healthy4u: Avandia

To Sir Andrew? With a Settlement - GlaxoSmithKline to Settle for $3 Billion, CEO Said to Pursue Knighthood

Two weeks ago, reports of the largest legal settlement involving a pharmaceutical company to date in the US appeared.  The $3 Billion Settlement In summary, <a href="http://articles.philly.com/2011-11-04/business/30359814_1_glaxo-diabetes-drug-medicaid-pricing">per the Philadelphia Inquirer</a>, <blockquote>In perhaps the largest penalty ever paid by a pharmaceutical company, GlaxoSmithKline said Thursday it had reached a tentative deal with the U.S. Justice Department to pay $3 billion to settle criminal and civil allegations of illegal marketing practices and pricing under a Medicaid program.</blockquote> Why the deal was announced this month is not clear. Neither are all its provisions: <blockquote>Glaxo said the deal would be made final in 2012, but it was unclear why it was announced now. A spokeswoman declined to say whether Glaxo would have to live by a corporate integrity agreement, which the government sometimes requires in such cases.</blockquote> The Inquirer listed some possible reasons for the settlement, <blockquote>As for Glaxo's latest situation, one investigation, started by the U.S. Attorney's Office in Colorado and later run on a national level by the U.S. Attorney's Office in Boston, looked at Glaxo's marketing practices related to nine of its best-selling drugs, including Paxil, Wellbutrin, and later Advair. In a second investigation, the Justice Department looked at Glaxo's possibly inappropriate use of rules exceptions when reporting prices charged for drugs for different situations in the marketplace. Under part of the Medicaid Rebate Program, drugmakers are supposed to report the lowest price they charge most organizations, which is then used to calculate the price that Medicaid ultimately pays for its drugs. The third investigation, also by the Justice Department, was over how Glaxo promoted the diabetes drug Avandia, which was pulled from European markets and severely restricted last fall by the Food and Drug Administration after it was shown to cause heart attacks.</blockquote> As commonly occurs in such cases, GSK and its CEO averred that all the sorts of conduct that lead to this settlement are old news: <blockquote>The company said in a statement that since 2008 it had 'established a new framework for compliance in the U.S., based on the company's values, policies and established industry codes of practices. It is supported by a larger compliance staff and strengthened training programs that require certification by employees.' The changes included new incentive formulas for sales representatives, eliminating sales targets for bonuses. 'This is a significant step toward resolving difficult, long-standing matters which do not reflect the company that we are today,' Glaxo chief executive officer Andrew Witty said in the statement. 'In recent years, we have fundamentally changed our procedures for compliance, marketing and selling in the U.S. to ensure that we operate with high standards of integrity and that we conduct our business openly and transparently.'</blockquote> As is also usual, none of the reports included any acceptance of responsibility for the bad conduct by GSK or any of its leaders, and certainly they did not mention any negative consequences for any persons who might have authorized, directed, or implemented the misbehavior, even giving, as is apparently true in this case, that some of the behavior was at least alleged to be criminal. A Settlement for a Knight? It was not clear why this settlement was announced this early in such a preliminary, and vague manner. However, a <a href="http://www.pharmalot.com/2011/11/your-majesty-may-i-present-sir-andrew/">post</a> on the PharmaLot blog suggested one motivation: <blockquote>As the calendar year draws to a close, the UK government is busy readying the next list of individuals who are to be honored as members of the Order of the British Empire. These honors are bestowed on people from all walks of life who have somehow made a difference in their community. And there are various types of awards, including knighthood, that recognize a different type of contribution. The list, however, is a closely guarded secret. Presumably, even Rupert Murdoch employees would have a hard time hacking into the treasured line up of nominees. But one name that may be under consideration is Andrew Witty, the ceo at GlaxoSmithKline. Our sources say that Glaxo minions have been encouraged to find ways to hone his image in hopes that he becomes Sir Andrew.</blockquote> So one could speculate that being able to clear up these "difficult, long-standing matters," could be touted as a task that only could be accomplished by a knight. That might have been plausible if Mr Witty recently rode into town on a white horse, and then dispatched these old legal demons. Some More History In fact, that is not what happened. Per his <a href="http://www.gsk.com/about/bio-witty-cet.htm">official GSK biography</a>, <blockquote>Andrew Witty became Chief Executive Officer of GlaxoSmithKline plc on 21 May 2008. He is a member of the Board and Corporate Executive Team. Andrew joined Glaxo in 1985 and held a variety of Sales and Marketing roles in the UK business. He has worked in the Company’s International New Products groups, both in the Respiratory and HIV/Infectious disease fields and has been involved in multiple new product development programmes. He has also worked in South Africa, The USA and Singapore where he led the Group’s operations as Senior Vice President, Asia Pacific. While in Singapore Andrew was a Board Member of the Singapore Economic Development Board, the Singapore Land Authority and in 2003 he was awarded the Public Service