Another Key Opinion Leader Confesses

The Milwaukee Journal-Sentinel published another story in their series on physicians' entanglements with health care corporations. This one tells the story of a single university faculty member who was seduced by pharmaceutical companies, then eventually became disillusioned.

[Dr James] Stein, now a professor at the University of Wisconsin School of Medicine and Public Health, was a 29-year-old cardiology fellow in Chicago in 1994 when his faculty mentor asked him to fill in for him at a drug company-funded lecture to a large group of doctors.

It would be his first taste of life as a drug company speaker and consultant.

Stein got first-class airfare to Dallas. A limousine took him to a luxury hotel for the talk.

He walked off the stage, and a doctor from the conference handed him an envelope containing a $500 check.

'I got a pat on the back and he said, 'There's more where that came from, son.' I had no idea what that meant, but I went home and paid off part of my student loans,' Stein said in a presentation at UW this month.

Stein's first drug company talk led to more than a decade of work for drug companies before he gave it up for ethical reasons. Now he is speaking out.

Over the years, many of the big names in the drug industry would hire Stein to give speeches or serve as a consultant, eventually leading to fees of $2,000 to $3,000 per talk.

About a month after his first talk in 1994, Stein was asked by another drug company to give a lecture on cholesterol at a small hospital in Chicago, just as blockbuster statin drugs were coming on the market.

'I was really flattered because over and over again I was told that I was a future thought leader,' he said. 'I did my talk. I got a $750 honorarium and I was hooked.'

Stein said he now realizes that the speech at the hospital was just an audition.

'They wanted to know what I would say and how I would deliver,' he said. 'And I think they also wanted to know what I would say about their product.'

He joined speakers bureaus for several drug companies. It was a kind of badge of honor, he said. The more companies a doctor spoke for, the more highly he or she was regarded.

Stein, now 44, came to UW in 1996. Over the years, he would give talks and do other work for many of the top names in the pharmaceutical industry.

For instance, in 2005 Stein did work for six drug makers, according to a disclosure form filed with UW. That year, Pfizer paid him between $10,000 and $20,000 for four days of work as a speaker and advisory board member.

LipoScience, a firm that markets a cholesterol test, paid him $10,000 to $20,000 for four days of similar work.

Another firm, Schering-Plough, paid him about $12,000 for two days as a lecturer.

Although he said he had concerns about the propriety of his work, Stein said he was assured by his superiors there was nothing wrong with it as long as he did it on his own time. Indeed, they said it enhanced the reputation of the university.

And, he said, he considered himself an educator, not a salesman.

He said he tried to manage any conflicts of interest by disclosing who paid him, controlling the content of what he said and doing the work on personal time.

Things started to change rapidly beginning several years ago.

Drug companies began referring to the talks as promotional. They wanted him to use their slides; he refused. Then, medical journals and the lay press began printing articles questioning the ethics of the relationships.

A 2006 article in a Madison newspaper listed Stein as being among the UW doctors who reported the most money from the drug industry. Stein said he was embarrassed.

But, he said, he continued to try to manage his relationships with drug companies. He sent letters to patients disclosing his ties to industry. As of December 2006, he donated all the money from his talks to charity.

Why didn't he just stop doing the work?

He said he believed he could save more lives lecturing than by working in the emergency room. Stein said he saw no harm in being paid. But he admitted that giving the talks also made him feel important.

At the same time, new scientific articles suggested that it is impossible for doctors to be unbiased when they receive gifts or payments from drug companies.

'I have learned that human beings, physicians included, are incapable of recognizing bias in themselves, and even when you try not to be biased it is impossible to avoid it, especially when money is involved,' he said.

He said he came to realize that drug and medical device firms were no longer trustworthy partners in medical education.

He also said it has become obvious that patients have the least power and drug companies have the most power.

'I was wrong,' he said.

Stein said he stands by what he taught.

But, he added, 'I was naïve to think I was not influenced by the money and power of the drug and device companies.'

As of last December, he said, he stopped all drug company speaking and consulting other than bona fide research.

It is nice that a few commercially paid "key opinion leaders" have realized what they were really doing. Maybe, Dr Stein will follow in the footsteps of Dr Daniel Carlat, and try to atone for his previous role in drug marketing disguised as education. (See Dr Carlat's excellent blog here, and his now classic article, "Dr Drug Rep.")

This compelling narrative reinforces some points about relationships among physicians and health care corporations.

Health care corporations do not pay for nothing, and are not charitable organizations. If a company pays a physician to give talks, it is almost certainly because those talks will help market company products or services.

