As I posted yesterday, the increasingly noisy debate about health care reform in the US has not dealt much with the issues we often discuss on Health Care Renewal. These include problems in how health care organizations are led which threaten physicians' and other health care professionals' core values using tactics including perverse incentives, deception, and intimidation.
Last night, however, President Obama held a news conference mostly devoted to health care issues, in which he stressed the importance of changing not just how health insurance works, but how health care decisions are made. As Newsweek's "The Gaggle" blog reported,

Can I guarantee that there are going to be no changes in the health care delivery system? No. The whole point of this is to try to encourage changes that work for the American people and make them healthier. The government already is making some of these decisions. More importantly, insurance companies right now are making those decisions. And part of what we want to do is to make sure that those decisions are being made by doctors and medical experts based on evidence, based on what works, because that's not how it's working right now.

So what the President seems to be advocating is making health care more evidence-based, perhaps in the formal sense of evidence-based medicine.

As a card-carrying evidence-based medicine advocate, I certainly agree, but let me reiterate that evidence-based medicine is not just medicine based on some sort of evidence. As Dr David Sackett, and colleagues wrote [Sackett DL, Rosenberg WM, Muir Gray JA, Haynes RB, Richardson WS. Evidence-based medicine; what it is and what it isn't. BMJ 1996; 312: 71-72. Link here. ]

Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice. Increased expertise is reflected in many ways, but especially in more effective and efficient diagnosis and in the more thoughtful identification and compassionate use of individual patients' predicaments, rights, and preferences in making clinical decisions about their care. By best available external clinical evidence we mean clinically relevant research, often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens.

Furthermore,

Evidence based medicine is not 'cookbook' medicine. Because it requires a bottom up approach that integrates the best external evidence with individual clinical expertise and patients' choice, it cannot result in slavish, cookbook approaches to individual patient care. External clinical evidence can inform, but can never replace, individual clinical expertise, and it is this expertise that decides whether the external evidence applies to the individual patient at all and, if so, how it should be integrated into a clinical decision.

One can find other definitions of EBM, but nearly all emphasize that the approach is designed to appropriately apply results from the best clinical research, critically reviewed, to the individual patient, taking into account that patient's clinical characteristics and personal values.

So far, so good. I believe the proper application of "real" (as described above) evidence-based medicine has the potential to improve patient outcomes while moderating health care costs. However, we have pointed out how problems arising from concentration and abuse of power in health care threaten the evidence-based medical ideal.

First, there are major problems with the development of the sort of clinical research evidence required by the EBM process. We have discussed how clinical research is frequently manipulated by those with vested interests in producing results that favor the products or services that they sell. The critical review process inherent in EBM is meant to cope with less than optimally designed and implemented research. However, the process was designed to cope with honest mistakes and inevitable trade-offs, not deliberate manipulation by vested interests.

Worse, we have discussed how vested interests may engineer the suppression of research when manipulation fails to produce the desired results. The EBM process assumes that the research on which decisions should be based is an unbiased sample of research that was done (and done to advance science, not commercial or ideological interests). When research whose results are unwanted by vested interests is suppressed, the resulting distortion of the evidence base may irretrievably bias the EBM process.

Finally, we have posted about how vested interests have distorted the discussion, dissemination, and teaching of the results of clinical research. They may develop systematic stealth marketing campaigns, often employing supposed "key opinion leaders," who are paid on the side by marketers, and using "medical education and communication companies"as marketing fronts whose publication strategies include deceptive tactics such as "ghost-writing."

Thus, a rising tide of "pseudo-evidence based medicine" threatens to overwhelm even the most conscientious physicians trying to practice evidence-based medicine.

So, while I applaud President Obama's advocacy of reforming health care to emphasize what the best evidence suggests really works, I do not think this effort will get far unless we deal with the rising tide of pseudo-evidence based medicine. As a minimum, we need full and detailed disclosure of all the relationships among vested interests and medical research and education, and a much greater role for research and education that is not subsidized by corporations bent on using research and education to market their products and services.

