The $20 Million Dollar Journal Editor

Last week, the Milwaukee Journal-Sentinel reported on a royally paid journal editor:

In 2002, Thomas Zdeblick, a University of Wisconsin orthopedic surgeon who has pocketed millions of dollars in royalties from the spinal device maker Medtronic, took over as editor-in-chief of a medical journal about spinal disorders.

It would be the beginning of a beautiful friendship.

In the years to come, Zdeblick would receive more than $20 million in patent royalties from Medtronic for spinal implants sold by the company. And the medical journal he edited would become a conduit for positive research articles involving Medtronic spinal products, a Journal Sentinel analysis found.

Zdeblick took over editorship of the Journal of Spinal Disorders & Techniques seven years ago. Since then, studies involving Medtronic spinal products or that were funded by Medtronic appeared in the journal at least once per issue, on average.

Dozens of studies that mentioned Medtronic products have been published while Zdeblick has been editor. But in issue after issue, readers of the journal were not told that he was receiving millions of dollars in royalty payments from Medtronic at the same time.

Most of the time the articles, including some co-authored by Zdeblick himself about devices for which he gets royalties, had good things to say about the Medtronic products. Only on a small number of occasions did the articles find major problems with Medtronic devices.

And often the articles did not disclose financial ties the authors had to Medtronic.

Here are some specifics:

From 2003 through 2007, Zdeblick got more than $19 million in royalty payments for spinal devices from Medtronic, according to a January 2009 letter by U.S. Sen. Charles Grassley (R-Iowa), who has been investigating payments to orthopedic surgeons by Medtronic. In 2008, Zdeblick got another $2 million from Medtronic from royalties and working as a consultant, according to UW records.

To assess the relationship, the Journal Sentinel reviewed every article published in the journal since Zdeblick became editor.

The journal is published seven or eight times a year and typically has a dozen or so articles. The articles were searched to see if Medtronic products were used as a part of the study or if the study was funded by Medtronic.

At least 70 such articles were found in 56 issues of the journal from 2002 through October 2009.

• A 2005 study by researchers in France found favorable preliminary results with Medtronic's Maverick artificial disc.

In 2007, Medtronic paid Zdeblick $144,000 in royalties for the Maverick disc, according to Grassley's letter.

•  In August 2009, Zdeblick co-authored a study that involved Medtronic's Premier Anterior Cervical Plate as well as the plate of another company, Synthes. The study involved using two different kinds of bone grafts with the plates. Zdeblick got $654,000 in Premier royalties from Medtronic in 2007.

•  Zdeblick also co-authored three articles, in 2002, 2003 and 2005, involving Medtronic's BMP-2 and the LT-Cage, a device that paid him $1.4 million in royalties in 2007. None of those studies disclosed that he received millions of dollars in royalties from Medtronic.

Often articles in the journal had good things to say about Medtronic products:

•  In the 2002 study, Zdeblick and the co-authors concluded that BMP-2 and the LT-Cage led to a solid union and high fusion rates. In the 2003 study they found that BMP-2 may become 'the new gold standard.'

•  In a 2006 study, a different group of authors concluded that BMP-2 when used with a hip bone graft significantly improved the success of the fusion surgery with minimal risk to the patient. The 2005 French study of Medtronic's Maverick artificial disc that did not involve Zdeblick concluded it was a 'promising therapeutic technique.'

Dr Zdelblick declined to comment for the Journal-Sentinel, but:

In a statement, a spokesman for the spinal journal said Zdeblick has disclosed his financial relationship with Medtronic to the company that publishes the journal, Wolters Kluwer Health/Lippincott Williams & Wilkins.

All manuscripts submitted to the journal go through a rigorous review process using reviewers who have an objective viewpoint, Robert Dekker, director of communications with Philadelphia-based Wolters Kluwer Health & Pharma Solutions, said in a statement. 'Thanks to our strict peer review policies and processes, we have no concerns about the existence of this relationship,' Dekker said in an e-mail.

Dekker declined to provide a list of the reviewers used by the journal or information about their financial relationships with device companies. He also declined to comment on how Zdeblick made decisions about manuscripts and reviewers.

Of course, as the Journal-Sentinel pointed out, editors can make publication decisions independent of the recommendations of peer-reviewers. They also are free to select peer-reviewers who might have a particular viewpoint about a manuscript, its topic or authors, and to make and enforce editorial suggestions for changes in manuscripts.  It is beyond me what good that disclosure of conflicts of interest to a for-profit publishing corporation does in the absence of further disclosure.  Keep in mind also that the division of Wolters Kluwer that publishes the journals, Wolters Kluwer Health & Pharma Solutions, not only publishes journals and textbooks, but "provides marketing and publications services, business intelligence products, and advanced analytical tools and services" to pharmaceutical corporations.

