"The 'Third Rail' that No One Wishes to Analyze" - Conflicts of Interest Affecting Health Care Foundations

On Health Care Renewal we discuss what we think are important issues affecting health care that seem to be rarely mentioned in the medical and health care literature and the "main-stream media."  In particular, we focus on problems in health care leadership and governance, how they threatened the core values of health care professionals, and how these threats contribute to rising costs, and declining access and quality. 

One of our preoccupations has been why these problems remain so anechoic.  A new article in PLoS Medicine [Stuckler D, Basu S, McKee M. Global health philanthropy and institutional relationships: how should conflicts of interest be addressed? PLoS Med 8(4): e1001020. doi:10.1371/journal.pmed.1001020.  Link here. ] seems to have uncovered another missing link to the anechoic effect. 

Private Foundations and Their Influence on Global Health

The article noted the importance of the influence of private foundations on global health:

While corporate involvement in and government aid for health has been extensively analyzed and critiqued in the public health literature, less attention has been paid to the impact of private donors on public health. Over the past decade, the bulk of new health aid designed to reach the Millennium Development Goals has come from individuals and corporations. The influence of this private philanthropy on global health is profound and transformative.

So,

Private foundations operate outside the typical boundaries of democracy; unlike government ministries, private foundations cannot be influenced in the same way by the communities affected by the foundations' actions. In the interests of public health, and particularly because poor communities affected by foundations do not automatically have a feedback mechanism to influence the decisions of private funders, we argue that it is appropriate to subject private foundations to the same scrutiny received by public institutions.

In this paper, we examine the scope of potential conflicts of interests that exist among the private foundations that are major funders of global health.

I would add that private foundations may have an outsize influence not only on global public health policy, but also on health care policy within particular countries, including the US.   This may arise because of the perception that they are more independent and nearer the cutting edge than are government and industry sources of funding. For example, here in the US, the Kellogg and Robert Wood Johnson Foundations have been widely perceived by health care, services and policy researchers as especially influential and respectable sources of funding, possibly partially because of the perception that they have less self-serving agendas than do government agencies and for-profit health care corporations.

The Possibility of Conflicts of Interest

The authors noted increasing concern about conflicts of interest affecting the activities of for-profit corporations involved in public health and health care:

because tensions can arise between the profit motives of corporations and the promotion of public health. Whereas corporations make products that can improve health (such as pharmaceuticals and vaccines) and relationships between public health institutions and for-profit corporations can be seen as positive opportunities for corporations to improve public health, corporations also make products that damage health (such as tobacco or unhealthy foods). And because some corporations have a vested interest in the activities of public health bodies, there have been documented attempts to influence the public health agenda by establishing associations with health care institutions

Thus the authors thought it also made sense to address conflicts of interest affecting private foundations operating in the global health space. They performed a case-study of the largest global health foundation, the Bill & Melinda Gates Foundation, while also briefly discussing four other large global health foundations, the Ford Foundation, W. K. Kellogg Foundation, Robert Wood Johnson Foundation, and Rockefeller Foundation.

Stock Holdings

The article noted that the Gates Foundation had substantial investments in food and pharmaceutical companies:

The Bill & Melinda Gates Foundation's corporate stock endowment is heavily invested in food and pharmaceutical companies, directly and indirectly .... The Foundation holds significant shares in McDonald's (9.4 million shares representing about 5% of the Gates' portfolio), and Coca-Cola (>15 million shares, over 7% of the Foundation's portfolio, not counting Berkshire Hathaway holdings). In 2009 the Bill & Melinda Gates Foundation sold extensive pharmaceutical holdings in Johnson & Johnson (2.5 million shares), Schering-Plough Corporation (14.9 million shares), Eli Lilly and Company (about 1 million shares), Merck & Co. (8.1 million shares), and Wyeth (3.7 million shares).

Also, the Foundation indirectly invests in food and pharmaceutical companies through its holdings of Berkshire Hathaway:

Berkshire Hathaway's largest investment is in Coca-Cola. It owns an additional 8.7% of Coca-Cola (Warren Buffett's firm is the largest shareholder in Coca-Cola, having stock worth >$10 billion dollars) and 6.3% of Kraft (Buffett is also the largest shareholder of Kraft). Berkshire Hathaway also has significant ownership in GlaxoSmithKline, Sanofi-Aventis, Johnson & Johnson, and Procter & Gamble, and is one of the main global investors in the latter two pharmaceutical companies.

The article also noted that the Ford, Rockefeller, Kellogg and Robert Wood Johnson Foundation had significant holdings in Coca-Cola, Kellogg, PepsiCo, Pfizer, GlaxoSmithKline, McDonalds, Nestle, NovoNordisk, YumBrands, Pizza Hut, KFC, Johnson & Johnson, and Sanofi-Aventis, and that the Ford Foundation held shares in a tobacco company, Lorillard, and the Kellogg and Rockefeller Foundations "were indirectly invested in tobacco corporations through conglomerate equity funds...."

This admittedly case-based data suggested that the major private foundations active in global health may have financial holdings that could possibly influence their actions in favor of the vested interests of food, pharmaceutical, and even tobacco companies.

Conflicts Affecting Foundation Leadership

The article noted that:

Several of the [Gates] Foundation's members of the management committee, leadership teams, affiliates, and major funders are currently or were previously members of the boards or executive branches of several major food and pharmaceutical companies ... including Coca-Cola, Merck, Novartis, General Mills, Kraft, and Unilever....

In addition,

Further overlaps between Bill & Melinda Gates Foundation leadership, other private foundations, and circular flows of personnel with food and pharmaceutical companies were observed .... Such patterns of interlinked board directorships, common among corporations and nonprofit organizations, were similarly found in the other private foundations studied.

