You Say You Want Some Revolutions? - Famed Academic Physician Dr Milton Packer's Endless Alternating Turns as Drug Company Spokesperson and FDA Advisor

Last week, we noted  we again discussed the web of conflicts of interest that is draped over medicine and health care, and seems responsible for much of our current health care dysfunction.  We have discussed examples of conflicts of interest affecting clinical research, clinical teaching, clinical care, and health care policy.  Each time I think we must have cataloged all the useful examples, a striking new one appears.

Only a few days later, yet another new variant has in fact appeared.

A New Kind of Revolving Door

A new version of the "revolving door" apparently was first noted by Public Citizen, and then reported by Ed Silverman at Pharmalot. 

The usual version of the revolving door occurs when a person transitions from a full-time job in industry to a government position which has regulatory authority or other influence over that same industry, or vica versa.  We have discussed various health care manifestations of that revolving door here.

The new version, as described by Mr Silverman, in its manifestation at the US Food and Drug Administration (FDA) is:

the agency allows some experts who serve on its advisory panels to also make presentations at other meetings of these same panels on behalf of drug makers. By allowing some people to wear different hats within a short amount of time, the advocacy group charges the FDA creates the potential for bias to creep into the proceedings.

The Public Citizen letter to the FDA summarized the problem,

In particular, a sponsor’s use of an individual who serves, or has recently served, as a voting member of an FDA advisory committee to present its case before that member’s colleagues on the committee takes advantage of the special collegiality existing among members in order to improve a company’s chances of a favorable vote. Furthermore, such a revolving door raises concerns about the objectivity of committee members who accept such paid arrangements, with FDA’s approval, at future hearings involving the same or a rival company.

Someone Familiar Going Round and Round

The Public Citizen letter used as an example one well-known academic physician who seemed to have made many revolutions in this sort of revolving door.  As summarized in the PharmaLot post,

As an example, Public Citizen cites a meeting this past March 27 of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, which was held to review an application for a Novartis drug called serelaxin to treat acute heart failure. And Milton Packer, who chairs the department of clinical sciences at UT Southwestern, appeared as a paid speaker on behalf of Novartis.

In his opening remarks, Packer disclosed that Novartis paid for his time and travel, according to the advocacy group. But because he is also considered to be a ‘special government employee,’ which is how advisory panel members are classified, he obtained permission from the FDA to participate as a paid speaker for Novartis (see page 31 here).

However, Packer served as a temporary voting member of the same FDA advisory committee less than two months earlier. Moreover, Public Citizen says this was the sixth time, since Packer first presided as chair of this committee in 1997, that he had 'spoken on behalf of and/or served as a (presumably) paid consultant' to drug makers whose meds were being reviewed at those meetings.

The other occasions in which Packer appeared before the Cardiovascular and Renal Drugs Advisory committee involved speaking on behalf of Bristol-Myers Squibb in 2002; acting as a consultant and speaker for GlaxoSmithKline in 2003; appearing as a speaker for NitroMed in 2005; appearing as a speaker for Sanofi in 2009 and acting as a consultant on behalf of Pfizer in 2010.

In fact, the Public Citizen letter also asserted that

Dr. Packer’s presence as an FDA advisory committee member at hearings extends beyond the CRDAC, as he has also participated in at least three meetings of the Arthritis Advisory Committee and served at least once on the Endocrinologic and Metabolic Drugs Advisory Committee since 2005.

We note with concern that, as with his revolving-door tenure at CRDAC, Dr. Packer has similarly worked with industry in the following capacities at non-CRDAC advisory committees while intermittently serving as a recurring member of some of these same committees:

- As a consultant to Centocor for its presentation on infliximab (Remicade) to the March 4, 2003, meeting of the Arthritis Advisory Committee;
- As an 'external expert' cited by GlaxoSmithKline at the July 30, 2007, joint meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees to discuss the cardiac ischemic risks of the thiazolidinedione diabetes drugs, with a focus on rosiglitazone (Avandia); and
- As a consultant to Boehringer Ingelheim for its presentation concerning the drug tiotropium (Spiriva HandiHaler), made before the November 19, 2009, meeting of the Pulmonary-Allergy Drugs Advisory Committee.