Medal by the Government of Singapore. In 2003 Andrew was appointed President of GSK Europe, and joined GSK’s Corporate Executive Team. </blockquote> So he has been with GSK a long time. However, the misbehavior that the current settlement is apparently designed to resolve has been going on for a long time. As we previously <a href="http://hcrenewal.blogspot.com/2010/10/glaxosmithkline-subsidiary-pleads.html">posted</a>, Paxil (Seroxat in the UK, or paroxetine), was the anti-depressant whose marketing lead GlaxoSmithKline (GSK) to settle allegations of fraud brought by then New York Attorney General Elliott Spitzer in 2004. That case included allegations of suppression and manipulation of clinical research, and was discussed in great detail in the book <a href="http://www.alison-bass.com/books.html">Side Effects</a> by Alison Bass. We posted about various aspects of this case, e.g., more recently <a href="http://hcrenewal.blogspot.com/2007/01/not-something-we-want-to-publicise-spin.html">here</a>, <a href="http://hcrenewal.blogspot.com/2008/03/british-government-concludes-gsk.html">here</a>, and <a href="http://hcrenewal.blogspot.com/2008/09/brown-university-student-journalists.html">here</a>.  The case continues to echo to this day: see <a href="http://alison-bass.com/blog/2011/11/international-group-seeks-brown-universitys-help-in-getting-controversial-paxil-study-retracted">this post</a> by Alison Bass about attempts to have a questionable journal article that was used to market Paxil retracted.  Then there was Avandia (rosiglitazone), the anti-diabetic drug whose use was just restricted by the US Food and Drug Administration. This GlaxoSmithKline product inspired a <a href="http://hcrenewal.blogspot.com/2010/07/avandia-spin-cycle-continues-even-after.html">"spin cycle"</a> which provided us with endless grist for the Health Care Renewal mill. A good summary of the case appeared in September, 2010, in the British Medical Journal (Cohen D. Rosiglitazone: what went wrong: Brit Med J 2010; 341: 530-534. Link <a href="http://www.bmj.com/content/341/bmj.c4848.fu%20%20ll">here</a>) Once again, it appears that research was suppressed and manipulated (e.g., see <a href="http://hcrenewal.blogspot.com/2010/02/bring-back-dsi-avandia-case-as-spy.html">here</a>), Avandia critics were attacked by "experts" whose financial relationships with GSK were not always obvious (e.g., see <a href="http://hcrenewal.blogspot.com/2007/06/avandia-spin-cycle-continues.html">here</a>), and there were allegations that GSK executives tried to intimidate those who disagreed with them (e.g., see <a href="http://hcrenewal.blogspot.com/2010/02/bring-back-dsi-avandia-case-as-spy.html">here</a> and <a href="http://hcrenewal.blogspot.com/2007/11/more-about-who-called-dogs-out-on.html">here</a>).  All this about Avandia came out after Mr Witty became President of GSK Europe and joined the Corporate Executive Team.  While there is no reason to think he was directly responsible for any of it, as a member of this team, he ought to be accountable for the corporation's major actions, and misbehavior.  By the way, we <a href="http://hcrenewal.blogspot.com/2010/10/glaxosmithkline-subsidiary-pleads.html">posted</a> last year about another settlement by GSK, in which a GSK subsidiary pleaded guilty to criminal charges for selling adulterated drugs, including a version of Paxil. In the Washington Post <a href="http://www.washingtonpost.com/business/economy/3billion-settlement-expected-in-glaxosmithkline-drug-marketing-probe/2011/11/03/gIQAYf7sjM_story.html">report</a> of the $3 billion settlement, there is this quote from Dr Sidney Wolfe, <blockquote>'The size of the penalties, although large, are not as large as the money [the drug companies] make and so they keep doing it over again,' said Sidney M. Wolfe, director of Public Citizen’s health research group. 'The only way this is going to stop, or get reversed, is to greatly increase the size of the penalties or to start sending some of the executives to jail, if appropriate.'</blockquote>Summary I have no idea whether there is evidence supporting criminal charges for any executives in this case. However, GSK and its leadership have not covered themselves in glory recently as shown by now three major legal settlements. I am just an American and not very knowledgeable about how the UK decides to dub people knights. However, in my humble opinion, it would be grotesque to honor the current CEO of GlaxoSmithKline with a knighthood based how his company has been lead since he became a member of its Executive Team in 2003. I thus will end on my usual, repetitive note for such cases.... 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. 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. Further, expect organizations that did not uphold high standards in one instance to fail to uphold them in other instances. ADDENDUM (18 November, 2011) -  See additional posts on attempts to have Study 329, a particularly questionable study of Paxil, withdrawn on <a href="http://loathingbioethics.blogspot.com/2011/11/fraud-what-fraud-brown-remains-silent.html">the Fear and Loathing in Bioethics blog</a>, <a href="http://brodyhooked.blogspot.com/2011/11/will-brown-university-investigate.html">the Hooked: Ethics, Medicine and Pharma blog</a>, and on <a href="http://www.margaretsoltan.com/?p=33573">the University Diaries blog</a>. ADDENDUM (21 November, 2011) - See also these posts on the call for the withdrawal of Study 329 on the <a href="http://alison-bass.com/blog/2011/11/international-group-seeks-brown-universitys-help-in-getting-controversial-paxil-study-retracted">Alison Bass blog</a>, and the <a href="http://1boringoldman.com/index.php/2011/11/20/a-walk-on-the-wrong-side-side-of-the-street">1BoringOldMan blog</a>.