Examples provided in an appendix were:

Anne Fudge, the chairman of the Gates Foundation�s US Program Advisory Panel is also on the board of directors of Rockefeller Foundation (in addition to General Electric, Novartis, Unilever, and Harvard University, among others).

Furthermore,

Members of personnel also move between the Foundation and pharmaceutical companies. For example, in April 2010, a former Merck senior vice president, Richard Henriques, became the chief financial officer of the Gates Foundation. At least two other members of the Gates Foundation leadership have transferred from the leadership of GlaxoSmithKline to sit on the Foundation�s board of directors, including Kate James, the chief communications officer, and Tachi Yamada, until February 2011, the head of the Foundation�s global health program. Similar patterns were observed with the other foundations studied.

Again, this admittedly case-based data suggested that the major private foundations active in global health may have leaders who have financial relationships that could possibly influence their actions in favor of the vested interests of food and pharmaceutical companies.

Program Initiatives Possibly Related to Conflicts

The article asserted:

The bulk of the Bill & Melinda Gates Foundation's financial transfers in global health have been to programs developing medical technologies....

In particular,

Overall, about 42% of all funding was spent on health care delivery or increasing access to drugs, vaccines, and medical commodities, while an additional one-third was allocated to technology development (mainly for vaccines and microbicides) or basic science research.

Specific programs were related to companies in which the the Gates Foundation or its leaders had financial interests:

The Foundation has established partnerships with the Coca-Cola Company, which, in the words of the Foundation, are intended to 'create new market opportunities for local farmers whose fruit will be used for Coca-Cola's locally-produced and sold fruit juices'.

Also,

many of the Foundation's pharmaceutical development grants may benefit leading pharmaceutical companies such as Merck and GlaxoSmithKline....

and

Johnson & Johnson has entered a clinical partnership to develop new HIV-prevention technology, noting 'the work between Johnson & Johnson and the Gates Foundation is a strong, strategic, comprehensive relationship'.

While there are many needs in global health, and many approaches to addressing these needs, this limited case-based data suggested that a strong focus of the Gates Foundation was on approaches that revolve around drugs, devices and biotechnology, again which would tend to favor the vested interests of the pharmaceutical companies which the Foundation holds in its investment portfolio and with which some of its leaders have or had financial relationships.

Discussion

While the data from this case-study were limited, they do suggest that major private foundations that support global health, and by extension, health care, services, and policy research may have institutional conflicts of interest, and their leaders may have personal conflicts of interest. It is possible that these conflicts have steered global health policy to favor vested interests, particularly towards approaches that depend on drugs and devices, perhaps instead of more effective ones using less technology.

Furthermore, it is possible that that these conflicts of interest have helped create the anechoic effect.  Conflicts of interest could have pushed the foundations in directions that favored specific vested interests, and away from others that may threaten such interests.  Many of the issues we discuss on Health Care Renewal may threaten such interests.  Private health foundations have been notably uninterested in addressing how problems in leadership and governance of health care organizations can threaten core values, They have been particularly uninterested in addressing specific tactics used when leadership is ill-informed, incompetent, self-interested, conflicted, or even corrupt, e.g., deceptive practices used to promote products and services, and promote policies favorable to vested interests, including, of course, deliberate creation of conflicts of interest (such as the cultivation of key opinion leaders).

In fact, a particular version of the anechoic effect surrounds the private foundations themselves, as described by Stuckler et al:

Although the philanthropic activities of wealthy individuals and corporations have attracted controversy in the past (Text S1), their charitable mission often means that they face less scrutiny than governments; critical analysis of foundations can be seen as 'biting the hand that feeds us.' As a result, within the global health community, private donors are sometimes viewed as the 'third rail' that no one wishes to analyze.

We have often commented on the pervasiveness of conflicts of interest in health care. Now we see them affecting even the most respected private health care foundations which were previously regarded as independent. The web of conflicts of interest may benefit those personally involved, but to the detriment of patients' and the public's health. Unfortunately, as the web has gotten more complex, it stifles awareness of the problem by the unconflicted, much less their ability to respond.

At a minimum, I urge that private health care foundations fully disclose their institutional conflicts of interest, and the conflicts of interest of their leaders. If they wish to maintain their previously sterling reputations, they ought to consider divesting themselves of financial holdings that generate institutional conflicts, and of leaders who have financial relationships that generate personal conflicts.

Hat tip: to Ed Silverman on the PharmaLot blog.

...THEM OR YOUR LYING EYES?

�THEM OR YOUR LYING EYES?

A few days ago I discussed stonewalling by the American Psychiatric Association over charges that they were partners in a ghostwritten textbook. The issue resonated with many people, including Daniel Carlat, John Nardo, the POGO blog, Alison Bass, Ed Silverman, and others. The APA has not seen its way clear to releasing key documents that might clear up the charges. By stonewalling, the APA just does more damage to its image and credibility. They come across as uninterested in transparency, and they appear to be fighting a rearguard action to defend the indefensible.

What kind of key documents could the APA have released? In our letter last January we suggested several, including the contract involving the American Psychiatric Press, the medical communications company (Scientific Therapeutics Information, Inc. or STI), the grant-giving drug company, the professional writers, and the nominal authors of the allegedly ghostwritten book. What might the contract have told us? Well, it probably looks a lot like this contract, which involves the same medical communications company, the same drug company, and one of the same professional writers, Sally Laden. It was developed right around the same time as the textbook was planned, and it is for a ghostwritten journal article promoting the infamous Paxil Study 329. Look carefully at this contract and you will be in no doubt about who did the essential work of writing and framing the article or about whether the corporation had control over the content. Now ask yourselves, if the contract for the textbook doesn�t look like this then why ever would the APA want to suppress it? That behavior just makes people conclude that the contract for the textbook does look like this contract and that the APA knows it has plenty to hide.