All things that fall must converge?

The escapades of the former Emory University Chair of Psychiatry, Dr Charles Nemeroff, now have gotten quite a lot of press, but we were writing about some of them here on Health Care Renewal before the good doctor became so well-known. Dr Bernard Carroll, for instance, posted here and here, and I posted here (with links backward).

We have also posted about how well-intentioned public broadcasters seem to have got caught up in the web of health care conflicts of interest. Here we talked about how a drug company ended up funding a special on obesity, and here we talked about the involvement of a device and a drug company in the "Mysterious Human Heart."

In late June, the Columbia Journalism Review included an article by Paul Scott about how a US Public Broadcasting System show won an illustrious Peabody award for a show featuring Dr Nemeroff pontificating about depression.

Last May, a Peabody was awarded to the film Depression: Out of the Shadows, a documentary which aired in 2008 on PBS, was produced by Twin Cities Public Television and WGBH Boston, and was written and directed by Minneapolis-based filmmaker Larkin McPhee.

But where her film was generous in its inclusion of heartbreaking personal stories about depression, its broad survey of the science of the illness included frequent appearances by Charles Nemeroff, M.D., a leading—some say powerful—mood disorders researcher from Emory University. Last fall, Nemeroff also became one of the most prominent psychiatrists to be rebuked for failing to disclose funds earned from the drug industry.

Last October, Senator Charles Grassley of Iowa notified Emory that Nemeroff had received $2.8 million from drug companies between 2000 and 2007, $1.2 million of which he failed to report to the university, as he was required to do according to federal rules. To reduce their risk of bias, National Institutes of Health (NIH) researchers must limit to $10,000 their annual receipt of payments from the makers of drugs they are studying. As the lead investigator for a five-year, $3.95 million federal grant to study Paxil and other GlaxoSmithKline drugs, Nemeroff pocketed seventeen times the NIH limit from GSK in 2004 alone, and exceeded his limit every year from 2003 through 2006, without informing his employers. Following his rebuke, Nemeroff lost his chairmanship at Emory, saw $9.2 million in NIH funds meant for Emory frozen, and was banned from federal research for two years.

Some might argue that little about this episode matters, since Nemeroff’s downfall took place in October and Depression: Out of the Shadows aired five months earlier. Yet a simple Google search would have alerted McPhee to the fact that Nemeroff, though the author of hundreds of research papers and well respected in his field, has been dogged by conflict of interest allegations for years. In 2003, he came under fire for praising three pharmaceutical products in the journal Nature Neuroscience without disclosing he held a financial stake in their success, one of which he held the patent on.

Three years later, Nemeroff resigned from his editorship of the journal Neuropsychopharmacology after The Wall Street Journal reported he held an undisclosed financial stake in a treatment for depression he praised in an article. Nemeroff is either great at making excuses for his conduct or extremely unlucky. Following his 2003 misstep, he blamed the journal in question for not requiring him to mention his conflicts. Following his omission in 2006, Nemeroff blamed a clerical error. Following his rebuke by Sen. Grassley, Nemeroff told his employers he did not realize that drug-industry sponsored continuing education appearances were payments requiring disclosure.

All defenses aside, by the time of production for Depression: Out of the Shadows, his drug industry entanglements were both widely distributed and widely known. “With financial ties to nearly two dozen drug and biotech companies,” wroteShannon Brownlee in The Washington Monthly in 2004, “Dr. Charles B. Nemeroff may hold some sort of record among academic clinicians for the most conflicts of interest.”

That PBS producers either did not know about Nemeroff’s drug industry entanglements or did not believe they tainted his discussion of the science of depression is disappointing.

But what made the praise bestowed on this PBS documentary particularly troubling were the erroneous, drug-industry serving statements made by Nemeroff within the film—statements which had the potential to negatively affect public health, and which the documentary left unchallenged. During a segment on the FDA’s 2004 decision to require “black box” safety warnings stating that antidepressants can increase the risk of suicide in children and teenagers, a risk it extended in May of 2007 to users under twenty-five, Nemeroff seized the occasion to claim that the federal safety warning was mistaken.