Summary

Dr Milton Packer served as a presumably paid spokesperson for six different pharmaceutical companies advocating for six different drugs at meetings of the FDA Cardiovascular and Renal Drugs Advisory Committee.  Over roughly the same time period he served as the chair, acting chair, or voting member of that same committee in numerous instances.  Also, Dr Packer served as a presumably paid spokesperson for one of the same drug companies, and for two additional drug companies advocating for another three drugs at meetings of three other FDA advisory committees.  On various occasions he had also served as a member of these three committees.  Parenthetically, one of the drugs for which Dr Packer, a cardiologist, advocated, Avandia, to a non-cardiologic committee was subsequently pulled from the market because of concerns about excess cardiologic complications (look here). 

Dr Packer repeatedly went back and forth between roles as a paid advocate for drug companies and as a member or chair of federal advisory committees which could influence FDA decisions about the drugs for which he advocated and which were made by the companies that employed him.


It certainly seems that Public Citizen was right in that the sorts of transitions Dr Packer made constituted multiple conflicts of interest, and that his work for multiple drug companies was likely to have distorted the recommendations of the committees on which he served.  Rapid transitions between temporary committee memberships and paid advocacy positions before such committees does seem to be a new version of the revolving door, and newly discovered type of conflict of interest.  It seems that conflicts of interest now pervade every aspect of health care, with huge cumulative effects on clinical and health policy decision making.

Note also that the person whose conflicts of interest were used as examples by Public Citizen just appeared in Health Care Renewal in another capacity.  Earlier this month we discussed a study (PARADIGM - HF) of a new drug for congestive heart failure (sacubitril) which received prominent media attention.  After various people, not limited to yours truly, pointed out that this study seemed to have multiple flaws which undercut claims that the new drug would be a "game changer," the principal investigator of the study delivered a written whupping to a critic whose writing appeared prominently on a cardiology web-site .  The scathing comeback, however, seemed based on a volley of logical fallacies, including repetitive ad hominem attacks on the critic (look here).  The PARADIGM - HF Principal Investigator was none other than the same Dr Milton Packer whose revolving door cycles were discussed above.  Note that the company that sponsored, and largely ran and designed PARADIGM - HF, and which paid Dr Packer to serve as Principal Investigator, was the same Novartis for whom Dr Packer was a spokesperson in the first example above. 

We wondered whether Dr Packer's conflicts of interest contributed to confused, illogical thinking and his apparently logically fallacious response to his critic.  Now it appears that Dr Packer has been immersed much more deeply in conflicts of interest than were apparent a few days ago.  So should he be regarded mainly as a heart failure "expert," or mainly as a paid marketer and public relations man for drug companies?  Obviously, he is both, but the mixture is not so clear.  The concern is all the more important because Dr Packer has become such a prominent medical academic.

So once again, again, again,...  we call for all conflicts to be disclosed in the interests of honesty.  Beyond that, as we have been saying for years, patients' and the public's health would benefit from an aggressive effort to reduce conflicts of interest affecting clinical and health policy decision making.    

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, per the Philadelphia Inquirer,

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.

Why the deal was announced this month is not clear. Neither are all its provisions:

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.

The Inquirer listed some possible reasons for the settlement,

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.

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:

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.'

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 post on the PharmaLot blog suggested one motivation:

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.

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 official GSK biography,

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.

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 posted, 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 Side Effects by Alison Bass. We posted about various aspects of this case, e.g., more recently here, here, and here.  The case continues to echo to this day: see this post 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 "spin cycle" 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 here) Once again, it appears that research was suppressed and manipulated (e.g., see here), Avandia critics were attacked by "experts" whose financial relationships with GSK were not always obvious (e.g., see here), and there were allegations that GSK executives tried to intimidate those who disagreed with them (e.g., see here and here).  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 posted 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 report of the $3 billion settlement, there is this quote from Dr Sidney Wolfe,

'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.'

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 the Fear and Loathing in Bioethics blog, the Hooked: Ethics, Medicine and Pharma blog, and on the University Diaries blog.

ADDENDUM (21 November, 2011) - See also these posts on the call for the withdrawal of Study 329 on the Alison Bass blog, and the 1BoringOldMan blog.

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 Side Effects by Alison Bass.  We posted about various aspects of this case, e.g., more recently here, here, and here. 

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 "spin cycle" 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 here)  Once again, it appears that research was suppressed and manipulated (e.g., see here), Avandia critics were attacked by "experts" whose financial relationships with GSK were not always obvious (e.g., see here), and there were allegations that GSK executives tried to intimidate those who disagreed with them (e.g., see here and here). 