To Sir Andrew? With a Settlement - GlaxoSmithKline to Settle for $3 Billion, CEO Said to Pursue Knighthood

Two weeks ago, reports of the largest legal settlement involving a pharmaceutical company to date in the US appeared. The $3 Billion SettlementIn summary, per the Philadelphia Inquirer,In perhaps the…

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18 Nov 2011

GlaxoSmithKline Subsidiary Pleads Guilty to Manufacturing Adulterated Drugs: Three Strikes and ...?

Paxil First there was Paxil (Seroxat in the UK, or paroxetine), the anti-depressant whose marketing lead GlaxoSmithKline (GSK) to settle allegations of fraud brought by then New York Attorney General Elliott Spitzer in 2004.  That case included allegations of suppression and manipulation of clinical research, and was discussed in great detail in the book <a href="http://www.alison-bass.com/books.html">Side Effects</a> by Alison Bass.  We posted about various aspects of this case, e.g., more recently <a href="http://hcrenewal.blogspot.com/2007/01/not-something-we-want-to-publicise-spin.html">here</a>, <a href="http://hcrenewal.blogspot.com/2008/03/british-government-concludes-gsk.html">here</a>, and <a href="http://hcrenewal.blogspot.com/2008/09/brown-university-student-journalists.html">here</a>.  Avandia Then there was Avandia (rosiglitazone), the anti-diabetic drug whose use was just restricted by the US Food and Drug Administration.  This GlaxoSmithKline product inspired a <a href="http://hcrenewal.blogspot.com/2010/07/avandia-spin-cycle-continues-even-after.html">"spin cycle"</a> which provided us with endless grist for the Health Care Renewal mill.  A good summary of the case appeared in September in the British Medical Journal (Cohen D. Rosiglitazone: what went wrong: Brit Med J 2010; 341: 530-534.  Link <a href="http://www.bmj.com/content/341/bmj.c4848.fu%20%20ll">here</a>)  Once again, it appears that research was suppressed and manipulated (e.g., see <a href="http://hcrenewal.blogspot.com/2010/02/bring-back-dsi-avandia-case-as-spy.html">here</a>), Avandia critics were attacked by "experts" whose financial relationships with GSK were not always obvious (e.g., see <a href="http://hcrenewal.blogspot.com/2007/06/avandia-spin-cycle-continues.html">here</a>), and there were allegations that GSK executives tried to intimidate those who disagreed with them (e.g., see <a href="http://hcrenewal.blogspot.com/2010/02/bring-back-dsi-avandia-case-as-spy.html">here</a> and <a href="http://hcrenewal.blogspot.com/2007/11/more-about-who-called-dogs-out-on.html">here</a>).  Adulterated Drugs And now it is adulterated drugs.  Here is the <a href="http://www.bloomberg.com/news/2010-10-26/glaxo-said-to-settle-u-s-drug-manufacturing-lawsuit-for-750-million.html">version</a> from Bloomberg: <blockquote>GlaxoSmithKline Plc, the U.K.’s largest drugmaker, will pay $750 million to settle a U.S. whistleblower lawsuit over the sale of defective drugs. Glaxo and the U.S. Justice Department announced the agreement yesterday, resolving a false-claims lawsuit first filed in 2004 by Cheryl D. Eckard, a former global quality assurance manager for the London-based company. 'This is not something I wanted to do, but because of patient safety it was necessary,' Eckard, 51, told reporters following a Justice Department press conference in Boston. As a whistleblower, she will receive $96 million from the settlement money. Glaxo was accused in court papers of selling tainted drugs under false pretenses. The medicines, made at a Glaxo plant in Cidra, Puerto Rico, were misidentified as a result of product mix-ups, according to papers filed in federal court in Boston. The affected drugs included the antidepressant Paxil CR and the diabetes treatment Avandamet. [Note that this is a combination drug that includes Avandia - ed] The settlement includes a criminal fine and forfeiture totaling $150 million and a $600 million civil settlement under the False Claims Act and related state claims, the Justice Department said in a statement. 'We will not tolerate corporate attempts to profit at the expense of the ill and needy in our society -- or those who cut corners that result in potentially dangerous consequences to consumers,' Carmen M. Ortiz, the U.S. Attorney in Boston, said at yesterday’s news conference. SB Pharmco Puerto Rico Inc., a Glaxo unit, agreed to plead guilty to charges relating to the manufacture and distribution of adulterated drugs made at the now-shuttered plant, the Justice Department said. Glaxo said in July it had agreed in principle with the U.S. to pay 500 million pounds ($791 million) to resolve the investigation. 'We regret that we operated the Cidra facility in a manner that was inconsistent with current Good Manufacturing Practice requirements and with GSK’s commitment to manufacturing quality,' PD Villarreal, a Glaxo senior vice president, said in an e-mailed statement. Eckard’s take is the largest ever for a single whistleblower, said Patrick Burns, spokesman for Taxpayers Against Fraud, a nonprofit Washington group that publicizes the use of legal means to combat fraud against the U.S. The federal government will receive $436.4 million from the settlement and participating states will split as much as $163.6 million, the Justice Department said. Other drugs made at the plant include Kytril, an anti- nausea medication, and Bactroban, an ointment used to treat skin infections, the Justice Department said. 