He did so by citing a 2007 study partially funded by Pfizer and published in The American Journal of Psychiatry, a paper ostensibly linking the warning with a subsequent increase in teen suicides. “The FDA put a black box warning for all age groups,” Nemeroff said in the documentary. “I believe this was a mistake, because in hastening our awareness, what we’ve shown is there’s been a marked drop in prescriptions of antidepressants, particularly for children and adolescents…and an increase in suicides and suicide attempts.”

But as critics quickly pointed outto The Boston Globe and The New York Times, the increase in suicides Nemeroff described actually occurred a year before a drop-off in antidepressant use. (You can’t blame a rise in suicides in 2003 on a drop off in prescriptions in 2005.) At the time, most parties to this debate agreed that the question of whether black-box warnings were inadvertently dangerous would not be further clarified until the release of Centers for Disease Control suicide data from 2005.

That data came out a month later, and showed that suicides have fallen overall; a follow-up report showed that suicides have fallen among youth specifically. The total number remains higher than in 2003, but less than in 2004, when the FDA warning went into effect.Given the complexity of epidemiological data and the rarity of suicide, those findings prove little except that any effort to link an uptick in suicides to reduced prescribing of antidepressant medications to children and teenagers is not supported by the epidemiological data.

Mr Scott concluded, memorably,

Something about the simultaneously complex and sympathetic nature of mental health reporting is making reputable journalistic organizations and well-meaning reporters sloppy.

Were health care journalists to dig deeper into the financial entanglements of some of the "key opinion leaders" who may be so eager to appear in well-meaning, and at times feel-good documentaries, the public might learn more about the web of conflicts of interest that now ensnares health care. They might also learn how much of what appears to be health care education is just marketing in disguise. That marketing is often of expensive, and not terribly effective treatments. Realizing that many seeming miracle cures aren't might lead to the skepticism that could help us control health care costs without hurting patients.

This new variation on a now old theme first appeared in the New York Times:

A former surgeon at Walter Reed Army Medical Center, who is a paid consultant for a medical company, published a study that made false claims and overstated the benefits of the company’s product in treating soldiers severely injured in Iraq, the hospital’s commander said Tuesday.

An investigation by Walter Reed found that the study cited higher numbers of patients and injuries than the hospital could account for, said the commander, Col. Norvell V. Coots.

'It’s like a ghost population that were reported in the article as having been treated that we have no record of ever having existed,' Colonel Coots said in a telephone interview on Tuesday. 'So this really was all falsified information.'

The former Army surgeon, Dr. Timothy R. Kuklo, reported that a bone-growth product sold by Medtronic Inc. had much higher success in healing the shattered legs of wounded soldiers at Walter Reed than other doctors there had experienced, according to Colonel Coots and a summary of an Army investigation of the matter.

Dr. Kuklo, 48, now an associate professor at the Washington University medical school in St. Louis, did not respond to numerous e-mail messages and telephone calls to his office and home seeking comment over the last two weeks. Walter Reed officials say he did not respond to their inquiries during their investigation.

Army investigators found that Dr. Kuklo forged the signatures of four Walter Reed doctors on the article before submitting it last year to a British medical journal, falsely claiming them as co-authors. He also did not obtain the Army’s required permission to conduct the study.

In its March edition, at the Army’s request, the journal retracted the article — something that has gone largely unnoticed outside orthopedic circles.

While at Walter Reed and since, Dr. Kuklo has given talks to other doctors around the country about the bone-growth product, a protein called Infuse, according to meeting agendas and published documents.

A Medtronic spokeswoman, Marybeth Thorsgaard, confirmed that Dr. Kuklo was a paid consultant to the company and that the company financially supported some of his research at Walter Reed, through a foundation affiliated with the hospital.

During his time at Walter Reed Dr. Kuklo was extensively involved in research and writing about various Medtronic products, including editing two books published by the company and conducting three studies that were approved by his Army superiors, according to his list of publications and an Army report.