Adulterated Drugs

And now it is adulterated drugs.  Here is the version from Bloomberg:

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.

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 parade of legal settlements 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 Baxter International and Johnson and Johnson. 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 pointed out:

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.

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 Postscript blog.

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 here.) 

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 "Avandia spin cycle."

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 writing in the New York Times)
-A former FDA reviewer "withheld from regulators a study showing its Avandia diabetes drug may cause heart attacks." (per Bloomberg News)
- 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 writing 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 writing in the New York Times.)

So the Avandia saga has brought to the front pages the concerns we have had with suppression and manipulation 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 conflicts of interest.  Doctors thus should be worried whether those of us who try to practice evidence-based medicine have been fooled into practicing pseudo-evidence-based-medicine.

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."  (NY Times editorial)
-  "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 in Slate.)

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 story noted:

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.

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,

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.'

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 Corporate Liaison Board Members. The American Diabetes Association lists GSK as one of its Banting Circle Supporters, 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 Corporate AACE Partnership. (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 this post by Howard Brody on the Hooked: Ethics, Medicine and Pharma blog, and this by Alison Bass on the Alison Bass Blog.

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 (query link).

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 "Association between industry affiliation and position on cardiovascular risk with rosiglitazone: cross sectional systematic review" (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 Philadelphia Inquirer:

"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.

From the BMJ article itself, free full text available as of this writing at link above:

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.

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):

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.

While causality is not proven, these results are still stunning. Per the Inquirer's summary:

... 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.

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:

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.

Their findings about the effects of this "progress" was particularly disappointing, that only about half of the articles carried conflict-of-interest statements:

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.]

One wonders about the publishers of the articles themselves omitting COI statements, either acknowledging possible COI's or confirming that no COI's exist.

... 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.]

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:

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."

"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:

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.

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 ("Has Ghostwriting Infected The Experts With Tainted Knowledge, Creating Vectors for Further Spread and Mutation of the Scientific Knowledge Base?"), 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

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 here] 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 web-site run by GSK. 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 here and our post here).

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 here).
 
I originally thought 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 here, here, here, and here)
 
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 here.]  Dr Nissen provided a narrative history of the Avandia case from his viewpoint, and summarized it thus:

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.

Meanwhile, the New York Times published 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:

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,' ....

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 here], and an op-ed in Forbes. The latter sums it all up nicely:

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.

So,

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.

Policy Implications

Finally, Dr Krumholz concludes with some solutions with which I heartily agree:

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.

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 Hardy Boys mysteries, then the slightly more mature Tod Moran series.  While on the Neiuw Amsterdam (the 1938 version) one day out of Kingston, Jamaica, I viewed Dr No, 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 Agatha Christie, Earl Stanely Gardner, Rex Stout, Ellery Queen, 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 Health Care Renewal.

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 on the Hooked: Ethics, Medicine and Pharma blog.

FDA Accuses GSK of Suppressing Clinical Research

We have posted quite a lot about what came to be called the "Avandia" case. This started with the publication in the New England Journal of Medicineby Nissen and Wolski of a meta-analysis focused on cardiac adverse effects of rosiglitazone (Avandia, by GlaxoSmithKline) (see post here). One of the most important aspects of this case, in my humble opinion, which we posted about here, but has not been widely discussed, is that it is a case of the suppression of clinical research.

As we posted last year, 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 here] was to be the first published article to combine data from all relevant clinical trials of rosiglitazone completed to date. Although two major trials of Avandia had been published, its manufacturer, GlaxoSmithKline, had performed many other smaller trials of the drug, most of which have not been published to date. They did eventually appear on a web-site run by GSK. However, this web-site was relatively obscure, and it was not 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 here and our post here).

Nissen and Wolski found it, compiled the results of trials on Avandia, and combined their results with those of the few published trials in their meta-analysis.It is to the credit of Nissen and Wolski 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 done by Nissen and Wolski (see post here).

Now, as first reported on the PharmaLot and WSJ Health Care blogs, the US Food and Drug Administration (FDA) issued a warning letter to GSK about its suppression of multiple studies about Avandia. (Link here courtesy PharmaLot.)

In particular, the letter asserted,

The inspection found that your firm failed to report multiple postmarketing studies involving Avandia in mandatory Periodic and/or NDA Annual Reports.