'The false claims arose out of chronic, serious deficiencies in the quality assurance function at the Cidra plant and the defendants’ ongoing serious violations of the laws and regulations designed to ensure the fitness of drug products for use,' the government said in court papers. The U.S. Food and Drug Administration in 2005 seized some Paxil CR lots after it was discovered that the pills sometimes split inappropriately, according to court papers. Some of the pills lacked an active ingredient. </blockquote>It seems that not only questions about GSK sponsored clinical research about and GSK marketing of Paxil and Avandia, but the company has problems even supplying tablets that contain the pure drugs at the right dose. Summary and Discussion First, this is another dreary marcher in the <a href="http://hcrenewal.blogspot.com/search/label/legal%20settlements">parade of legal settlements</a> that we have now been chronicling for years. This case has some particular features. It included a guilty plea to a crime. Although the allegations included fraud, the fundamental problem seemed to be the selling of adulterated, impure drugs. So my first comment is that this is the latest instance of a major pharmaceutical company not being able to fulfill its most basic responsibility and reason for being, the manufacture of pure, unadulterated drugs. We previously discussed problems with adulterated drugs made by <a href="http://hcrenewal.blogspot.com/search/label/Baxter">Baxter International</a> and <a href="http://hcrenewal.blogspot.com/search/label/Johnson%20and%20Johnson">Johnson and Johnson</a>. We have discussed, seemingly endlessly, how big health care corporations, including but certainly not limited to pharmaceutical companies, have engaged in various sophisticated deceptions involving marketing and clinical research to sell more products at higher prices. Now it seems that while these companies have put so much of their resources into marketing and public relations, not necessarily in honest ways, they have neglected to put the necessary expertise and resources into their most basic manufacturing functions. So while drug industry sycophants prattle on endless about life-saving innovations, not only have industry marketing and research become less trustworthy, but now we cannot even trust the companies to supply the drug that is on the label in a pure form at the labelled dose. My next comment is that this is the third big case involving GlaxoSmithKline reported in the last few years. (Although, like the previous cases, the events that lead to recent relevations actually occurred over the last 10+ years.) This would suggest that there is a serious problem with the culture, leadership, and governance at this corporation. Maybe one reason such problems are allowed to fester is that in the current case, like the last two involving GSK, and as is typical for the legal settlements and crimes we have discussed before, no individuals who authorized, directed, or implemented the problematic behavior seem to have suffered any negative consequences or paid any penalty. In fact, the Guardian just <a href="http://www.guardian.co.uk/business/2010/oct/28/glaxosmithkline-executives-allegedly-ignored-eckard">pointed out</a>: <blockquote>Five of the six senior GlaxoSmithKline executives cited by a whistleblower as part of a cover-up of contamination problems at the group's Puerto Rico factory are understood to still be employed by the pharmaceuticals company. Cheryl Eckard, who was sacked by the company as a quality control manager in 2003 after repeatedly raising her concerns with a series of GSK executives, received a $96m (£61m) reward this week as part of a $750m criminal and civil settlement between US regulators and the company. Her evidence stated that she believed company executives refused to acknowledge the gravity of the production violations – which included the wrong strength of pills being shipped – because it would delay the approval of two new drugs by the US Food and Drug Administration. The court documents allege that Eckard, who had recommended the factory be shut until the issues were resolved, communicated the quality violations at the plant in Cidra to David Pulman, president of global manufacturing and supply; Janice Whitaker, senior vice president of global quality; Peter Savin, vice president of global quality assurance; Diane Sevigny, director of global quality assurance, risk management and compliance; and Jonathan Box, vice president of manufacturing and supply for North America. All five executives are believed to be still working for the London-listed company, while Pulman is also a member of the company's 18-strong corporate executive team, which includes chief executive Andrew Witty.</blockquote> As we have said endlessly, 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.  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.  Further, expect organizations that did not uphold high standards in one instance to fail to uphold them in other instances. See also comments on the <a href="http://postscript.communitycatalyst.org/?p=1832">Postscript blog</a>.