A first principle of cover-ups and stonewalling is that everyone needs to be on the same page with the cover story. When they are not, the fa�ade collapses and the actors come across like the Three Stooges, all heading for the door at the same time. Today, thanks to the sleuthing of Phyllis Vine at Mental Illness Watch, we saw the stooges exposed in their clumsiness. Phyllis Vine discovered material on the corporate website of STI that has them featuring the textbook in the �portfolio� that aims to attract new business to the company. Juxtapose that with the adjacent claim that STI�s skills are to "develop, write, edit, and submit a high-quality article to your target audience." Now is there any doubt about how this game is played? Now is there any doubt about whether the APA has come clean?

Well, if there were any remaining doubt it has been removed by another development: All the materials describing the STI �portfolio� have been removed from the company�s website. Fortunately, Phyllis Vine had captured it here, and so did Daniel Carlat through the Wayback machine. It was picked up some more by Mickey Nardo today. It looks like the APA is going to have more explaining to do.

As the old Groucho Marx line goes, Who you gonna believe, them or your lying eyes?

Bernard Carroll

WHO YOU GONNA BELIEVE?

WHO YOU GONNA BELIEVE?

Ghostwriting Charges and Stonewalling at the American Psychiatric Association

The American Psychiatric Association came under a searchlight this past December over allegations of ghostwriting. The story originated with a public letter from Project on Government Oversight (POGO) to the Director of NIH, and it was picked up by Duff Wilson writing in the New York Times. The book was Recognition and Treatment of Psychiatric Disorders: A Psychopharmacology Handbook for Primary Care. The named authors were Charles Nemeroff, now chairman of psychiatry at the University of Miami, and Alan Schatzberg, formerly chairman of psychiatry at Stanford University. Both are well known for ethical controversy � see here and here. Soon, these allegations were being dissected in the blogosphere, with stellar contributions from Daniel Carlat, 1boringoldman, Ed Silverman, and Alison Bass.

The APA and its publishing arm, known as American Psychiatric Press, Inc. or APPI, came to the defense of the two prominent academic authors over the ghostwriting charge. In particular, an APA employee named Mark Moran authored a denial of the charge in the January 2011 issue of the APA news magazine, Psychiatric News. As the controversy played out, letters from attorneys demanded retractions, and partial qualifications of the original story appeared in the New York Times and on the POGO weblog. There was never any doubt that the heavy lifting was done by a pair of professional writers employed by a medical communications company under a financial grant from a drug company. Nemeroff defended his role by averring that he �scrutinized� the work product of the professional writers. Threatening letters from lawyers for Nemeroff and Schatzberg were publicized, and the APA weighed in.

The coup de gr�ce was administered by blogger Daniel Carlat�s withering review of the book�s artful construction to highlight the use of the sponsoring company�s antidepressant and anti-anxiety drug in primary care, while muting important information about the drug�s liabilities. Nevertheless, the APA held to its legalistic stance in defense of the �authors.� This behavior is counterproductive for professional medical organizations, as I have discussed before, because it misses the ethical forest for the legal trees.

Now comes the good part. In response to the piece by Mark Moran in Psychiatric News, Leemon McHenry prevailed on Robert Rubin and myself to write with him to the magazine�s editors. Leemon is a faculty member in the Department of Philosophy at California State University, Northridge. He also has experience evaluating legal documents arising in litigation over antidepressant drugs. Robert Rubin has partnered with me in outing several notable ethics compromises involving Nemeroff and Schatzberg, going back as far as 2002, though we always call ourselves equal opportunity critics.

Our letter sent in late January to Dr. Carolyn Robinowitz, the Interim Editor of Psychiatric News, has been posted today on the POGO site. In our letter, we challenged much of Mr. Moran�s defense, and we called attention to what WASN�T in the public domain, despite all the claims and counterclaims. Essentially, the partial qualifications of the original reports that appeared in The New York Times and in the letter to NIH from POGO resulted from the inconclusiveness of some of the documents. We called on the APA to come clean with the release of all relevant materials, in the interest of transparency.

For instance, what WASN�T known were the specifics of the contract involving the corporation, the (ahem) authors, the publisher (APPI), and the medical communications company. Or the money flow to the �authors� from the contract in addition to their royalties. Or the legal release form transferring ownership of the work product to the �authors� and APPI. Or the corporation�s planned marketing activities, given that the corporation ordered 10,000 copies of the book. Or the correspondence among all parties that might reveal who actually did what.

Leemon McHenry�s perspective is that this hidden layer of documents may well be available if they could be unsealed in pending litigation. Naturally, corporations and their attorneys strive to keep the information hidden. But our general point is that the APA has a different duty � which is to transparency rather than to stonewalling. Did the APA do that? Sadly, no, they did not. Here is the curt reply from the Executive Editor Catherine Brown denying publication of our letter after a delay of almost 8 weeks. Now that�s what I call stonewalling.

"I'm Not Here to Sell Drugs" - Then Why Use Company Provided "Correct" Slides?

In October, 2010, we discussed a series of reports by Pro Publica and multiple other respected news organizations about payments by seven pharmaceutical companies to thousands of doctors.  Industry often claims that they only pay the best and the brightest physicians and academics to provide education relevant to their products.  However, the ProPublica et al report suggested that they mainly recruited physicians who already showed their favor to their products by prescribing them often, but soothed their consciences by dubbing them "thought leaders" or "key opinion leaders."  While some of the physicians were well-known academics, others had notably blemished records. 