The letter listed numerous studies which GSK failed to report

Furthermore, the letter stated,

Your firm lacked appropriate knowledge of the studies associated with Avandia, resulting in the reporting deficiencies noted. Absent a clear explanation of the extent and cause of these deficiencies and an adequate plan to correct them, we are concerned that similar deficiences in the postmarket reporting for your firms other FDA-approved drugs may exist.

Thus,

The specific violations noted in this letter are serious and may be symptomatic of underlying postmarketing safety reporting failures.

So I guess I wasn't just whistling Dixie when I discussed the Avandia case in terms of suppression of research.

Let's just review why it's bad to suppress research.

First, suppression of research can distort medical decision making, leading to poor decisions for particular patients and thus bad outcomes for some of them. Patients and physicians ideally should base decisions on the best available clinical evidence relevant to the patients' problems. Suppressing evidence that is unfavorable to particular companies' products may lead to use of that product in situations in which it may do no good, or in situations in which it is more likely to produce adverse effects than some alternative. Furthermore, unreasonably delaying or attempting to suppress publication of results of clinical research betrays the trust of the research subjects. Research subjects usually volunteer with the understanding that results of research done on them would be published. Such results could only have been obtained because of their willingness to participate.

At least more cases of attempted suppression of research are now getting the bad publicity they deserve. No we need to fix the problem An obvious solution would be decreasing or abolishing control of clinical research by those with vested interests in the research coming out a certain way.

"Why I Sent It Is a Mystery" - More About Avandia, Conflicts of Interest, and Confused Thinking

We have posted frequently about the controversy about rosiglitazone (Avandia, by GlaxoSmithKline). Some of the distressing aspects of the case were various efforts made to keep information and opinions unfavorable to Avandia away from physicians, patients, and the public, including efforts involving obfuscation, deception, and intimidation. (For example, see this post about the "spinning" of Avandia and the ridiculing of Avandia critics, and this post about attempts to silence an early Avandia critic.)

So it is ironic that the latest Avandia controversy is about the premature release of a manuscript submitted for publication.

Recall how the story began, with the publication in the New England Journal of Medicine by Nissen and Wolski of a meta-analysis focused on cardiac adverse effects of rosiglitazone (Avandia, by GlaxoSmithKline) (see post here). The main achievement of 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 here] was to be the first published article to combine data from all relevant clinical trials of rosiglitazone completed to date. Although two major trials of Avandia had been published, its manufacturer, GlaxoSmithKline, had performed many other smaller trials of the drug, most of which have not been published to date. They did eventually appear on a web-site run by GSK. However, this web-site was relatively obscure, and it was not 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 here and our post here). Nissen and Wolski found it, compiled the results of trials on Avandia, and combined their results with those of the few published trials in their meta-analysis.

Now it turns out one of the NEJM peer reviewers of the Nissen and Wolski manuscript leaked it to GSK well before the manuscript was published. From the News section of Nature,

17 days earlier [before the article was published], the reviewer, diabetes researcher Steven Haffner of the University of Texas Health Science Center at San Antonio, had faxed his copy of the article to Alexander Cobitz, a GSK employee whom Haffner knew from working on an earlier clinical trial of the drug.

This was a serious breach of the reviewers' code of conduct. Having reviewed many articles for many medical journals, (but not the NEJM), I can say with conviction that reviewers are forbidden from releasing unpublished manuscripts to anyone, with only one major exception. Reviewers can seek reviewing help from a colleague, as long as this is disclosed to the journal, and the colleague does not further release the manuscript.

As pointed out by an article by Stephanie Saul in the New York Times,

Under The New England Journal’s rules, reviewers are prohibited from disclosing an article’s contents before publication, as a way of protecting the exclusivity of the journal’s material and protecting the intellectual property of scientists who submit articles.

Besides violating The New England Journal’s rules, disclosing a pending article would also be considered a breach of professional ethics, according to Dr. Jerry Avorn, a professor of medicine at Harvard Medical School. Dr. Avorn said that he was not familiar with the specific allegations against Dr. Haffner.

So why did Dr Haffner do it? His explanation of why he sent the manuscript was at best incoherent.

'Why I sent it is a mystery,' Haffner told Nature . 'I don't really understand it. I wasn't feeling well. It was bad judgement.' Haffner says that Cobitz did not ask to see the draft and was 'probably a bystander'.