GlaxoSmithKline Subsidiary Pleads Guilty to Manufacturing Adulterated Drugs: Three Strikes and ...?

PaxilFirst there was Paxil (Seroxat in the UK, or paroxetine), the anti-depressant whose marketing lead GlaxoSmithKline (GSK) to settle allegations of fraud brought by then New York Attorney General E…

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29 Oct 2010

The Avandia Spin Cycle Continues Even After the FDA Safety Hearings

We have posted multiple times about Avandia (rosiglitazone), GlaxoSmithKline's star-crossed glucose-lowering drug.  While Avandia has received considerable media coverage, we focused on two questions: 1 - what are the benefits and harms of rosiglitazone as a treatment of type 2 diabetes, and therefore for which patients under what circumstances should this drug be used? 2 - what barriers have prevented physicians and patients from getting the best possible answer to the first question, and what can be done about them?  (See recent post <a href="http://hcrenewal.blogspot.com/2010/02/bring-back-dsi-avandia-case-as-spy.html">here</a>.)  In particular, the Avandia case has illustrated how those with vested interests in the success of a health care product have done their best to obscure information that might threaten its success, even when doing so obscures the information that physicians and patients need to make the best possible decisions.  At one point, (in 2007, no less) we called this the "<a href="http://hcrenewal.blogspot.com/2007/06/avandia-spin-cycle-continues.html">Avandia spin cycle</a>." Avandia once again has been in the news after the US Food and Drug Administration's hearings on the safety of the drug.  These hearings were so well covered in the media that a lengthy summary would be superfluous.  However, their main points demonstrated the persistence of the Avandia spin cycle: - An FDA reviewer felt that "the company's misreadings of the ... Record trial ... were so profound, he concluded, that they 'suggest serious flaws with trial conduct.'" (per Gardiner Harris <a href="http://www.nytimes.com/2010/07/10/health/10diabetes.html">writing</a> in the New York Times) -A former FDA reviewer "withheld from regulators a study showing its Avandia diabetes drug may cause heart attacks." (<a href="http://www.bloomberg.com/news/2010-07-09/glaxo-withheld-avandia-study-former-fda-manager-said-to-testify-in-suit.html">per Bloomberg News</a>) - GlaxoSmithKline's forerunner SmithKline Beecham "secretly began a study to find out if its diabetes medicine, Avandia, was safer for the heart than a competing pill, Actos, made by Takeda."  However, "the study also provided clear signs that it [Avandia] was riskier to the heart.  But instead of publishing the results, the company spent the next 11 years trying to cover them up." (per Gardiner Harris <a href="http://www.nytimes.com/2010/07/13/health/policy/13avandia.html">writing</a> in the New York Times. - "Government experts and a panel of medical advisers repeatedly voiced skepticism on Tuesday about the trustworthiness of GlaxoSmithKline, which makes the controversial diabetes drug Avandia." (per Gardiner Harris again <a href="http://www.nytimes.com/2010/07/14/health/policy/14diabetes.html">writing</a> in the New York Times.) So the Avandia saga has brought to the front pages the concerns we have had with <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppression</a> and <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation</a> of clinical research, especially when pursued by health care organizations with vested interests in the results of specific research projects coming out a certain way, and how they have been enabled by those with <a href="http://hcrenewal.blogspot.com/search/label/conflicts%20of%20interest">conflicts of interest</a>.  Doctors thus should be worried whether those of us who try to practice evidence-based medicine have been fooled into practicing <a href="http://hcrenewal.blogspot.com/search/label/pseudo-evidence%20based%20medicine">pseudo-evidence-based-medicine</a>. Those commenting on the story focused on the need for transparency when clinical research is funded and run by the corporations whose products are being evaluated. -  "GlaxoSmithKline, the maker of Avandia, can't be trusted to report adverse clinical results fairly.  The company must be watched like a hawk as additional trials that it sponsors go forward."  (<a href="http://www.nytimes.com/2010/07/15/opinion/15thu1.html">NY Times editorial</a>) -  "What America should demand in return for ... [generous patent] protection is that the FDA be able to make an honest evaluation of the efficacy of drugs.  When drug companies make this impossible by suppressing test results, not only do they violate their fundamental obligation of honesty with the public, their customers and their regulator, but they also break the bargain they have struck in return for the protection of their intellectual capital."  (Former NY Attorney General Eliot Spitzer<a href="http://www.slate.com/id/2260470/"> in Slate</a>.) Instead, as I have written before, maybe we ought to consider whether those with vested interests in drugs or devices ought to be running clinical research meant to evaluate their own products.  Ironically, while this discussion of how the Avandia spin cycle first began to revolve were going on, others were still trying to add revolutions (per minute).  In particular, a Reuters <a href="http://www.reuters.com/article/idUSN1511649320100715">story</a> noted: <blockquote>Three influential groups of doctors who treat diabetes urged patients not to stop taking Avandia, saying on Thursday that while news about the controversial drug may be frightening, it would be worse to suddenly stop taking it.</blockquote> That is odd, given that Avandia has never been shown to improve clinical outcomes for patients with diabetes, and that there are many other drugs that control blood sugar which appear to be safer. But wait, there is more, <blockquote>The Endocrine Society, American Diabetes Association and the American Association of Clinical Endocrinologists worried that patients may be afraid to take Avandia. 'Patients should continue taking all currently prescribed medications unless instructed otherwise by their health care provider,' Dr. Robert Vigersky of the Endocrine Society said in a statement. 'Stopping diabetes medications can cause significant harm and result in higher levels of blood glucose that may cause severe short term health problems and could increase the risk of diabetes-related complications in the long term.'</blockquote> Would not it make more sense to advise patients still on Avandia to consult with their doctors urgently about possible alternatives?  Meanwhile, it does not seem irrational to be afraid of taking Avandia, given the increasing evidence about its harms, and increasing evidence that what we know about its harms may be an under-estimate. So I wondered why these august medical societies seemed so unaffected about the doubts about Avandia's safety, and about the evidence offered to support its use that the latest news ought to generate. It turns out that all three of the medical societies get financial support from, -- wait for it --, GlaxoSmithKline. The Endocrine Society lists GSK as one of its <a href="http://www.endo-society.org/industry/CLB_about.cfm">Corporate Liaison Board Members</a>. The American Diabetes Association lists GSK as one of its <a href="http://www.diabetes.org/donate/sponsor/our-corporate-supporters.html">Banting Circle Supporters</a>, that is, those that give at least $1,000,000 a year. The American Association of Clinical Endocrinologists lists GSK as a member of its <a href="http://www.aace.com/org/cap/capdirectory.php">Corporate AACE Partnership</a>. (I was not able to find out the total amount contributed by GSK to either the Endocrine Society or the AACE.) So once again, the loudest voices in support of the product come from those used to, and perhaps dependent on financial support from its manufacturer. As a physician, I have been particularly disappointed that our medical societies, whose missions are ostensibly to support our professional values, seem to act more and more like marketers for the companies whose contributions, rather than members' dues increasingly support them. The cycle keeps spinning. For further thoughts on the latest in the Avandia case, see <a href="http://brodyhooked.blogspot.com/2010/07/side-trip-into-diabetes-selling-wrong.html">this post</a> by Howard Brody on the Hooked: Ethics, Medicine and Pharma blog, and <a href="http://alison-bass.blogspot.com/2010/07/when-will-big-pharma-learn-story-of.html">this</a> by Alison Bass on the Alison Bass Blog.