Since then, news media around the US have looked into interactions among local physicians and academic medical institutions and the seven pharmaceutical companies.  In November, 2010, here we discussed cases that suggested that pharmaceutical companies like physician speakers because they are more "believable" than pharmaceutical representatives, and choose physicians who already are prolific prescribers of the drug to be promoted, and that suggested that some physicians realized that speaking for pharmaceutical companies influenced their own prescribing.

Since then, more investigations of local physicians' interactions with pharmaceutical companies have appeared that reinforced contrasts between rationalizations that physicians and drug companies use to support continued payments for "drug talks," and what these talks are really about.

"Leaders in Their Field" vs Sanctions and Crimes

 Many pharmaceutical (and other health care corporations) have repeated the mantra that the physicians they hire to give talks are the best and the brightest.  The physicians who give the talks sometimes get to believe this.  For example, a ProPublica follow-up report[1] on discrepancies between data the pharmaceutical companies put on the web and gave to state regulators noted:

Pfizer, for example, told the state it paid Dr. Randy Schapiro $1,770 last year. But on the firm�s website, it reported spending $43,827 on him in the second half of 2009 alone.

It then quoted Dr Schapiro:

Schapiro said the doctors paid by pharmaceutical companies are 'leaders in their fields,' and patients should want to see their physician among them. 'If their doctor is not on the list,' he said, 'maybe they should look for a different doctor.'

On the other hand, several of the local news articles focused on physicians who were paid drug company speakers despite having chequered backgrounds, shall we say. In the Elmira Star Gazette[2]:

Tulio Ortega, a Rochester psychiatrist who made $144,548 from Eli Lilly and AstraZeneca for speaking to groups of peers during the last two years - was put of [sic] probation for two years in 2008 and ordered to pay a $7,500 fine after being sanctioned for negligence and incompetence.

Also,

Lilly also paid Yonkers physician Ali Sherzoy $4,334 in the first two quarter of this year, even though he had his license suspended in New York and New Jersey earlier this year after pleading guilty to a count of criminal sexual contact in 2008.

Sherzoy told ProPublica the incident involted his family's nanny and had nothing to do with his ability to practice medicine.

Other New York doctors were sanctioned for incidents ranging from deficiencies in handling controlled substances to being convicted of tax evasion.

Another article by the same author[3] noted two more cases:

In 1991, Johnson City doctor Louis Mateya was charged with professional misconduct after a 22-year-old woman accused him of unzipping his pants and fondling himself during an examination.

Mateya admitted guilt to the charge. The State Board for Professional Medical Conduct suspended his license for two months, followed by a 58-month probationary period, during which he was monitored by a psychiatrist and a health professional selected by the board.

During the last nine months of 2009, GlaxoSmithKline paid Mateya, an internist at United Health Services, $1,750 to speak on behalf of Lovaza, Glaxo's prescription omega 3 fish oil, according to an e-mail from a United Health Services spokeswoman.

Also,

A second Southern Tier physician, Robert Douenias, of Corning, was also paid by Glaxo: $20,000 during the same time frame to deliver speeches, even though he received sanctions in 1992.

According to the Office for Professional Medical Conduct (OPMC) records, Douenias lied about a previous criminal conviction on his application for a New York medical license. He received a censure and reprimand from the OPMC, was ordered to perform 200 hours of public service and was placed on probation for two years. Douenias said on his application he had never been convicted of a crime in any state or country, even though he had a previous conviction, according to OPMC records.

Note that the original ProPublica reporting from their database emphasized cases of physicians paid to speak by pharmaceutical companies who also had been sanctioned by medical boards or the criminal justice system (see post here).

Although drug marketers like to tell physicians they are selected as "thought leaders" because of their brilliance, it appears that the selection of such "key opinion leaders" is not necessarily based on sterling character.

"I'm Not There to Sell a Drug," But Then Why Use the Company's Slides?

A number of the reports featured physicians who asserted their independence, at least from marketing goals. 

For example, as reported by the Duluth (MN) News Tribune[4],

A Duluth psychiatrist has received more than $525,000 since 2002 in payments from pharmaceutical companies, far more than any other Northland doctor, an analysis by the News Tribune shows.

Dr. Tracy Tomac of St. Luke�s hospital was paid by the companies to give presentations on health and drug issues.

Furthermore,

'I�m there as an educator and resource,' she said. 'I�m not in business to do a sales pitch. I�m not a salesperson.'

Also,

In 2007, [Dr] Tomac said her presentations included content that was screened and approved by the FDA,....

However, other reporting suggested that content "screened and approved by the FDA" was content provided by the pharmaceutical companies.

For example, The Tennessean noted[5]:

Dr. Jan Brandes heads the Nashville Neuroscience Group, a clinic that's now part of Nashville-based Saint Thomas Health Services. She made $111,150 in outside income over the past two years, largely in speaker fees paid by drug company GlaxoSmithKline, which markets a wide array of brand-name drugs, literally from A to Z.

Dr Brandes also asserted,

'The real point is I'm not there to sell a drug,' Brandes said. 'I'm there to interpret trial results, talk about disease states and help physicians understand where this research might fit in the context of their practice.'

However,

Most drug companies now require physicians to use the company's slides and presentations if they pay them to speak at an event. The industry says that is to ensure that all U.S. Food and Drug Administration rules are met and that physicians don't wander off into discussing uses for a particular product that haven't been approved by regulators.

