods and services.  If we do not do that, we will forever need to worry that we really have no idea what "works in medicine," and whether any particular test, treatment, or program provides benefits that outweigh its harms.

When Clinical Trials are Meant for Marketing, not Science

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19 Oct 2012

The Editorial that Wasn't: Evidence for Systematic Research Manipulation Undetectable by Critical Review

Woe to those of us who have been advocates for evidence-based medicine.  A short description of the evidence-based medicine is medicine whose practice is informed by critical, rigorous review of the best available evidence from clinical research as revealed by systematic search of the published research literature, as well as by the clinician's understanding of biology and the medical and biopsychosocial context, and by the patient's own values. Evidence-based medicine is based on some key assumptions.  One is that a systematic review will reveal all the results of research studies that are relevant to the issue at hand.  A second is that while the research studies may be flawed and imperfect, they are reported honestly. Unfortunately, as we have repeatedly discussed, there is more and more evidence that a systematic review will not reveal all relevant results, because research studies may be suppressed, perhaps often, when their results are unfavorable to vested interests.  (Look <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">here</a> for further discussion.)  There is also considerable anecdotal evidence that the design, implementation, and analysis of research studies may be manipulated to make the results more likely to favor vested interests.  (Look <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">here</a> for further discussion.) An article by Vedula et al just published in the renowned New England Journal of Medicine suggests that such manipulation might be systemic, and that the reporting of manipulated studies may not clearly show what manipulation was done. (1) To summarize, the authors got access through legal proceedings to internal study protocols and research reports from clinical trials sponsored by Parke-Davis (later merged into Pfizer Inc) of gabapentin (Neurontin) for a variety of clinical problems other than seizures.  Gabapentin was originally marketed as an anti-seizure drug, but Pfizer later "admitted guilt for off-label marketing."  (We discussed the stealth marketing campaign for Neurontin <a href="http://hcrenewal.blogspot.com/2006/08/stealth-marketing-of-neurontin.html">here</a>.)  Vedula et al compared the primary outcome variables specified in the original research protocols, internal research reports, and any publications of the trials' results.  They identified 21 trials, 13 of which were published.  For 12 of the 13, the authors had access to the internal protocol, report, or both.  The main results were: <blockquote>For 8 of the 12 published trials, there was a disagreement between the definition of the primary outcome in the protocol and that in the published report.... Sources of disagreement included the introduction of an entirely new primary outcome in the published report (in the case of 6 trials); failure to distinguish between primary and secondary outcomes in the published report, even though the protocol did distinguish between them (2 trials); relegation of a primary outcome in the protocol to a secondary outcome in the published report (2 trials); and failure to include in the published report one or more primary outcomes specified in the protocol (5 trials). </blockquote> Furthermore, it appeared that failure of published articles to clearly and fully report results in terms of the original, pre-specified primary outcome variables occurred when these comparisons were not favorable to gabapentin. As the authors summarized: <blockquote>Thus, trials with findings that were not statistically significant (P≥0.05) for the protocol-defined primary outcome, according to the internal documents, either were not published in full or were published with a changed primary outcome. As shown in Figure 3, all the changes that took place between what was specified in the protocol, what was known before publication (as presented in the internal company research reports), and what was reported to the public led to a more favorable presentation in the medical literature of gabapentin's efficacy for unapproved indications. </blockquote> They concluded: <blockquote>We are concerned that the reporting practices observed in our analysis do not meet the ethical standards for clinical research or maintain the integrity of scientific knowledge. Fair and honest treatment of patients enrolled in clinical trials of any kind requires full, open, and unbiased reporting. Journal publication, a formalized platform for scientific discourse and dissemination of knowledge, should not be used as a marketing tool for off-label drug use. Reporting biases such as those we describe here increase the likelihood that interventions will appear to be effective when they are not. Such biases can lead to the omission of negative findings in systematic reviews of intervention effectiveness and in evidence-based guidelines. For example, the 2005 Cochrane systematic review regarding the effectiveness of gabapentin for acute and chronic pain concluded that it is effective on the basis of published findings and should now be updated with the inclusion of unpublished information made available through litigation. </blockquote> I believe that the article by Vedula et al is particularly important because it shows what appears to be systematic manipulation of the analysis and reporting of multiple clinical trials of the same drug (but for different indications) that had the effect of making the drug appear efficacious when it likely was not. Furthermore, the manipulation was concealed. The published research articles did not completely describe what the intended primary efficacy outcome variables were, did not provide results in terms of these variables, and instead provided results only in terms of variables that were chosen post-hoc as new primary outcome variables. To address that latter point, I independently reviewed three of the research publications cited by Vedula et al.