The Avandia Spin Cycle Continues Even After the FDA Safety Hearings

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18 Jul 2010

Study: Researchers with Glaxo ties favored Avandia

As mentioned in my previous post on the MIT controversy surrounding an economist's testifying to Congress on healthcare policy without revealing possible economic conflicts of interest that could affect his views, frequently expressed on this blog are concerns about undisclosed conflicts of interest and their corrosive effects upon healthcare (<a href="http://hcrenewal.blogspot.com/search/label/conflicts%20of%20interest">query link</a>). One major question that arises is the degree to which conflicts of interest can affect the integrity of the scientific literature. Answering this question is more a matter of social science research rather than biomedical inquiry. One internal medicine resident at the Mayo Clinic took on this challenge and published such a study, a systematic review, in the British Medical Journal. It is entitled "<a style="font-weight: bold;" href="http://www.bmj.com/cgi/content/full/340/mar18_1/c1344">Association between industry affiliation and position on cardiovascular risk with rosiglitazone: cross sectional systematic review</a>" (BMJ 2010;340:c1344). Mayo Clinical researchers led by the resident, Amy Wang, examined more than 200 articles that appeared after an analysis in the NEJM linked Avandia to a 43 percent increased risk of heart attacks, and a subsequent clinical trial found no greater danger of heart disease. The results are fascinating. From a summary in the <a href="http://www.philly.com/inquirer/business/homepage/20100320_Study__Researchers_with_Glaxo_ties_favored_Avandia.html">Philadelphia Inquirer</a>:<blockquote> "We aimed to determine whether financial conflicts of interest with pharmaceutical manufacturers could be fueling this fire," wrote the researchers, led by Amy Wang, a resident in internal medicine at the Mayo Clinic in Rochester, Minn. "From our findings, it appears that the answer is yes.</blockquote> From the BMJ article itself, free full text available as of this writing at link above: <blockquote>For each article, we sought information about the authors’ financial conflicts of interest in the report itself and elsewhere (that is, in all publications within two years of the original publication and online). Two reviewers blinded to the authors’ financial relationships independently classified each article as presenting a favourable (that is, rosiglitazone does not increase the risk of myocardial infarction), neutral, or unfavourable view on the risk of myocardial infarction with rosiglitazone and on recommendations on the use of the drug.</blockquote> The "and elsewhere" can be a valuable addition to the capabilities of today's researchers, often enabled via the internet (e.g., non-literature based resources such as conference brochures, personal web pages, corporate and other financial disclosures. etc.) when articles themselves prove unrevealing. Overall, this is a straightforward methodology, and while potentially subject to bias and expertise issues, nonetheless seems an excellent new contribution to the needed social research on undisclosed COI's. As to results (see the full article for statistical details I am omitting here): <blockquote> Of the 202 included articles, 108 (53%) had a conflict of interest statement. Ninety authors (45%) had financial conflicts of interest. Authors who had a favourable view of the risk of myocardial infarction with rosiglitazone were more likely to have financial conflicts of interest with manufacturers of antihyperglycaemic agents in general, and with rosiglitazone manufacturers in particular, than authors who had an unfavourable view. There was likewise a strong association between favourable recommendations on the use of rosiglitazone and financial conflicts of interest. These links persisted when articles rather than authors were used as the unit of analysis, when the analysis was restricted to opinion articles or to articles in which the rosiglitazone controversy was the main focus, and both in articles published before and after the Food and Drug Administration issued a safety warning for rosiglitazone.</blockquote> While causality is not proven, these results are still stunning. Per the Inquirer's summary: <blockquote>... Almost 90 percent of scientists who wrote positive articles, reviews, or commentaries about Avandia had financial ties to London-based Glaxo, the study published in the British Medical Journal found. Almost three of every four authors who expressed negative views of the drug had no financial ties to manufacturers of diabetes medicines, while just 6 percent of those with positive opinions of the drug received no funding or fees from industry.</blockquote> The authors cite prior literature also demonstrating an associations of COI with pro-industry views (references 2-6; #2 is regarding the mid 1990's calcium channel blocker controversy). The authors observe that: <blockquote>In the past decade, research and policy has focused on this association [between COI and pro-industry views - ed.], leading to important progress in policies to manage and encourage disclosure of such financial conflicts of interest. </blockquote> Their findings about the effects of this "progress" was particularly disappointing, that only about half of the articles carried conflict-of-interest statements: <blockquote> Of the 202 eligible studies (10 reported original research, 91 were letters, editorials, or commentaries, and 101 were reviews, meta-analyses, or guidelines), 108 articles (53%) included a conflict of interest statement. [The other 47% did not - ed.] </blockquote>One wonders about the publishers of the articles themselves omitting COI statements, either acknowledging possible COI's or confirming that no COI's exist. <blockquote>... A total of 90 (45%) of the 202 articles were authored by individuals who had financial conflicts of interest. Of the 90 studies with conflicts of interest, 69 (77%) had a statement disclosing the conflict of interest in the article itself. The other 21 studies with financial conflicts of interest (23%) did not disclose these relationships, which were discovered through searching other publications by the same author or the internet. Three (14%) of these 21 studies published a statement declaring no conflicts of interest. [Oops - ed.]</blockquote> So, almost one quarter of articles with author COI did not disclose that fact, and several misrepresented the issue. Finally, the pharmaceutical company's view, also published in the Inquirer article cited above: <blockquote>A Glaxo spokeswoman said the company posted information and results from all its clinical trials on its Web site. "It's vital that people have trust in the way we do research and the way it's made public," Jo Revill, Glaxo spokeswoman, said yesterday. "Part of that is sharing data. What we have done is develop policies that will have disclosure and encourage disclosure." </blockquote> "Encouraging" disclosure of COI's is far too weak a stand for a pharmaceutical company to take on such a critical issue, in my view. The Mayo researchers wisely conclude: <blockquote> Disclosure rates for financial conflicts of interest were unexpectedly low, and there was a clear and strong link between the orientation of authors’ expressed views on the rosiglitazone controversy and their financial conflicts of interest with pharmaceutical companies. Although these findings do not necessarily indicate a causal link between the position taken on the cardiac risk of rosiglitazone in patients with diabetes and the authors’ financial conflicts of interest, they underscore the need for further changes in disclosure procedures in order for the scientific record to be trusted.</blockquote> Finally, I add that these findings are not too surprising. It's human nature not to bite the hand that feeds you. Money is also a powerful stimulant to the brain's rationalization (as opposed to rational) centers. We as a culture do truly need to understand the potential corrosive effects on the scientific literature of dysfunctions such as ghostwriting, financial and other conflicts of interest, publish-or-perish pressures of academia, and other such social issues. These practices also simply need to be abolished, for as I have written before on these pages ("<a style="font-weight: bold;" href="http://hcrenewal.blogspot.com/2009/08/has-ghostwriting-infected-experts-with.html">Has Ghostwriting Infected The Experts With Tainted Knowledge, Creating Vectors for Further Spread and Mutation of the Scientific Knowledge Base?</a>"), once a "critical mass" of faux knowledge is put into circulation via the scientific literature, even the ostensibly impartial experts' views can become tainted, dependent as they are on that very same scientific literature. Even worse, we don't know what that critical mass is - or whether we've reached it already. -- SS