Also, an article in the Alexandria (VA) Gazette Packet[6] noted:

Whistleblower lawsuits filed in recent years have accused firms of using doctors to push pills for unapproved uses during dinnertime talks, prompting at least 10 firms to settle cases for nearly $7 billion in the last three years. Since that time, pharmaceutical companies have tightened control over what happens during presentations given on their dime. Last year, for example, GlaxoSmithKline instituted a new policy prohibiting doctors from using their own slides during presentations. Starting in 2010, all doctors giving speeches sponsored by GlaxoSmithKline must use slides presented by the pharmaceutical company in the order specified.

'We want to make sure that everything is correct,' said Mary Anne Rhyne, a spokeswoman for GlaxoSmithKline. 'The best way to do that is to have our team prepare the slide.'

Note that Dr Brandes above was paid mainly by GlaxoSmithKline, who presumably also provided all her slides and made sure that everything she said was "correct," at least in terms of what GlaxoSmithKline thought was correct.

And one more example per MyFoxAtlanta[7]:

Some of Georgia's highest paid physicians? .... and Roswell psychiatrist Dr. Michael Banov: over $68,000, also from Lilly.

Dr Banov asserted:

We don't sell medications. We simply educate physicians about data, and they make their own mind up.

However,

Banov says, the drug company - not him - creates the materials used in his speeches, and he says there's a reason for that.

'We are only able to present the data. We're not able to present our personal opinions. Our personal preferences, how we use the medication off label. any of that. So we're held to a very tight standard by the FDA,' said Banov.

Drug companies may say they make their paid physician speakers use slides provided by the company to prevent them from talking about "off-label" uses.  However, there is no reason for a physician-educator not to talk about "off-label" uses, and physicians can prescribe any legal drug for whatever purpose they see fit, whether or not the drug is on or "off label." 

But drug companies are prohibited by law from promoting off-label uses.  Requiring physicians to use drug companies' slides and preventing them from talking about "off-label" uses demonstrates that the physicians are functioning as marketers, not educators. 

Summary

As local reporters look into more cases, it becomes increasingly clear that up to now, pharmaceutical companies have been none too fussy about which physicians they pay to speak about their products. It is self-serving, but inaccurate for both sets of parties to assert that the companies choose only the "best and the brightest." 

Furthermore, it has now become glaringly obvious that the purpose of "drug talks" is, well, to sell drugs.  Some physicians paid by drug companies to speak may bluster about their independence, but if they are using company provided slides, who can deny they are influenced  by the company.  Furthermore, when companies insist not merely on providing slides, but on ensuring that "everything is correct," then it is clear that it is the companies' talks that the physicians are giving.  Physicians giving company talks cannot be speaking independently, and hence must be regarded as company sales personnel, whose disguises as independent doctors or medical academics are now in tatters.

Doctors who still choose to go to "drug talks" should have no illusions that they are being exposed to anything other than marketing.  Thus, I urge my colleagues to forgo the nice meals and the company prepared "correct" slides, and spend the time trying to more critically assess the clinical evidence. 

References


1.  Ornstein C, Weber T. In Minnesota, drug company reports of payments to doctors arrive riddled with mistakes.  ProPublica, Dec 10, 2010.  Link here.
2. Hunter J. Rochester psychiatrist, sanctioned for incompetence, made $144K from drug companies. Elmira Star-Gazette, Dec 4, 2010.
3. Hunter J. Despite sanctions, physicians hired as drug company pitchmen. PressConnects.com, Dec 4, 2010. Link here.
4. Stahl B. Duluth doctor denies payments from drug companies sway decisions.  Duluth News Tribune, Dec 20, 2010.  Link here.
5. Ward G. They say they prescribe based on patients, not Big Pharma. Tennessean, Dec 19, 2010. Link here.
6. Pope ML. Conflict of interest? - Alexandria doctors receive thousands of dollars from Big Pharma.  Alexandia Gazette Packet, Jan 13, 2010.  Link here.
7. Galvin B. Health watch: doctors and drug companies. MyFoxAtlanta, Dec 29, 2010. Link here.

Why I Shouldn't Read Non-Systematic Review Articles: Special Pleadings and Undercover Authors

I usually resist looking at non-systematic review articles in medical journals, but because the title interested me, and things seem to be getting slow this holiday season, prompted by an update email from the American Journal of Medicine, I looked at Ram CVS. Beta-blockers in hypertension. Am J Cardiol 2010: 106: 1819-1825. (Link here.)

The Ram Article in Praise of Vasodilating Beta-Blockers

The article focused on the results of meta-analyses:

Concerns have also been raised by meta-analyses in which � blockers were reported to have a suboptimal effect on reducing stroke risk and increasing the risk for new-onset diabetes compared with other antihypertensive agents.

The article discussed several meta-analyses in which beta-blockers, [a specific class of blood pressure lowering drugs] but mostly atenolol (mostly sold generically), usually combined with a diuretic, were compared with other antihypertensive drugs, usually including angiotensin converting enzyme inhibitors (ACEIs) and calcium channel blockers. But after discussing these comparative results, the author jumped to descriptions of another group of drugs which were not included in any of these comparative studies. This was the category of vasodilating beta-blockers, consisting of labetolol (mostly sold generically), carvedilol (Coreg, GlaxoSmithKline [GSK]), and nebivolol (Bystolic, Forest Laboratories. Based on physiologic studies of these drugs and trials in which they were compared with placebo, but not on studies which directly compared clinical outcomes of patients given these drugs or other kinds of antihypertensives, Dr Ram reached conclusions that they were a better alternative:

The review of the evidence provided herein confirms that there are valid reasons to question the utility of certain � blockers in treating hypertension. However, many of the perceptions about � blockers are derived from data obtained from studies of traditional agents or combinations of diuretics and � blockers. Evidence suggests, and the guidelines concur, that there are intrinsic differences among members of the �-blocker class. Indeed, the vasodilatory �-blockers, which have generally not been included in comparative meta-analyses, lower blood pressure to a similar degree as other antihypertensive drugs, may provide better central aortic pressure reductions than traditional � blockers, and are associated with neutral or favorable metabolic effects.