Furthermore,

'It's absolutely a conflict,' said Richard Smith, the former editor of the British Medical Journal.

At a minimum, Zdeblick's conflict should be fully disclosed by his journal whenever a study involving a Medtronic product is published, said Smith, the author of 'The Trouble with Medical Journals.'

However, because he makes so much money from Medtronic royalties, he really should not be editing the journal at all, Smith said.

Just to add icing to the cake, Prof Margaret Soltan pointed out on her University Diaries blog that Dr Zdeblick is not only a journal editor, but a Professor and Chairman of Orthopedics and Rehabilitation at the University of Wisconsin.  In addition, his web-page at the University notes that he is on the editorial board of another orthopedics journal, Spine, also published by Wolters Kluwer Health. 

So here we go again.  How should we assess the objectivity of an ostensibly scholarly medical journal whose editor was made rich by royalties from a company whose devices were often evaluated in the articles published in the journal?  How should we assess the honesty of a journal editor who received millions in royalties from Medtronic, but who only deigned to disclose as an author in his own journal, "One or more of the author(s) has/have received or will receive benefits, (e.g., royalties, stocks, stock options, decision making position) for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript." (as in Zdelblick TA, Phillips FM. Interbody cage devices.  Spine 2003; 28: S2-S7.)  (Note that this sort of disclosure seems to be standard operating procedure for orthopedic surgeons who make millions from royalties and consulting fees, e.g. see this post.)

Prof Zdelblick had numerous opportunities to influence his colleagues, trainees, and students in his roles as journal editor, journal editorial board member, author of scholarly articles, and professor and chair of orthopedics.  At the very least, the people who read his journal or his articles, listened to his lectures, or participated in his clinical teaching should have at least had the opportunity to judge for themselves whether being paid over $20 million might have just biased what he wrote and said a tiny bit.  But can anyone doubt that $20 million dollars would profoundly influence one's thinking?  Can anyone doubt that an inventor who got rich from royalties might not be more enthused about the use of the devicesthat generated the royalties than would an academic whose salary is unrelated to the use of any device?   It seems to be an abuse of entrusted power for a journal editor, professor, and department chairman not to clearly disclose such huge conflicts of interests to readers, learners and colleagues.

This is just the latest vivid example of the conflicts of interest that permeate health care.  When multi-million dollar men pretend to be unbiased editors and professors, is it any wonder that we regularly overuse and overvalue the devices and drugs that they are selling?

ADDENDUM (6 January, 2010) - See also comments on the Spine Blogger, and by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog.

Post Title → The $20 Million Dollar Journal Editor

How Industry Views the Research It Sponsors

We have posted frequently about threats to the integrity of the clinical evidence-based, and to the practice of evidence-based medicine.  In particular, we have discussed how research may be manipulated in favor of vested interests, or suppressed when the results do not favor such interests.

Last week, the British Medical Journal electronically published a set of guidelines for how industry sponsored clinical research ought to be published, sponsored by the International Society for Medical Publication Professionals.  The authors came from pharmaceutical companies (Johnson & Johnson, AstraZeneca, Pfizer and Cephalon), medical device companies (LifeScan), and medical publishing and medical education and communication companies (John Wiley & Sons, Excerpta Medica, Field Advantage Medical Communications, PharmaWrite, and Knowledgepoint 360 Group).  [Graf C, Battisti WP, Bruce-Winkler V et al. Good publication practice for communicating company sponsored medical research: the GPP2 guidelines.  Brit Med J 2009; 339:b4430.  Link here.]

These guidelines are remarkable for the questions they raise about how people from industry view clinical research and how it should be reported in medical journals. 

Who's in Charge?

Nowhere does the article acknowledge that any one person has overall responsibility for a research project.  Clinical research projects funded by the US National Institutes of Health, Agency for Healthcare Quality and Research, and other federal agencies must have "principal investigators," who are the people who take overall scientific responsibility for the project.  The Graf et al article does not use this or an equivalent term.   There is no sense that they expect anyone to be in completely in charge of industry sponsored research. 

Particularly confusing is the following passage:

Before writing begins one author (a lead author, who may also be guarantor) should take the lead for writing and managing each publication or presentation. One author (identified as guarantor) should take overall responsibility for the integrity of a study and its report.