Pharmaceutical and device companies have argued that they only pay the best and the brightest physicians as speakers and consultants. But this story (and others, e.g. here) suggest that they recruit young physicians who seem to be malleable and likely to go along with the company line, and groom them to do marketing in the guise of education.

The company's money thus helps mold "key opinion leaders." Worse, at many medical schools, being a commercially supported speaker or consult was a badge of honor. Thus, faculty chosen by commercial firms as most tractable and sympathetic to the companies' viewpoints, came to be regarded as the best and the brightest.

Why getting money from commercial firms was regarded as indicative of honor and intelligence, rather than gullibility, naivete, or worse, is not clear. I wonder whether it correlated with increasing alignment of the leadership of medical schools with commercial interests, and domination of the very top leadership, that is, the universities' board of directors, by those formerly regarded as Masters of the Universe (but now often seen as stupid, arrogant, greedy, or even corrupt. See posts about how the boards of Dartmouth, Harvard, and Yeshiva were disproportionately populated by leaders of [faux] finance).

At any rate, this is truly a cautionary tale of seduction of academia into hucksterism.

Hat tip to Margaret Soltan at University Diaries.

ADDENDUM (30 April, 2009) - See also the comments by Dr Daniel Carlat on the Carlat Psychiatry Blog.

Shut Up, They Explained (to Ezetimibe Critics)

One of our scouts alerted me to a remarkable editorial just published by Harrison, Brown and Raggi on the ezetimibe controversy [Harrison DG, Brown WV, Raggi P. Enhanced hype. Am J Cardiol 2008; 102: 368-369. Link here, requires subscription.]

We have posted before (as have many others,) about problems with the ENHANCE trial of ezetimibe (Zetia, by Schering-Plough, and one component of Vytorin, by Merck), and how the trial seemed to be designed and implemented so as to increase the likelihood of a favorable result for the sponsors' interests. Particularly controversial was the sponsors' decision to change the definition of the trial's outcome variable after the data was collected, (later reversed after it was publicized.) It also turned out that the supposedly "independent" panel responsible for that decision included a majority of members who had previous financial ties to Merck and/or Schering-Plough.

The ENHANCE trial was not meant to determine whether ezetimibe had any effects on clinical outcomes, that is, whether it made patients feel or function better, avoid morbid events, or live longer. Its focus was on whether the drug reduced the thickness of arterial walls in patients with very high cholesterol levels. The study failed to show even this effect.

Since no previous study had shown that ezetimibe leads to symptom reduction, functional improvement, prevention of morbidity, or extension of life, it was surprising that the American College of Cardiology and the American Heart Association rushed to the drug's defense, counseling physicians not to take patients off it. Why continue to give patients a drug that has never been shown to provide clinical benefit? In this post, we wondered whether this enthusiasm unsupported by clinical research evidence had to do with undisclosed conflicts of interest affecting the defenders of ezetimibe.

Since then, in the continuing absence of evidence about the benefits of ezetimibe, there has been continuing controversy over its use. Harrison, Brown and Raggi continued in this vein. They clearly sided with the American College of Cardiology's statement that physicians should not take patients off ezetimibe, which they contrasted with what they characterized as

hysterical coverage from Web sites, news organizations, and cardiologists who seem to seek high visibility.

So the "hype" and hysteria, according to Harrison, Brown and Raggi, were criticisms of attempts to manipulate the ENHANCE trial, and observations about the lack of clinical evidence supporting the use of ezetimibe. What made their article remarkable, however, was its suggestion that purveyors of "hype" and "hysteria" as defined by Harrison, Brown, and Raggi, should just shut up. First the three authors wrote,

Strong statements regarding guidelines or policy in the use of this drug by cardiologists (with little background in lipid research and atherosclerosis biology) are inappropriate and certainly premature.

Then,

unsupported premature claims regarding a drug’s effectiveness or lack thereof should be conveyed properly, as in the case of the American College of Cardiology’s official statement. There seems to be a recent love affair with the issuance of headline-grabbing statements to the press, and this should be discouraged. When done in haste without proper study and thought, they appear to be self-aggrandizing, and at worse, they are very misleading.

So this editorial is noteworthy not because it defended ezetimibe, or belittled its critics, but because it seemed to question the right to criticize the established dogma.