According to a report in theHeart.org, a GSK spokesperson rationalized Haffner's conduct thus,

Haffner, who consulted for GSK on Avandia, had concerns and questions regarding the methodology of the analysis and sent the article to GSK for advice from company statisticians.

This begs the question of why he did not simply note in his review his lack of expertise on the relevant statistical issues, or seek help from a statistician at the University of Texas.

So perhaps we should seek other explanations. Dr Haffner, it turned out, had a number of financial ties to GSK. As reported in Nature.

Haffner had earlier served on the steering committee of a GSK-sponsored clinical trial of Avandia. He says that he has given many talks for the company, although he declined to say how much he had earned from them. 'I've got a considerable amount of money. I didn't do it to raise my income or anything like that,' he says.

Furthermore, in the NY Times article,

Dr. Haffner, who had been involved in a clinical study that found Avandia worked better at controlling blood sugar than two other treatments, was quoted last year in the online medical publication TheHeart.org criticizing the publication of Dr. Nissen’s study and of editorials that supported it in two other journals.

'The three major medical journals are becoming more like British tabloid newspapers. All they lack is a bare-chested woman on Page 3,' Dr. Haffner was quoted as saying.

In fact, Dr Haffner was one of the co-investigators for the ADOPT study, which compared rosiglitazone to metformin or glyburide, and was sponsored by GSK. [Kahn SE, Haffner SM, Heise MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43. See link here.] In that article, Haffner disclosed,

Dr. Haffner reports receiving consulting fees from AstraZeneca and Takeda; consulting fees and grant support from Novartis and Pfizer; grant support and consulting and lecture fees from GlaxoSmithKline; consulting and lecture fees from Merck; and lecture fees from Sanofi-Aventis.

Furthermore, an article in the Philadelphia Inquirer noted,

Haffner is a national expert in diabetes. His university Web site calls him 'one of the highest-funded investigators, in terms of [National Institutes of Health] funding, in Health Science Center history.'

And we know that in this age of "greed is good" as the reigning philosophy in medical schools and academic medical centers, the biggest "tax-payers" like Haffner can do no wrong in the eyes of the administrators of these institutions.

So the Avandia story gets more complex, involving more people with more conflicts of interest, and not only suppression of research, but the breach of confidentiality of an unpublished manuscript submitted for publication.

Dr Haffner's nearly nonsensical explanation of why we went running to his fax machine to send the confidential manuscript to his part-time GSK employers is another reminder of the confused reasoning often displayed by people with conflicts of interest, even full professors of medicine who are supposed to be national authorities. As noted before, "people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult." Apparently becoming a consultant for a pharmaceutical company makes one susceptible to faxing confidential manuscripts in a fugue state, something like the sleep-driving pheonomenon reportedly caused by sleep medications like Ambien.

This latest development in the Avandia case is yet another argument that physicians should not only not accept pens, coffee mugs, and free pizzas from companies trying to sell their medical and health care products and services, but that academic physicians should shun all financial ties to these companies. (A physician who wants to work for a pharmaceutical, biotechnology, or device company should do so full-time, or not at all, in my humble opinion.)

Otherwise, prepare to appear on the national news blinking like a deer in the headlights, saying "Why I did it is a mystery."

ADDENDUM (31 January, 2008) - See also this post on the Clinical Psychology and Psychiatry Blog.

BLOGSCAN - An "Infomercial" for Avandia and Zyprexa?

On the Hooked: Ethics, Medicine and Pharma blog, Dr Howard Brody critiqued a newspaper op-ed that ostensibly decried excessive litigation in health care, but also seemed unduly concerned with defending Avandia and Zyprexa, two drugs that did turn out to have more adverse effects than expected.

The Avandia Case, and a Warning About How Bad Things Can Get

We have posted frequently about the controversy about rosiglitazone (Avandia, by GlaxoSmithKline). Some of the distressing aspects of the case were various efforts made to keep information and opinions unfavorable to Avandia away from physicians, the patients, and the public, including efforts involving obfuscation, deception, and intimidation. (For example, see this post about the "spinning" of Avandia and the ridiculing of Avandia critics, and this post about attempts to silence an early Avandia critic.)

This month, the British Medical Journal printed a news article about the US Senate report that claimed that the critic, Dr John Buse, was intimidated by top GSK executives.

Perhaps with deliberate irony, on the same page was another news article, headlined, "One in 20 East German doctors spied on patients or colleagues." It was based on a study by the Hannah Arendt Institute for Research on Totalitarianism,

About 5% of doctors in the former East Germany spied on their colleagues or patients as unofficial members of the East German secret police (the Staatssicherheit or Stasi), a new report has shown.