Here are some questions it raises.  If the guarantor could be chosen only when writing a paper is contemplated, which presumably could be years after the study that the paper would report was designed and implemented, who then would have been responsible for study "integrity" before the guarantor was chosen? Who would chose the guarantor for a particular paper? If a study generates more than one paper, could they each have a guarantor, and then how could they share responsibility for study "integrity?"  If the guarantor and lead author of a paper are different people, how would they share responsibilities, what would happen if they were not to agree, and who would be finally accountable?

So the guidelines seem to completely diffuse accountability for research projects, and the reports written about them.

Who is an Author?

In my experience with US federally and foundation funded research, research papers are written by the investigators, the people who actually did the research project.  However, in the guidelines by Graf et al, the concept of authorship is also ambiguous.  They suggest that "recognised criteria should be used to determine which of the contributors to an article should be identified as authors."  This is already confusing, since how could one be a "contributor" to an article without authoring it?  A later discussion of "contributors" as "investigators, sponsor employees, and individuals contracted by the sponsor" was not very helpful.  Why should a "sponsor employee" who was not an "investigator" be a "contributor" or an "author," whatever the distinction is between them? 

So the guidelines blur distinctions among people who do research, and people employed by companies that may have vested interests in the research favoring their products or services.

What do Professional Medical Writers Do?

There has been considerable recent controversy, not directly acknowledged by Graf et al, about the role of professional medical writers in the reporting of research and the writing of ostensibly scholarly medical publications, particularly in cases where the writers were paid by and reported to corporate sponsors, but were not recognized as such in the publications they wrote (a type of ghost-writing).  The guidelines by Graf et al do not clearly explain what the roles of professional medical writers ought to be:

Professional medical writers must be directed by the lead author from the earliest possible stage (for example, when the outline is written), and all authors must be aware of the medical writer’s involvement. The medical writer should remain in frequent contact with the authors throughout development of the article or presentation. The authors must critically review and comment on the outline and drafts, approve the final version of the article or presentation before it is submitted to the journal or congress, approve changes made during the peer review process, and approve the final version before it is published or accepted for presentation.

Note that this would not prevent a professional medical writer from writing an initial outline, the first draft, and all subsequent drafts. including the final draft of a paper. (The role of an "author" above might be restricted to simply commenting on and accepting the outline and all drafts.) Thus, the "authors" could function as distant editors, and the professional writer would assume authorship, as most people would define it. (Merriam-Webster: "1. one that originates or creates 2. the writer of a literary work.")

Furthermore, while the professional writer could take one the role of authorship, the guidelines do not require him or her to publicly acknowledge this role:

Professional medical writers, depending on the contributions they make, may qualify for authorship. For example, if a medical writer contributed extensive literature searches and summarised the literature discovered, and by doing so helped define the scope of a review article, and if he or she is willing to 'take public responsibility for relevant portions of the content' then he or she may be in a position to meet the remaining ICMJE criteria for authorship.

Presumably, a professional writer could dodge authorship by simply being "unwilling" to take such public responsibility.

So the guidelines apparently condone nearly all functions commonly assumed to be those of an author to be performed by a professional writer paid directly by the sponsor, without the writer being listed as an author.  The guidelines thus appear to condone ghost-writing in its most pernicious form.

Who Owns and Analyzes the Data?

Cases in which various the implementation and analysis of clinical research seems to have been manipulated to favor vested interests have raised concerns about the integrity of the data collected in the course of a research project, and how it is analyzed.  This is what Graf et al say about the ownership and use of the data:

Sponsors have a responsibility to share the data and the analyses with the investigators who participated in the study. Sponsors must provide authors and other contributors (for example, members of a publication steering committee or professional medical writers) with full access to study data and should do so before the manuscript writing process begins or before the first external presentation of the data. Information provided to the authors should include study protocols, statistical analysis plans, statistical reports, data tables, clinical study reports, and results intended for posting on clinical trial results websites. Sufficient time should be allowed for authors and contributors to review and interpret the data provided and to seek further information if they wish (for example, access to raw data tables or the study database).

The guidelines by Graf et al suggest that the company that sponsors the research should own the data. The investigators who collected the data and implemented the research project should not. At best, the company should "share" summaries, analyses, or pieces of the data, but at best investigators could have only "sufficient time" to "seek ... access to raw data tables or the study database."

So the guidelines would allow corporate research sponsors to analyze the data from studies evaluating their own products and services as they see fit, and the scientists who implemented the study and collected the data could only ask for access to it. 