Obviously, the authors of the editorial have no legal authority to censor those whose views offend them. But even veiled questioning of the right to express dissent are contrary to the core values of science and medicine. For science to advance, open discussion and criticism of methods, results and interpretations is vital. For physicians to take the best possible care of patients, they must have access to the best possible evidence from clinical research, even if that evidence offends the powers that be or those with vested interests.

A clue as to why the authors took such an extreme position may be found in the last sentence of their article,

In the case of ezetimibe, we are concerned that this drug or its makers will be eliminated on the basis of hyperbole, misinformation....

Why would they be so worried as to raise the hyperbolic concern that the controversy over ENHANCE could cause ezetimibe, and even Merck and Schering-Plough to be "eliminated?" A quick Google search revealed disclosed that the authors collectively have multiple relevant financial relationships that they did not disclose.

• Dr David G Harrison is on the scientific advisory board of Atherogenics, Inc.
• Dr W Virgil Brown, according to a financial disclosure statement provided by the National Lipid Association, on whose board he sits, "has advisory relationships" with AstraZeneca, Bristol-Myers Squibb, Merck, Merck Shering Plough, Pfizer, Reliant, Kos, Lilly; has "research relationships" with AstraZeneca, Lilly, Kos, Pfizer, Takeda; has "educational relationships" with Abbott, Lilly; and has "speakers' bureau relationships" with AstraZeneca, Bristol-Myers Squibb, Merck, Merck Shering Plough, Pfizer, Reliant, Kos, Lilly, Abbott, Takeda, Kos.
• Dr Paolo Raggi, according to disclosure statements provided by HDCN for a 2001 meeting, "received grant support and honoraria from Genzyme Therapeutics and is a stockholder in Pfizer Inc;" and according to disclosure statements provided by the Office of Continuing Education for Johns Hopkins University School of Medicine for a 2007 meeting, received an honorarium from Amgen, and received grants, consulting fees, and speakers' honoraria from Genzyme.

Perhaps the authors' financial identification with Merck and Merck Schering-Plough, and with the pharmaceutical and biotechnology industries in general lead to such exaggerated concern. In any case, the authors should have revealed these financial relationships, and allowed readers to decide whether they might have affected their views. Nonetheless, while conceivably such relationships could have somewhat explained the authors' partiality to censorship, it does not excuse it.

As documented on the FIRE web-site, it is now commonplace for academic administrators to try to silence those who disagree with the prevailing campus dogma. This impulse to censor those who provide inconvenient opinions or facts now seems to be extending to the scholarly medical literature. It is ironic that those calling for censorship simultaneously seem loathe to reveal their financial relationships with those with vested interests in maintaining the status quo.

The inconvenient truths that we censor or hide surely will return to afflict us.

ADDENDUM (3 August, 2008) - See also comments by anonymous blogger "PM" on Gooznews.

BLOGSCAN - Throwing Money at Zetia Marketing

On the Question Authority blog, Dr Peter Rost takes some time off from having fun discussing the Emperors Club VIP, i.e., the organization which NY Governor Eliot Spitzer allegedly patronized, to his downfall, to address Schering-Plough's alleged new marketing campaign for Zetia. He has a great anonymous post from someone who may be a Schering-Plough drug rep, "throwing money at a problem is not the way to fix things - it will only make matters worse. Have the company come clean about the study, give us some good (or even not so good) evidenced based medicine - and let us earn back the business the right way." Hear, hear.

Lawyers to have cholesterol feast: lawsuits target Vytorin's makers - and, who is responsible for the "confusion?"

In today's news we find that Merck and Schering Plough are coming under lawsuits as a result of the ezetimibe/Vytorin controversy. This was perhaps to be expected:

Lawsuits target Vytorin's makers
Plaintiffs contend the firms knew the drug didn't work.
Sat, Jan. 26, 2008

By Karl Stark
Inquirer Staff Writer

First came the negative publicity, then the lawsuits.

Merck & Co. and Schering Plough Corp., makers of the cholesterol-lowering combination drug Vytorin, are getting hit with a wave of lawsuits asserting the companies knew its product didn't work and delayed telling the public about it.

At least 10 lawsuits have been filed in federal courts, with half the filings in New Jersey, where both parent companies are based. Other federal suits have landed in California, New York, Ohio and Colorado.

The drugmakers "reaped billions of dollars in profits" by failing to release negative results, asserted a class-action complaint filed by a Philadelphia firm on behalf of Lionel D. Galperin of Washington state. The companies also caused patients to spend more money on Vytorin, which sells for more than $100 for 30 pills, compared with a lower-cost generic, the suit alleges.