Study: Researchers with Glaxo ties favored Avandia

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20 Mar 2010

Bring Back the DSI*? - the Avandia Case as Spy Novel

Starting in 2007, we posted quite a bit about the "Avandia case," which centered on whether Avandia (rosiglitazone, by GlaxoSmithKline), a glucose lowering drug for type 2 diabetes, presented excess cardiovascular risks, and how evidence about these risks was handled.  Summary The Nissen and Wolski meta-analysis [Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online <a href="http://content.nejm.org/cgi/content/full/NEJMoa072761">here</a>] was to be the first published article to combine data from all relevant clinical trials of rosiglitazone then available.  Although two major trials of Avandia had been published, its manufacturer, GlaxoSmithKline, had performed many other smaller trials of the drug which remained unpublished.  These results eventually appeared on a <a href="http://www.gsk-clinicalstudyregister.com/">web-site run by GSK</a>. However, this web-site was relatively obscure.  It had not been created voluntarily, but in response to a settlement of legal action that alleged GSK had suppressed clinical research about its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link <a href="http://content.nejm.org/cgi/content/full/351/18/1820">here</a> and our post <a href="http://hcrenewal.blogspot.com/2007/01/not-something-we-want-to-publicise-spin.html">here</a>). Nissen and Wolski found the site, compiled the results of trials on Avandia it contained, and combined their results with those of the few published trials in their meta-analysis. It is to the credit of Nissen and Wolski that they were able to figure out how to do this. It is not to the credit of GSK that they sat on the data from these trials, only put it on this web-site when compelled to do so, did not make any effort to publicize the web-site, and did not publish a meta-analysis done by company scientists that showed qualitatively similar results to that eventually done by Nissen and Wolski (see post <a href="http://hcrenewal.blogspot.com/2007/05/dream-turns-to-nightmare-avandia-and.html">here</a>).   I originally <a href="http://hcrenewal.blogspot.com/2007/06/avandia-spin-cycle-continues.html">thought</a> the case raised two questions:  1 - what are the benefits and harms of rosiglitazone as a treatment of Type 2 diabetes, and therefore for which patients under what circumstances should this drug be used?  2 - what barriers have prevented physicians and patients from getting the best possible answer to the first question, and what can be done about them?   But the immediate response to the Nissen and Wolski meta-analysis was a spin cycle that seemed to obfuscate these questions, and the answers to him (see posts <a href="http://hcrenewal.blogspot.com/2007/06/more-on-avandia-why-we-need-to-call-off.html">here</a>, <a href="http://hcrenewal.blogspot.com/2007/06/wall-street-journal-gives-avandia-whirl.html">here</a>, <a href="http://hcrenewal.blogspot.com/2007/06/avandia-spin-cycle-continues.html">here</a>, and <a href="http://hcrenewal.blogspot.com/2007/11/silencing-avandia-whistle-blower.html">here</a>)   A Reconsideration   In the last few weeks, several articles about Avandia have appeared in the media, and in medical journals, that reconsider the issues, and in particular, the "Avandia Spin Cycle."  First was a commentary in the European Heart Journal by Dr Steven E Nissen, the first author of the meta-analysis [Nissen SE. The rise and fall of rosiglitazone. Eur Heart J 2010: published online <a href="http://eurheartj.oxfordjournals.org/content/early/2010/02/11/eurheartj.ehq016.long">here</a>.]  Dr Nissen provided a narrative history of the Avandia case from his viewpoint, and summarized it thus: <blockquote>What were the key mistakes and lessons learned from the rosiglitazone affair? 1. The FDA rushed to approve rosiglitazone because of hepatotoxicity concerns about troglitazone, resulting in failure to consider the ‘signals’ suggesting cardiovascular toxicity. 2. An early critic of rosiglitazone was intimidated by company representatives and effectively silenced, a process antithetical to the principals of open scientific discourse. 3. Although early warnings were issued for the risk of heart failure, these warnings went largely unheeded in the face of aggressive marketing and promotion suggesting cardiovascular benefits. 4. No well-designed cardiovascular outcome trials were ever conducted for rosiglitazone, despite evidence suggesting increased cardiovascular risks. The only cardiovascular outcome trial was an open label study driven by a soft endpoint (hospitalization) with low adherence to randomized medications, seriously underpowered, and not completed until 10 years following launch. 5. Although both the FDA and the company were aware of evidence of an increased risk of adverse cardiovascular outcomes, certainly by 2005, neither warned physicians nor the public. 6. When a meta-analysis of rosiglitazone was eventually submitted for publication, the company subverted the editorial review process by stealing a copy of the manuscript and used this advance knowledge inappropriately to unblind an ongoing randomized trial. 7. Approval of diabetes drugs based exclusively upon their glycaemic effects has been short-sighted and scientifically unwise. Drugs that lower blood sugar may have other adverse effects that overcome any inherent benefits. 8. The failure of  50 other PPARs, many for adverse cardiovascular effects, went largely unreported because of negative publication bias. Such knowledge might have warned the medical community about the potential risk of these agents.</blockquote> Meanwhile, the <a href="http://www.nytimes.com/2010/02/20/health/policy/20avandia.html">New York Times published </a>conclusions of some internal US Food and Drug Administration (FDA) reports, and of an investigation by the US Senate Finance Committee. FDA safety officials suggested that Avandia should be taken off the market. Some key points from the Senate investigation were: <blockquote>The bipartisan multiyear Senate investigation — whose results are expected to be released publicly on Monday but which were also obtained by The Times — sharply criticizes GlaxoSmithKline, saying it failed to warn patients years earlier that Avandia was potentially deadly. 'Instead, G.S.K. executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk,' ....</blockquote>In combination, the Nissen commentary, and the Senate report nicely summarized what I called the "Avandia spin cycle" above.  It appears that research was suppressed, marketing was deceptive, and critics and whistleblowers were intimidated.  