(2,3,4) All three were noted to have reported significant results favoring gabapentin in terms of a primary efficacy outcome variable that was not identified as such in the corresponding studies' original research protocols or reports (see the <a href="http://content.nejm.org/cgi/content/full/361/20/1963/DC1">supplementary data</a> provided with the New England Journal article.) Per my review, none of the three published articles offered any hint that what they reported as primary outcome variables were not the variables originally chosen in that capacity, nor did they identify what those original primary outcome variables were, or how comparisons made using them turned out. The implications of the article by Vedula et al are very important. Hence, I was surprised that the article appeared without an accompanying editorial to discuss these implications, and that its publication did not generate much media interest. So that gives me an opportunity to comment further. One could start with the implications for evidence-based medicine. As noted above, a short description of the evidence-based medicine is medicine whose practice is informed by critical, rigorous review of the best available evidence from clinical research as revealed by systematic search of the published research literature, as well as by the clinician's understanding of biology and the medical and biopsychosocial context, and by the patient's own values. Evidence-based medicine depends on critical, rigorous review, but the review process is generally done under the assumptions that research publications honestly describe what was done and what its results were. The review process was never designed to detect dishonest reporting or find information that was deliberately concealed. Manipulation of research (design, analysis, and implementation), concealment of that manipulation, and outright suppression of research threaten the foundations of evidence-based medicine. Yet the article by Vedula et al is part of a growing body of evidence that such manipulation, concealment and suppression are widespread, and done to serve vested interests, often commercial. That is a huge problem for proponents of evidence-based medicine, but also for physicians who want their practices to be based on science, for patients who want their care to be based on science, and for all those in society who see the advancement of medical science as a way to improve peoples' lives. As senior author Professor Kay Dickersin noted in an interview <a href="http://www.bloomberg.com/apps/news?pid=20601087&sid=azEz6zlMyS0I&pos=7">with Bloomberg</a> "The trouble is, as a scientist, the publication has always been held up to me as the truth. It's the scientific record. What this study indicated is we can't believe that record." Furthermore, to be a bit more concrete, most physicians, patients, and policy makers depend on what appears to be honest clinical research to make decisions about individual care and health policy. Deliberate and deceitful manipulation of clinical research to favor sponsors' products has likely lead to excessive use of and payments for drugs and devices that are less effective than advertised, if not useless or dangerous. Thus, it is likely that such manipulation is partially responsible for ever increasing health costs and poor health outcomes. Finally, we need to start thinking about how we can detect and compensate for manipulation of clinical research in the past, and deter such manipulation in the future. One possible deterrent would be, as was noted by Vedula et al, detailed clinical trials registries that contain complete information about trial protocols.  For this to be effective, there need to be mechanisms to assure compliance, and penalties for non-compliance.  Moreover, since clinical research is now global, the registries must have global scope, and enforced assurance of compliance must also be global. Registries might decrease future manipulation and suppression of research.   No one has suggested, as far as I know, a systematic way to detect and correct for previous manipulation. It would require a major, global investigative effort to uncover manipulation, and it would be a major scientific and policy endeavor to reveal most suppressed research and correct most manipulations. However, before anything is done, patients, physicians and policy makers must acknowledge and understand the problem.  Yet it seems that even discussing these may be topics that are very uncomfortable for some of us. The longer we shrink from addressing them, however, the worse will be the results for patients, physicians, science and society. References 1. Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in industry-sponsored tirals of gabapentin for off-label use. N Engl J Med 2009; 361: 1963-1971. Link <a href="http://content.nejm.org/cgi/content/short/361/20/1963">here</a>. 2. Mathew NT, Rapoport A, Saper J et al. Efficacy of gabapentin in migraine prophylaxis. Headache 2001; 41: 119-128. Link <a href="http://www3.interscience.wiley.com/cgi-bin/fulltext/119014515/PDFSTART">here</a>. 3. Vieta E, Goikolea JM, Martinea-Aran A et al. A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J Clin Psychiatr 2006; 67: 473-477.  Link <a href="http://www.psychiatrist.com/privatepdf/2006/v67n03/v67n0320.pdf">here</a>. 4. Caraceni A, Zecca E, Bonezzi C et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the gabapentin cancer pain study group. J Clin Oncol 2004; 22: 2909-2917. Link <a href="http://jco.ascopubs.org/cgi/reprint/22/14/2909">here</a>.

The Editorial that Wasn't: Evidence for Systematic Research Manipulation Undetectable by Critical Review

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16 Nov 2009

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