Here is where I step off the alleged "anti-pharma" bandwagon ... sort of.

While I have criticized Merck's and Schering's mammoth marketing campaign for these drugs here ("Merck and Vytorin ... Who, Exactly, is Confused?") and here ("Full page ads in major newspapers: Does pharma really spend twice on marketing what it spends on R&D?"), I believe lawsuits with the slant of "Bush lied, people died" (i.e., the firms knew the drug didn't work but withheld the information) are both unmerited and especially unhelpful to those attempting to advance medical science.

This claim is in part based on the following:

The companies completed the [Enhance] study [on these drugs] in April 2006 but did not release preliminary results until a press release was issued on Jan 14 [2008]. That was more than a month after congressional investigators had written to company executives, asking about the delay and demanding documents.

The implication is that actual knowledge of the results were withheld from the public to protect the drug. I do not believe this to be the case. I recall genuine excitement at Merck about Zetia's cholesteral-lowering effects, and great confidence that it was a true breakthrough drug that would generate much needed revenue after multiple drug failures and patent expirations. Clinical medicine, however, is full of surprises.

While such excitement could motivate a company to withhold negative new information, I have a different interpretation of why such delays occurred. Pharma is in a state of downsizing. At Merck, a company that carried on a succcesful business for over 100 years without downsizing, the mass downsizing that began in Nov. 2003 and continues to this day was a major cultural "hammer over the head."

Such social changes tend to sink morale very severely. While Catbert the Evil HR Director might find this amusing, most productive poeple do not. It's also something that cannot be "massaged away" with HR propaganda and "employee appreciation days." As I noted in "Happy Accidents in pharma doubtful: Tax Break Used by Drug Makers Failed to Add Jobs" here, the stress of losing a job is like the stress of a death in the family or a divorce, and the stress of fear of losing a job is also pretty darn bad. As the Alaska state government piece on "surviving a layoff" cited in the above posting states, "remaining employees become overworked, burned out, extremely unhappy and put in a position of fear and uncertainty." It doesn't exactly take a rocket scientist to realize this.

Anecdotally, I reside in a Merck community and hear as much about morale from my local car dealer, haircutter, family medicine physician, restaurant waiters, and others. In fact, I don't believe clinical trials information was withheld deliberately. I believe morale is low, departments are understaffed, and people are playing "CYA" like their lives depended on it (as their careers and ability to pay mortgages and support families depends on their jobs, this is actually not unwise).

Taking morale issues into account, and adding in the three late-stage pre-launch drug failures of 2003, resulting cultural shift to mass layoffs, and the Vioxx debacle, extra long "CYA" to make sure the data and conclusions are correct is understandible in context.

In such an environment, where overworked, stressed out people basically give themselves (effectively speaking) hourly pay raises via doing less per hour, and return to seeing jobs as a value-for-value proposition where an employee in a mirrorlike fashion gives a company what it has earned (i.e., deserves) in terms of their committment and willingness to make sacrifices, long delays in handling complex clinical trials results sets - this study, of course, being just one of many - is not at all surprising.

In addition, politics being what they are in any corporate layoff, many good people (the movers and shakers) get laid off, and other good people can't stand the environment and leave for greener pastures. This leaves behind many less capable colleagues to pick up the slack. I believe the cause of the delays in data release are more likely to be found attributable to low morale, a lesser % of "stars" among the workforce than necessary for optimal effectiveness, dysfunctional self protection-style politics, and resultant lowered productivity.

As an aside, it would not surprise me if recent chemical spills of "liquid mustard gas" into the creeks in my community had at its roots a similar cause:

Pharmaceutical giant Merck has agreed to pay $20 million in assorted fines, environmental improvements and cleanup costs to make up for killing untold fish, fouling drinking water supplies and spoiling a season of recreation on the Wissahickon Creek in Pennsylvania with a toxic "liquid mustard gas," the Philadelphia Inquirer is reporting. The massive impact came from an old-school problem: Dumping toxic chemicals down the drain at a vaccine plant, from which they reacted with chlorine disinfectants and washed into the creek, wreaking havoc downstream for miles.

I do not believe the company would deliberately withhold clinical trials data, and therefore do not believe a "deliberately withheld" charge is reasonable with regard to the ENHANCE clinical trial results on ezetimibe (Zetia) and ezetimibe-Zocor(Vytorin) . If there is a good basis for a lawsuit, perhaps the people who should be sued are those in management and in consulting organizations that recommended layoff strategies and stole the soul of such a once-stellar company.