Finally, Dr Harlan Krumholz published a commentary about the thiazolidinedione drugs (a group that includes rosiglirazone) in Circulation Cardiovascular Quality and Outcomes [Krumholz HM. A perspective on the American Heart Association Presidential Commission Advisory on thiazolidenedione drugs. Circ Cardiovasc Qual Outcomes 2010; 3 available online, link <a href="http://circoutcomes.ahajournals.org/cgi/rapidpdf/CIRCOUTCOMES.110.936070v1.pdf">here</a>], and <a href="http://www.forbes.com/2010/02/24/diabetes-glaxosmithkline-avandia-business-healthcare-heart-attack.html">an op-ed in Forbes</a>. The latter sums it all up nicely: <blockquote>I want to believe in America's pharmaceutical companies. I want to believe that people in these companies believe that the best strategy for success is to do what is best for patients. I want to believe that they are interested in scientific truth and eager to know of any safety issues and ready to share that information with the public. This week I was disappointed again. Over the years GlaxoSmithKline ( GSK - news - people ) has repeatedly reassured the public about the safety of its blockbuster diabetes drug Avandia. But this weekend the Senate Finance Committee released a report revealing that inside the company Glaxo's own experts and advisors were raising concerns about whether the drug could cause heart problems all along. The report, based on more than 250,000 internal documents, provides a rare and unsettling glimpse into the decision by company executives to deflect safety issues--even as their own experts agreed with conclusions of outside researchers who were warning the public about possible harms. The documents reveal that company researchers were deeply concerned about the cardiovascular safety of the drug as far back as 2003. The pages of the Senate report read like a spy novel: Glaxo receiving confidential documents leaked by a sympathetic academic who consulted for the company; the company embarking on a campaign to intimidate critics who warned about potential safety issues with the drug; and executives pulling strings to release data early from a scientific study that was supposedly controlled by an 'independent' committee of researchers.</blockquote> So, <blockquote>The story here is less about the drug--the Senate report breaks no new ground about Avandia's safety issues (even among experts there remains some controversy)--and more about the ethical behavior of a company. What is clear: Glaxo failed to disclose its own concerns even as it sought to discredit outside researchers who were raising questions about the drug. This type of behavior is eroding the public trust in the pharmaceutical industry.</blockquote>Policy Implications Finally, Dr Krumholz concludes with some solutions with which I heartily agree: <blockquote>The fix is simple: Once a drug is approved, all data relevant to drug safety should be placed in the public domain and independent investigators across the country should be able to use it. There should be big financial penalties for withholding relevant information. Drug studies sponsored by industry must be truly independent--outside of company control. Companies should give outside investigators independence over every aspect of the study. There are too many examples of companies wresting control of clinical studies from their consultant investigators for reasons that seem more related to product promotion than clinical science. And on all sides there should be a commitment to protect against the intimidation of academics who are willing to raise questions about the safety and effectiveness of company products. The free flow of information about the effects of drugs and medical devices will best serve the public's interest.</blockquote>Here in the US, the debate over health care reform has reached a new phase. Today the President is hosting an attempt to get bipartisan discussion of reform going again. Now that there is a new opportunity for discussion, I submit that would be health care reformers ought to think about the underlying causes of our continuing problems with rising costs, declining access, stagnant quality, and demoralized health care professionals. One set of causes that is rarely discussed has to do with the distortion of clinical research by commercial research sponsors with vested interests in the results turning out in favor of their products, and the further distortion of clinical discourse and decision making by the deceptive marketing practices of these same organizations. If we started introducing steps like those suggested by Dr Krumholz into health care reform, maybe we really could decrease costs, increase access, improve quality, and renew professionalism. *Bring Back the DSI? To lighten things up a bit, and to explain the title... When I was in school in the 1960s, I first became a fan of the <a href="http://hardyboys.bobfinnan.com/">Hardy Boys</a> mysteries, then the slightly more mature <a href="http://www.aandc.org/research/biblio_pease_h.htm">Tod Moran series</a>.  While on the <a href="http://www.oceanlinermuseum.co.uk/nieuw_amsterdam.htm">Neiuw Amsterdam</a> (the 1938 version) one day out of Kingston, Jamaica, I viewed <a href="http://www.imdb.com/title/tt0055928/">Dr No</a>, the first James Bond movie, a sophisticated spy thriller, not a spoof like some later entries in the series.  I later read all the classics, like those by <a href="http://www.agathachristie.com/">Agatha Christie</a>, <a href="http://en.wikipedia.org/wiki/Erle_Stanley_Gardner">Earl Stanely Gardner</a>, <a href="http://www.nerowolfe.org/">Rex Stout</a>, <a href="http://en.wikipedia.org/wiki/Ellery_Queen">Ellery Queen</a>, etc.  So it should be no surprise that I, like many other schoolboys and girls, collaborated to form an amateur detective and intelligence agency.  But this was the sophisticated 1960s, so we called it the Department of Scientific Investigation (DSI).  We skulked around New York City and its suburbs looking for spies, saboteurs, and common criminals.  Luckily, we never really found any.  As more realities intruded, I gave up any ideas about becoming an investigator or intelligence agent (although I still read mysteries, spy novels, and thrillers to this day, but mainly on airplanes.)  Once I became a physicians, those days in the DSI seemed very remote (although the title does now seem like it ought to be part of the NIH ;-) ). However, after reading Dr Krumholz's article above, maybe we need to resurrect the DSI.  At least, maybe we health professionals ought to consider how we can become better and more organized watchdogs for the kind of problems revealed in the Avandia case, and in many other cases discussed on <a href="http://hcrenewal.blogspot.com/">Health Care Renewal</a>. But if any of my old DSI colleagues want to set up a reunion, it would be fine with me.  ADDENDUM (25 February, 2010) - see also comments by Dr Howard Brody <a href="http://brodyhooked.blogspot.com/2010/02/avandia-story-failures-of-regulation.html">on the Hooked: Ethics, Medicine and Pharma blog</a>.

Bring Back the DSI*? - the Avandia Case as Spy Novel

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25 Feb 2010

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