Special Pleading

Dr Ram's questioned the old-fashioned beta-blocker atenolol (perhaps only when added to a diuretic)  based on the results of meta-analyses which attempted to compare it to other drugs. Such meta-analyses could suggest that atentolol (again, perhaps only in combination with a diuretic) might be in some way less preferable than the other drugs to which it was compared. However, the meta-analyses did not address the vasodilating beta-blockers at all. Dr Ram concluded that they were preferable based on different kinds of and probably less definitive evidence. He did not seek to compare such studies done on the vasodilating beta-blockers to similar studies done on the conventional beta-blockers.  Thus it seems his conclusions were based on a double standard.

In the vocabulary of logical fallacies, this was an example of a special pleading:

Special Pleading is a fallacy in which a person applies standards, principles, rules, etc. to others while taking herself (or those she has a special interest in) to be exempt, without providing adequate justification for the exemption.

Here was more reason not to bother reading a narrative review articles to learn how to better practice clinical medicine.  They often are based on idiosyncratic, if not biased evidence used to support illogical arguments.

But having read so far, I wondered why the authors of this article were so happy to use a double standard as the basis of their arguments.

Undercover Author

Those paying attention may also now be wondering why I referred to the authors in plural, when the citation lists only one author. The clue is at the end of the article:

Acknowledgment

I would like to thank Tamalette Loh, ProEd Communications, Inc. (Beachwood, Ohio), for her editorial assistance and literature validation in the preparation of this report.

Sensitized as I have been to the many recent discussions of ghost-writing, I immediately wondered who Ms Loh is, and what sort of "editorial assistance and literature validation" she provided. So first I looked at what her company, ProEd Communications does, wondering if its business is to help syntactically challenged academics and professionals write better sentences and more organized papers.

The ProEd Communications web-site states:

ProEd Communications balances diverse perspectives�clinical, regulatory, marketing, and customer�to create compelling messaging to maximize a product's potential.

So it appears that ProEd Communications does not provide independent editorial services. Instead, it is a medical education and communications company (MECC) which works mainly to market its clients' products, and further, its clients are essentially only pharmaceutical companies:

Of the world's 50 largest pharmaceutical companies, ProEd has worked with 18 in the past 3 years and currently supports projects for 7 of the top 10 largest pharmaceutical companies, as ranked by MedAdNews (2008).

Furthermore, a few minutes on Google reveals that Ms Loh seems to specialize in papers on anti-hypertensives, particularly Coreg (carvedilol), one of the three drugs in the vasodilating beta-blocker group favored by Dr Ram. In fact, two other papers whose authors she assisted sounded hauntingly familiar.

Let me first display the quote above from the Ram paper:

Concerns have also been raised by meta-analyses in which � blockers were reported to have a suboptimal effect on reducing stroke risk and increasing the risk for new-onset diabetes compared with other antihypertensive agents.

Now see this quote from Frishman WH, Henderson LS, Lukas MA. Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfucntion. Vasc Health Risk Management 2008; 4: 1387-1400.  (Link here):

However, concerns have been raised recently from hypertension meta-analyses regarding suboptimal outcomes with use of beta-blockers, specifically atenolol, compared with outcomes for other antihypertensive drug classes.

Also see this relatively similar quote from McGill JB. Optimal use of beta-blockers in high-risk hypertension: a guide to dosing equivalence. Vasc Health Risk Management 2010; 6: 363-372. (Link here):

Concerns about the use of �-blockers as first-line agents for hypertension have been raised because of a 2005 metaanalysis that found �-blockers do not significantly reduce
cardiovascular events, especially stroke, compared with other antihypertensive drug classes

Furthermore, read this discussion of Coreg by Ram:

Carvedilol is a nonselective � blocker with a1 receptor�blocking activity and no intrinsic sympathomimetic activity. Clinical data suggest that carvedilol reduces systemic vascular resistance in patients with hypertension.

Here is Frishman et al:

Carvedilol is a third-generation, vasodilatory beta-blocker that nonselectively blocks both the beta 1- and beta 2-adrenergic receptors.... vasodilatory beta-blockers can lower blood pressure by reducing systemic vascular resistance (SVR)

Both Frishman et al and McGill are very positive about Coreg.  Although the emphases of the three articles are different, they have organizational similarities.  Again, all three were written with the assistance of Ms Loh.

At the end of the Frishman article we again find:

The authors would like to thank Tamalette Loh, PhD, ProEd Communications, Inc.�, for her medical editorial assistance with this manuscript.

At the end of the McGill article we find:

Editorial assistance, specifically revisions to the final draft, was provided by Tamalette Loh, PhD, at ProEd Communications, Inc.�, whose services were also funded by GlaxoSmithKline. Dr Loh�s revisions were reviewed and approved by Dr McGill.

Note that now it seems that Ms Loh has a doctoral degree, of unclear kind. Note also that now it seems that GSK, the manufacturer of Coreg, funded Dr Loh's work on the McGill article.

Dr McGill further disclosed:

Dr McGill is a consultant for GlaxoSmithKline and a speaker for AstraZeneca and Forest Pharmaceuticals. Financial support for medical editorial assistance was provided by GlaxoSmithKline, Philadelphia, Pennsylvania.