The newspaper also notes the following:

...The drugmakers aren't the only ones facing scrutiny. Both the American College of Cardiology, which represents most cardiologists, and the American Heart Association echoed the companies' assurances and urged patients on Vytorin not to panic after a major test of Vytorin was released on Jan 14. But their stands have drawn criticism from congressional investigators and others because both groups take in substantial sums from pharmaceutical firms.

I'm not going to comment further on this other than to say "that sounds familiar", as the conflict of interest issue affecting medical professional societies has been well addressed by my Healthcare Renewal colleagues.

I will, however, comment on this:

W. Douglas Weaver, president-elect of the cardiologists, echoed those concerns. "We really had huge numbers of patients calling physicians' offices and not knowing how to interpret this information," Weaver said. "People were discontinuing statins because of the confusion."

The unstated but not-so-subtle implication (to those who understand marketing and "spin") appears to be that the big, bad, "anti-pharma" zealots and their allies in the media have gotten the poor public all confused, and the public is stopping their lifesaving meds as a result.

Having been involved in drug nomenclature activities at Merck as well as being familiar with the work of groups such as the Institute for Safe Medication Practices, one major goal in drug naming is to prevent confusion regarding the drug's nature and purpose. One creates drug names to assure that one drug is not confused for another, by healthcare professionals, patients, and others. Information scientists and others work very hard to select names for drugs that do not "resemble" others in spelling, phonetics, etc.

Now, just who is responsible for the confusion among patients "discontinuing statins because of the confusion?"

It seems to me the brainiacs who came up with the marketing scheme of giving a combination drug consisting of a newly-generic drug and a newly-approved one an entirely new name to milk more income out of a drug going generic -- and effectively discourage doctors/patients from simply prescribing/taking two pills (the generic and the new one) -- are largely responsible.

How many patients really understand that their wonder drug has two parts, one old, one new, that they could purchase and take separately likely for less cost than the combination, and that only the "new" part has come under scrutiny? How many understand that if the statin part of the new combination drug doesn't agree with them, they would have to discard the drug instead of simply replacing the statin? In addition, do busy general practice physicians understand this? One wonders.

It therefore seems the marketing folks as well as the drug naming approval organizations and the FDA carry significant blame for the "confusion." Perhaps this is a case of the unexpected (or should I say the predictable but undesired?) happening that provides evidence drug combinations should not be given snappy new names or approved as expensive "new" drugs.

Finally, I cannot but think it ironic that just as VIOXX and other similar drugs may have caused platelets and/or blood vessel walls to become more "sticky" and create vascular side effects, so ezetimibe might cause cholesterol and/or blood vessels to be more "sticky" for reasons not yet understood and negate some of the cholesterol lowering effects. It would be ironic indeed, as the newspaper article suggests by the observation "the combination drug failed to provide any benefit and even performed slightly worse than Zocor alone", if long term studies show ezetimibe to create more harm than good.

However, clinicians, the company and the regulators should be prepared if this occurs to get the data out ASAP when it is available fron ongoing studies - low morale or not.

-- SS

BLOGSCAN - The Sorts of People Who Get to Run Large Health Care Organizations

Back blogging on BrandweekNRX, Dr Peter Rost just posted about the sort of people who now run Schering-Plough, the company that, with Merck Inc, just got a lot of unfavorable publicity after it was involved in delaying the release of results from the ENHANCE trial of ezeimibe (see our last related post here.)

According to Rost, "Sean McNicholas is now Schering-Plough's Senior Vice President, responsible for ZETIA and VYTORIN, reporting directly to [Schering-Plough President] Carrie Cox, who dumped $28 million SGP stock last year." Previously, "Sean McNicholas was Vice President Marketing, Endocrine Care, Pharmacia, responsible for Genotropin marketing until the year 2001." But, "Pharmacia entered into a Deferred Prosecution Agreement with the Government for its illegal promotion of Genotropin for such 'off-label' uses as anti-aging, cosmetic use and athletic performance enhancement...."

Furthermore, "Carrie Cox was Vice President, Women's Health Care at Wyeth, responsible for marketing of Prempro and for Pondimin and Redux, two slimming products.... In September 1997, the FDA requested the withdrawal of Pondimin and Redux [parts of the fen-phen weight loss drug combinations] and Wyeth ended up paying well over $20 billion in class action settlements to women who alleged heart valve damage."

It makes one wonder about the sorts of people who get to run big health care organizations, especially in an environment where there seem to be no negative consequences when top leaders make poor decisions.