Colonel Coots said Tuesday that the total number of patients Dr. Kuklo reported as having been treated for extensive lower leg wounds at Walter Reed during the study period — 138 soldiers — was greater than the number for which the hospital could find records.

'It is a significant breach of academic protocol,' Colonel Coots said. 'It’s a breach of trust.'

This story has several familiar elements, but combines them in some interesting ways.

We have discussed how health care corporations, particularly pharmaceutical manufacturers, cultivate "key opinion leaders," and use them to market their products. This may amount to stealth marketing, since KOLs rarely disclose in detail their relationships with corporate sponsors, and instead further their marketing objectives cloaked as academics.

We have also discussed how health care corporations, particularly pharmaceutical manufacturers, may sponsor clinical research on their own products. However, such sponsors often manipulate the research projects' design, implementation, analysis, and dissemination so as to favor their products. While the sponsorship may be disclosed, the extent of the sponsors' control over the project may not be. Furthermore, scientific investigators running such projects may have their own personal financial relationships with the sponsors.

This case apparently shows how a medical academic can both be a paid "key opinion leader," and manipulative clinical researcher. While many examples of key opinion leaders as stealth marketers, and manipulated research involved pharmaceutical companies, this one involves a medical device company. In addition, this research project was not just manipulated, but allegedly falsified.

This variation has at least one other interesting element. Again, from the New York Times,

A former Walter Reed colleague, Dr. David W. Polly Jr., who is also a Medtronic consultant, said he believed that Dr. Kuklo’s data was “strong” and the episode had been overblown.

According to the Center for Public Integrity Paper Trail blog,

A former colleague of Kuklo’s at Walter Reed Army Medical Center, Dr. David W. Polly Jr., took even more expensive trips than Kuklo. Polly went on at least 12 Medtronic-sponsored trips costing about $30,000, including a $10,000 trip to Switzerland.

Furthermore, the New York Times reported,

[Senator Charles] Grassley, the ranking Republican [from Iowa] on the Senate Finance Committee, has been investigating since last year whether Medtronic illegally promoted unapproved uses for Infuse. Medtronic, which has denied that accusation, provided him last year with a list of Infuse consultants.

After Dr. Kuklo’s links to Medtronic and Infuse came to light last week in a New York Times article, Mr. Grassley’s staff checked the consultants list and noted that Dr. Kuklo’s name was not on it. In reaction, he wrote a letter to Medtronic’s president and chief executive, William A. Hawkins III, asking why Dr. Kuklo had been omitted. Mr. Grassley entered that letter and the list he had received into The Congressional Record.

'In the future, I hope that instead of not providing me with the name of the physician involved in Infuse, or any other matter that I am looking into, that Medtronic contact me to avoid the situation in which we find ourselves,' Mr. Grassley wrote to Mr. Hawkins.

So, as soon as this case came to light, the spinning of public discussion to favor Medtronic and its key opinion leaders began. Thus, this case also involved stealth policy advocacy. Stealth marketing, clinical research manipulation, and stealth advocacy all in one case, we seem to have hit the jackpot.

The most recent development, again according to the NY Times, is

Dr. Timothy R. Kuklo, a former Army physician accused of falsifying research involving injured soldiers, has taken a leave of absence from the Washington University School of Medicine in St. Louis and its affiliated hospitals, the medical school said Friday.

Dr. Kuklo, an associate professor of orthopedic surgery, will not be performing operations, conducting research or teaching students, said a medical school spokeswoman, Joni Westerhouse. The university granted the leave, she said, so that Dr. Kuklo 'can focus on responding to queries about his research and consulting.'

At least his absence was not ascribed to the need to spend more time with his family or pursue other opportunities.

Finally, note that we posted last year that Medtronic had submitted to a corporate integrity agreement after the US Department of Justice accused it of defrauding Medicare in connection with activities by its Kyphon subsidiary. So this case additionally suggests that such agreements have little effect on the actual integrity of corporate leaders.

Hat tip to and see further commentary by Prof Margaret Soltan on the University Diaries blog.