The study, by the Hannah Arendt Institute for Research on Totalitarianism, Dresden, and commissioned by the German Medical Association and the German medical journal Deutsches Ärzteblatt, showed that the percentage of unofficial members of the Stasi among doctors was higher than in the East German population as a whole.

'Doctors were one of the main targets of the Stasi because they were thought to belong to a reactionary class and were thought to be especially interested in escaping to West Germany,' said Francesca Weil, author of the study....

Of those doctors who were unofficial spies, about a quarter passed on information not only about colleagues but also about their patients' health and private lives. Psychiatrists and sports medicine experts were the most common specialists among the unofficial spies, and a third of them held a leading position in a hospital. The Stasi also recruited medical students.

Reasons for spying varied. Some doctors were trying to advance their career or were afraid that their careers would suffer if they did not participate; others were committed socialists; and another group liked the economic advantages, which ranged from monthly cash payments to fast tracked delivery of a car or other luxuries.

In my humble opinion, physicians in the West should not view the latter article as affirmation that we do not have things so bad. Rather it is a warning about how bad things can get.

Medical Academics Consulting for Industry: Riding the Tiger

On the Hooked: Ethics, Medicine and Pharma blog, Dr Howard Brody dissected the complex relationships among GlaxoSmithKline (GSK), and its physician consultants regarding the drug rosiglitazone (Avandia).

We had previously posted about the report of a US Senate committee implicating top GSK executives in an attempt to silence a physician who was one of the early critics of Avandia. Dr Brody went through the report in depth, and found that things were more complicated. The physician involved was simultaneously a consultant to GSK, and to the company that made a competing drug. Brody wrote,

I agree that it is bad when companies try to intimidate scientists to keep quiet about potential drug risks. But what about the academic physician-scientists, who think that they can ride the tiger and still stay in control? Dr. Buse, it appears, thought that on the one hand he could pocket his consulting fees (and perhaps speaker fees as well; we are not told) from these drug companies; and on the other hand could freely speak his mind as an academic scientist. His new owners told him in no uncertain terms that once the business deal had gone through, he had better remember who was calling the shots. Buse himself seems to have gotten the message as to who owns his opinion--when the press approached him recently to say something nasty about GSK, he refused, saying that the matter was over years ago, that they had apologized to him, and he was eager to let bygones be bygones.

My central message in HOOKED is: when we physicians are lacking in our own professional integrity, pointing fingers at the bad drug companies is hardly an adequate ethical response.

It's clearly an important point, and a reminder to us physicians that too often in health care, the old quote from Pogo applies: "we have met the enemy, and he is us."

These days, a lot of academic physicians and other medical school faculty are trying to ride the tiger. They may end up doing this because what counts most to their academic bosses is how much external funding they bring in (or, as one medical school dean said, whether they are "taxpayers.") Since health care corporations (pharmaceutical manufacturers, biotechnology companies, device manufacturers, etc) now are the largest collective source of medical research money, they are thus under great pressure to collaborate with these companies. An academic trying to raise research money from one such company might find it hard to resist offers of consulting fees, speakers honoraria, advisory board positions, etc from that company. But once the academic thus starts to work part time for the company, who knows where his or her interests lie? And how the academic has to try to stay on the tiger.

More About Who Had to Call Off the Dogs on an Avandia Critic

"Twice I have with my own ears heard the sound which resembled the distant baying of a hound." [The Hound of the Baskervilles: Another Adventure of Sherlock Holmes By Arthur Conan Doyle]

We just posted about a report by the US Senate Finance Committee charging that top executives of GlaxoSmithKline had tried to silence an critic of rosiglitazone (Avandia, by GlaxoSmithKline). (For our earlier discussion of the Avandia controversy, see this post and older links.) The Wall Street Journal just published a news article on Finance Committee report which provided a few more details.

Over a period of several years, drug maker GlaxoSmithKline PLC was so concerned about a prominent physician's negative views of its diabetes drug that it engaged in a concerted effort to intimidate him and stifle his opinion, a report by the U.S. Senate Finance Committee found.

The report offers a window into the rarely acknowledged practice among drug companies of monitoring and seeking to influence the opinions of leading physicians, who can make or break a drug's sales. The report alleges that Glaxo Chief Executive Jean-Pierre Garnier and former research chief Tachi Yamada were involved in the intimidation.