Finally, in another article, about angiotensin converting enzyme blockers combined with diuretics to treat hypertension (Egras AM, Ram CVS. Reduced cardiovascular risk and healthcare expenditures with angiotensin receptor blocker/ hydrochlorthiazide. Am J Pharmacy Benefits 2010; 2: 127-135. Lin here. ), Dr Ram acknowledged:

Dr Ram is in the speakers� bureau pool of Cogenix, ProCom, and Genesis, which manage medical education programs for Bristol-Myers Squibb, GlaxoSmithKline, and Novartis.

The series of articles above demonstrated a phenomenon I have not seen explored before. All articles were written with some sort of assistance from an employee of a MECC, perhaps partly funded by a company which marketed a drug which was the subject of all the articles. The assistance was openly acknowledged.  The three articles had some remarkable similarities not explained by an overlap among their listed authors.  This suggested that the ostensible editorial assistant they had in common was substantively involved in the content of the papers, that is, was truly an author. Her presence was not ghost-like. However, the substance of her contribution may have been downplayed.  So let's call her an "undercover author."  (If someone has a better term, please leave a comment to that effect.)

Summary

So the reasons I rarely read narrative review articles except to make teaching points about health care dysfunction are:
- They often are based on idiosyncratic, if not biased selections of data
- They may employ logical fallacies to make their points
- They may be written by people with conflicts of interest, that is, with financial arrangements with companies seeking to market products, particularly drugs and devices.

My conclusions for health care professionals are: be very skeptical of non-systematic review articles, look for evidence that they are parts of stealth marketing campaigns, and do not assume all conflicts of interest are disclosed and all authorship roles revealed.

My conclusions for journal editors are: strictly demand more complete disclosure of conflicts of interest, or risk losing the trust of your readers.

My conclusions in general: until we start to sweep away the pervasive web of conflicts of interest that is draped over medicine and health care, expect further discombobulation.

"This is Really Going to Set People's Hair on Fire" - the Justice Department Indicts a Pharmaceutical Company Vice President and Associate General Counsel

We have been posting nearly every week about the parade of legal settlements, sometimes including guilty pleas to criminal charges, made by health care organizations.  The settlements have involved charges of kickbacks, fraud, conspiracy, and other colorful offenses. Most of these settlements entailed fines or other payments by the organizations that may seem huge, but were fractions of the amounts made by the practices that lead to the charges that were settled.  Almost never have the cases involved penalties for any individuals who authorized, directed, or implemented the misbehavior.  We have also been saying (seemingly endlessly, but most recently here) that such settlements may be viewed by organizations as merely the costs of doing business, and so until the actual people who were involved in the bad behavior suffer some negative incentive or penalty, expect the behavior to continue. 

Maybe things are changing.  In the New York Times, Duff Wilson wrote:

In a rare move, the Justice Department on Tuesday announced that it had charged a former vice president and top lawyer for the British drug giant GlaxoSmithKline with making false statements and obstructing a federal investigation into illegal marketing of the antidepressant Wellbutrin for weight loss.

Specifically,

The indictment accuses the Glaxo official, Lauren C. Stevens of Durham, N.C., of lying to the Food and Drug Administration in 2003, by writing letters, as associate general counsel, denying that doctors speaking at company events had promoted Wellbutrin for uses not approved by the agency. Ms. Stevens 'made false statements and withheld documents she recognized as incriminating,' including slides the F.D.A. had sought during its investigation, the indictment stated.

An Associated Press story provided more detail about the allegedly false statements:

The Department of Justice alleges that in 2002, Lauren Stevens of Durham, N.C., signed several letters to the Food and Drug Administration denying that her company had promoted an antidepressant drug for unapproved uses. But Stevens knew that the company had paid numerous physicians to give talks touting unapproved uses of the drug, including weight loss,....

Also,

In one instance, prosecutors say Stevens withheld slides used by physicians promoting the company's drug, even though the FDA had asked specifically for the materials. Stevens claimed that the company's response to the FDA was 'final' and 'complete,' according to the indictment.

Stevens also falsely denied that Glaxo had paid doctors to attend special sessions where medical experts discussed unapproved uses of Wellbutrin, according to the Department of Justice.

'Attendees were not paid, reimbursed or otherwise compensated to attend these events,' Stevens wrote in a 2003 letter to the FDA. But prosecutors say attendees received gifts, entertainment and other compensation in return for attending the events.

During 2001 and 2002, Glaxo paid two expert physicians to speak about 500 times each about Wellbutrin, including how to use the drug to treat obesity.

In addition, a CBS News story suggested that Ms Stevens was made aware of the nature of the information withheld:

In March of 2003, the indictment alleges, Stevens received a memo from other lawyers at GlaxoSmithKline analyzing the pros and cons of turning over the slides to the FDA. One of the cons listed in that memo was that turning over the slides would provide 'incriminating evidence about potential off-label promotion of [the drug] that may be used against [the corporation] in this or in a future investigation.'

An indictment of an individual, particularly a high-ranking corporate executive, seems to have gotten people's attention, e.g., as Duff Wilson wrote in the Times:

The indictment grabbed the attention of pharmaceutical executives who have been bracing for a long-promised government crackdown on company officials � rather than the corporations themselves � in drug-fraud cases that have resulted in billions of dollars in fines and payments.

'This is absolutely precedent-setting � this is really going to set people�s hair on fire,' said Douglas B. Farquhar, a Washington lawyer who recently presided at a panel on law enforcement during a drug industry conference where federal officials warned they were focusing on individuals. 'This is indicative of the F.D.A. and Justice strategy to go after the very top-ranking managing officials at regulated companies.'