An editorial appeared in the latest edition of Nature Medicine that suggested "crusaders" are making much too much fuss over insignificant "competing financial interests." [Anonymous. A really serious conflict. Nature Medicine 2009; 15: 463-4]

The Editorial's Arguments

Instead of regarding all conflicts of interest as part of a "monolithic scourge," it suggested we should only attack them in two specific situations.

Bad Conflicts of Interest

The first is when it leads to falsification of research data:

If there is one reason we need to worry about CFIs [competing financial interests], it is because they could lead to misconduct whenever a researcher has a financial incentive to fabricate data. So, if a clinical trial goes ahead on the basis of fraudulent preclinical work or if a drug is approved on the basis of false clinical data, the problem is more profound than can be addressed by the declaration of a CFI. Researchers or clinicians who produce sham data to continue receiving funds from a company must be subject to severe disciplinary actions from their institutions and funding bodies.

The second is when it leads to withholding of data in certain circumstances:

Companies that conceal negative data from regulators to receive approval for their drug should face not only fines but also penalties as serious as criminal charges. In any case, the focus should move away from CFI declarations and toward exposing and punishing scientific misconduct.

Some Conflicts of Interest are Unavoidable

On the other hand, the editorial asserted that conflicts of interest are unavoidable in certain situations.

But even though a lot has been written about this subject, it is seldom acknowledged that not all CFIs are equally insidious and that some are even necessary for the success of translational research.

Scientists who share their expertise with a company and clinicians who agree to conduct a clinical trial have to be compensated for their work in the same way that every other professional ought to be rewarded for his or her labor. To suggest that they should make their contributions freely is disingenuous, and to argue that they should not get involved at all can only slow the development of new medicines.

Academic institutions and their employees must be free to benefit financially from the fruits of the advances made in their laboratories, either by independently developing them into products or by selling them to the highest bidder. In the US, the Bayh-Dole Act has protected this right for nearly three decades, and CFIs that result from a university's right to enact this policy should not raise eyebrows.

Bad Outcomes of the "Crusade" Against Conflicts of Interest

In addition, the editorial argued that because of excess attention paid to minor or unavoidable conflicts of interest, bad things may happen. Clinical trials would be discouraged.

However, the fact remains that clinical trials are very expensive, and only the pharmaceutical sector has both the incentive and the deep pockets to pay for them.

And innovation would be slowed.

A third issue that is rarely acknowledged is that the stridency with which the CFI crusaders fight financial interests has created a milieu in which pharmaceutical firms have increasingly less breathing space to conduct their business, leading to a further slowing of drug development.

Finally, the editorial exhorted:

Let us instead accept that most financial interests do not represent a conflict as a matter of course and that the influence of money is negative only if it leads to scientific fraud—the one infidel we need to burn at the crusader's stake.

Logical Fallacies and Inflammatory Rhetoric

It is discouraging to see such sloppy thinking and inflammatory rhetoric appear under the masthead of a prominent journal. How was the thinking sloppy? Let me count the ways, and explain the logical fallacies used by the editorial to support its contention.

Arguing that Conflicts are Unavoidable Using False Dilemmas and Appeals to Common Practice

The editorial suggests some conflicts of interest may be unavoidable, even necessary for the advancement of science. To do this, it provided a series of false dilemmas and appeals to common practice. A false dilemma is an argument that x and y are mutually exclusive, when they are not. An appeal to common practice is an argument that because something is common practice, it is necessary, moral, correct, or the only course possible.

The editorial argued that researchers would not work for free, implying that if drug and device companies could not pay researchers to perform clinical trials, no clinical trials would be done. This is a false dilemma, because it is based on the unstated assumption that there is no other possible source of payment for clinical trial researchers other than the companies whose products the trials evaluate. It may be true that it would be hard to get anyone to conduct clinical trials for free, but there is no law of nature that dictates that all clinical trials must be financed directly by companies whose products are the subjects of these trials, or that prevents clinical trials from being funded by government agencies and/or non-governmental organizations disinterested in whether the results favor one treatment or another. Such disinterested sponsors paying researchers would not create conflicts of interest.