[The report] said it feared the Avandia case was part of a 'troubling pattern of behavior by pharmaceutical executives.'

'The effect of silencing [Dr. Buse's] criticism is, in our opinion, extremely serious,' the report concludes, noting that patients may have needlessly suffered heart attacks during the period. 'Had GSK considered Avandia's increased cardiovascular risk more seriously when the issue was first raised in 1999 by Dr. Buse, instead of trying to smother an independent medical opinion, some of these heart attacks may have been avoided,' the report says.

A Glaxo spokeswoman, Nancy Pekarek, said the company strongly disputes the committee's conclusions. She said Glaxo had tried to correct Dr. Buse's 'inaccuracies' about Avandia but had never tried to intimidate or silence him. 'People at the time were very passionate about this new medicine and could perhaps have handled the interactions with Dr. Buse better,' she said. 'We did apologize to Dr. Buse for the tone of some of the conversations, and he accepted that apology eight years ago.'

She said Dr. Garnier had no additional comment. Dr. Yamada, who is now president of the global health program at the Bill & Melinda Gates Foundation, was traveling Friday and unavailable for comment, his assistant said. In an interview last month with Nature magazine, Dr. Yamada said that he never pursued any 'diabolical plot' against Dr. Buse. Dr. Buse was also traveling Friday and unavailable for comment.

The Nature interview with Dr Yamada is here. In it, Dr Yamada denied threatening Dr Buse with a lawsuit, “Nor did I ever discuss a lawsuit with anybody else … I wouldn't want the media to think it's some diabolical plot hatched by me against Dr Buse, because nothing could be further from the truth.” On the other hand, Dr Yamada favored a strategy "to launch a well-planned offensive on behalf of Avandia." Dr Buse acknowledged, "I don't think that Dr Yamada is the bad guy in this story,” but turned to Dr Yamada with his request to "call off the dogs."

Whatever the details, whether anyone threatened a lawsuit or not, it seems like Dr Buse clearly felt that someone let the dogs out to get him, and attributed to Dr Yamada the power to reduce this pressure. The Senate Finance Committee report put it a lot more strongly than that.

Therefore, this anecdote seems to demonstrate the flip side of the pharmaceutical (and biotechnology and device) industries' fascination with the use of well-paid "thought leaders" to promote its products. "Thought leaders" who criticize their products are liable to hear the dogs baying in the distance.

So, once more, with feeling, if the pharmaceutical (and biotechnology and device) industries do not want to be regarded as "shifty," (see post here) they should argue with, but not try to pressure, intimidate, threaten, or let the dogs out on people who criticize their products.

Furthermore, consider the Gates Foundation's stated guiding principles which include:

- We advocate—vigorously but responsibly—in our areas of focus.

- We must be humble and mindful in our actions and words. We seek and heed the counsel of outside voices.

- We demand ethical behavior of ourselves.

- We treat each other as valued colleagues.

Hopefully we will hear more from Dr Yamada about upholding these principles so that no one has to ever ask him again to "call off the dogs."

"We heard the hound on the moor, lo I can swear that it is not all empty superstition." [The Hound of the Baskervilles: Another Adventure of Sherlock Holmes By Arthur Conan Doyle]

ADDENDUM (20 November, 2007) - see additional comments on the Health Care Organizational Ethics blog.

Silencing an Avandia Whistle-Blower

Both Ed Silverman on the PharmLot blog and the Wall Street Journal Health blog covered the report by US Senator Charles Grassley (R - Iowa) about the attempt by GlaxoSmithKline executives to intimidate an early critic of the cardiovascular effects of Avandia (rosiglitazone). As we just noted, apparently chiefly responsible for this whistle-blower intimidation was then GSK executive "Tadataka Yamada, who now heads the global health program at the Bill & Melinda Gates Foundation and today was announced as a board member of the FDA’s new Reagan-Udall Foundation, which is designed to foster drug research," per Ed Silverman (see also our post here.)

Also the WSJ blog noted that Grassley "invited researchers who feel they have been bullied by the industry to contact him. And, he added, 'they can also anonymously provide information and documents by mail or by fax.' Grassley ... even helpfully announced the fax number — 202-228-2131 — on the floor."

Since support for health care whistle-blowers has been sorely lacking, at least the fax number is a welcome development.