My response is, of course, that the threat of this sort of action is absolutely what is needed to deter future bad behavior by health care organizations. As long as health care leaders could act with impunity, the fraud, kickbacks, conspiracy etc were continuing. Worse, given their impunity, why would anyone but an idealistic fool attempt to swim against the tide of rising sleaze in health care?  How could skeptics and critics of the status quo in health care gain any traction?

Now maybe this sort of action may finally lead self-satisfied, unreflective health care executives to think about what they are doing and its ethical and moral aspects. The NY Times article included this statement in defense of Ms Stevens:

Brien T. O�Connor, a lawyer with Ropes & Gray, said in a statement, 'Lauren Stevens is an utterly decent and honorable woman. She is not guilty of obstruction or of making false statements. Everything she did in this case was consistent with ethical lawyering and the advice provided her by a nationally prominent law firm retained by her employer specifically because of its experience in working with F.D.A.'

I actually would guess that Ms Stevens believes she did nothing wrong. I would guess that most of the numerous health care leaders who have been caught up in bad behavior also thought they did nothing wrong. After all, they were all very well paid, lived in nice houses in nice neighborhoods, drove fancy cars (when they did not have a paid car and driver), were respected in their communities, did charitable works, etc. How can fine people who look so respectable do anything wrong? But, of course, the veneer of respectability does not prevent unethical or immoral behavior. Making one's numbers, getting one's bonuses, all from doing the big boss' wishes do not certify one's actions as ethical or moral. Perhaps making corporate health care leaders actually accountable for their actions will lead them to think about whether their actions are really as upstanding as their accoutrements of social status make them feel.

My final comment is that it may be significant that this case involved a lawyer. On one hand, attorneys have been at the forefront of what little movement there is to improve the accountability, integrity, and transparency of health care organizations. On the other hand, the leadership of many health care organizations have lawyered up to defend their actions. Organizational lawyers have been known to sweet-talk, obfuscate or intimidate those who dare to criticize the organizational leaders' actions. Anyone who is a vocal skeptic of the powers that be in health care must know there is a constant risk of some corporate counsel or hired firm threatening a libel, slander, or tortious interference action. Any individual who dares to be skeptical must be worried that the leaders of large health care organizations can use a lot of other peoples' money to pay for lawyers to push such actions, while individual skeptics facing threats of suits for huge amounts of damages are not likely to have enough money of their own to keep fighting. So I hope that the current case will also push attorneys who make a lot of money protecting the status quo in health care to reflect on the ethics and morality of what they are doing.

ADDENDUM (10 November) - Also see comments by Prof Margaret Soltan on the University Diaries 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.

Quis Custodiet Ipsos Custodes?

HAPPY TIMES AT NIMH

Two weeks ago I discussed a Commentary in JAMA by Dr. Thomas Insel, Director of the National Institute of Mental Health. Over on Danny Carlat�s blog, Dr. Insel took exception to my linking him with Charles Nemeroff, and appeared to be putting distance between himself and Dr. Nemeroff. So, I did some checking, and a correction to one of my statements is in order.

I had said, � � that Insel appointed Nemeroff as an advisor soon after he (Insel) moved to NIMH.� That was my recollection. It turns out what I recalled was instead Insel showcasing Nemeroff in the NIMH Director�s 7th Annual Research Roundtable June 10, 2003, a few months after Insel moved from Emory University to NIMH. Let the record stand corrected.

At that gala meeting, held at the National Press Club in Washington, DC, Dr. Insel characterized Nemeroff as one of the �real stars of NIMH�s research community�� Nemeroff used the occasion to pimp GlaxoSmithKline�s drug paroxetine (Paxil), showing data on change in platelet stickiness after Paxil in patients with heart disease and depression. This highlighting of Paxil by Nemeroff focused on the surrogate outcome of platelet function, and contained no evidence that Paxil modified any important clinical endpoints. Nevertheless, Nemeroff speculated liberally about the place of antidepressant drugs in managing heart disease. This is the sort of stuff Insel described at the Roundtable as � � an excellent sampling of the Institute�s exciting research endeavors.�

My general point two weeks ago was that Dr. Insel, the Director of an NIH Institute, downplayed the seriousness of the ethics issues surrounding the seven academic psychiatrists he mentioned in his Commentary in JAMA. Though he spoke in platitudes about the need for transparency, the spirit of transparency did not move him to disclose his own close ties with Dr. Nemeroff, who is one of the seven. Lest there be any remaining doubt about those ties, here is Dr. Nemeroff lauding Dr. Insel at the 201st meeting of the National Advisory Mental Health Council September 13, 2002 in the presence of the NIH Director, Elias Zerhouni, MD. From the Minutes: Dr. Charles Nemeroff, Reunette W. Harris Professor and Chair, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, commended Dr. Zerhouni�s selection of Dr. Insel as the next NIMH Director and added that Dr. Insel is the epitome of courage defined as grace under pressure. Dr. Nemeroff added that Dr. Insel will leave his current position as a most beloved professor, a respected scientist, and a great person.

In the comments on Danny Carlat�s blog I called Dr. Insel�s objections to my linking him with Nemeroff disingenuous. I still think that. Dr. Insel and Dr. Nemeroff are closer than Insel now seems comfortable acknowledging. Their record of talking up each other is hard to ignore. The irregularities identified by Senator Grassley involving Nemeroff�s reporting to NIH, his conflict of interest, and his conflict of commitment occurred on Insel�s watch. Considering the appearance of cronyism in their relationship, is it even possible for Dr. Insel to investigate Dr. Nemeroff�s performance in areas like the Emory-GlaxoSmithKline-NIMH Collaborative Mood Disorders Initiative?

Bernard Carroll

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.