The editorial argued that if academic institutions and their employees cannot benefit financially from "the fruits of the advances made in their laboratories," there would be no drug and device development. This is a false dilemma, because it is based on the unstated assumption that the only setting for drug and device development is academic institutions. There is no natural law, however, that restricts drug and device development to academic institutions, or prevents drug development to be done by drug and device companies, or by independent laboratories. The editorial also appended an appeal to common practice. Bayh-Dole may be the current law in the US, but it is hardly natural law.

The editorial argued that without the "deep pockets" of the "pharmaceutical sector" and device companies, no one would pay for clinical research. This was a repetition of the false dilemma noted above. There is no natural law that prevents government and non-governmental organizations from sponsoring clinical trials. The editorial again appended an appeal to common practice. Current laws and social conventions have made drug and device companies extremely profitable, but continuation of their profitability is hardly inevitable.

Red Herrings to Distract from Other Bad Effects of Conflicts

While the editorial identified two particularly bad kinds of conflicts of interest, it ignored other instances that could be equally bad. This was something of a red herring. Although the two examples of bad effects of conflicts of interest were undeniably important, they distracted from other bad effects which the editorial chose to ignore.

The editorial correctly identified falsification of data as bad, but ignored the entire catalog of ways in which clinical research studies can be manipulated to make them more likely to favor a sponsor's product. See our posts (here and here) and the links contained therein for multiple examples of such manipulation.

The editorial noted that concealing data from regulators in order to win drug approval is bad, but ignored all the instances in which data has been suppressed outside of the regulatory process to make drugs or devices seem more efficacious or less dangerous than they really are. See this link for some of our posts containing relevant examples. If it is bad to fool people who must make regulatory decisions, why is it not so bad to fool physicians and patients who must decide whether to use drugs or devices?

The editorial further ignored that conflicts that affect how research is conducted or reported may be linked to conflicts that affect how research is disseminated or used in decision making. The clinical researcher who is paid by a drug or device company to conduct a clinical trial may also be an academic physician paid by the same company as a consultant or through a speakers' bureau to give talks and presentations, and write review articles favorable to the company's product. If it would be bad for the researcher to falsify data to make the product look better, why would it be acceptable for the researcher to act as a huckster for the product while pretending to be a disinterested academic? See this link for posts discussing stealth marketing, and this one for posts discussing the use of key opinion leaders.

Ambiguity and Ad Hominem Attacks Inflating the Bad Effects of Fighting Conflicts

While the editorial minimized the bad outcomes of conflicts of interest, it resorted to ambiguity and inflammatory language to exaggerate what might happen were conflicts to be reduced.

Its most dire prediction of the results of reducing conflicts was that doing so would create a "milieu" in which "pharmaceutical firms have increasingly less breathing space." Literally, this statement was nonsense. Metaphorically, it did not make a clear argument that these highly profitable companies (and even more profitable device companies) could not survive in a "milieu" in which their products were tested by researchers which the companies could not influence. This was not clearly a logical fallacy, but just word-play presented a reasoned argument.

Given how prevalent political correctness is, repeatedly characterizing people concerned about conflicts of interest as "crusaders" is inflammatory indeed. Being called "pharmascolds" is one thing, but "crusader" in some circles is regarded as equivalent to racist, a nasty term to label those who promote the separation of clinical research and medical education from commercial interests. Thus, the editorial winds up with a rather nasty version of an ad hominem attack.

We have seen numerous examples of the use of logical fallacies in defense of conflicts of interest, often by authors who were themselves conflicted. It is especially sad to see the editors of a scholarly medical journal employ such logical fallacies in the defense of conflicts of interest.

ADDENDUM (11 May, 2009) - See also the comments by Dr Doug Bremner in the Before You Take That Pill Blog.

ADDENDUM (20 May, 2009) - For an example of how the term "crusader" has become politically incorrect in the US context, see this article in the Boston Globe.