Summary

The guidelines by Graf et al seem based on a very strange conceptualization of clinical research. In their view, no individual may be responsible for a clinical research project. Research data is controlled by the company that paid for the project, not scientists who implemented the research and collected the data. Research papers may be written by anonymous professional writers while the scientists who did the research only need to review and approve what they have written.

So why should anyone give credence to industry sponsored research?

We have discussed numerous instances in which clinical research was manipulated in favor of vested interests, and when clinical research whose results did not favor vested interests was suppressed. In most cases, the vested interests were held by for-profit pharmaceutical, biotechnology or device anufacturers acting as research sponsors. The guidelines by Graf et al seem to have been cleverly written to to employ comforting platitudes while licensing manipulation and suppression.  They should inspire no confidence in the integrity of industry sponsored research.

Post Title → How Industry Views the Research It Sponsors

BLOGSCAN - Merck Hired Elsevier to Create Fake Peer-Reviewed Medical Journal

You just can't make this stuff up. On the Respectful Insolence blog, Orac recounted how pharmaceutical giant Merck hired medical publishing giant Elsevier to create what appeared to be a peer-reviewed journal, but theAustralasian Journal of Bone and Joint Medicine really was just a marketing outlet. The goal was to market Fosamax and Vioxx. This is another bizarre variant on the stealth marketing theme, taken to quite an extreme. And the pharmaceutical companies wonder why people don't trust them?

ADDENDUM (4 May, 2009) - Dr Aubrey Blumsohn is back online on his Scientific Misconduct Blog, and noted the academic luminaries who were willing to serve on the editorial board of this fake peer-reviewed journal.

ADDENDUM (11 May, 2009) - See also comments on Laika's MedLibBlog.

Post Title → BLOGSCAN - Merck Hired Elsevier to Create Fake Peer-Reviewed Medical Journal

What, The RUC, Again? - One of the World's Most Prominent Medical Journals Also Leaves Some Important Things Out

With health care reform continuing as a hot topic in the US, more discussions of issues of interest to Health Care Renewal are appearing. We previously posted about a prominent expert's discussion of how the US Medicare system pays physicians. We noted that he seemed to avoid critical issues, and thus may have failed to suggest changes that would address the real problems. Finally, we noted that his undisclosed financial relationships with several companies which have profited from the status quo may have affected his arguments, and failure to disclose these apparent conflicts of interest muddied the discussion.

In a similar vein, we will discuss an article just published entitled "Reforming Medicare's Physician Payment System," by Gail R Wilensky, PhD(1). [Note that the discussion will be formatted in the same manner as the previous post, and we will unashamedly borrow some language from that post.]

Ms Wilensky's summary of the main problems afflicting the payment system was:

Medicare originally based its reimbursement to physicians, like all its reimbursements, on the amounts that had historically been charged for particular health care services. In 1984, when the program moved away from a charge-based per-diem rate for hospitals, it introduced the use of the Medicare Economic Index — a measure of the annual change that physicians face in the costs of practice — for updating physicians' reimbursement. This change marked the start of an increasing divergence between Medicare's reimbursement of physicians and its reimbursement of other providers.

In general, however, physicians are paid for providing discrete services, according to a disaggregated fee schedule that uses more than 7000 billing codes. In 1989, a major change was made in physician payments: the disaggregated fee schedule based on historical charges was replaced with the Resource-Based Relative Value Scale, which is based on relative values for physicians' work effort, physicians' practice expenses, and malpractice liability insurance expenses. Although the scale was intended to correct for a historical undervaluing of primary care and overvaluing of procedures (which it does not appear to have done very successfully) and for larger differences between urban and rural reimbursements than could be justified by differences in the costs of practice, it retained the use of a largely disaggregated fee schedule.

Because the risk of inappropriate volume increases is much greater with a disaggregated billing system, as the experiences of the 1980s showed, updates to the fee schedule have followed a top-down strategy. Since the early 1990s, overall Medicare spending has been tied to a preset target — initially to the volume performance standard (an amount that was set into law each year) and now, through the sustainable growth rate (SGR), to the rate of growth in the economy. Fees are adjusted whenever overall spending is greater (or less) than the target level....

Most recent discussion of reforming physician payment has focused on the SGR, which has caused the pressure to lower physicians' fees.

Her main solution to these problems:

I believe the key to reforming physician payment is to develop a more aggregative payment strategy. In the near term, payments need to be developed that cover all the services that a single physician provides to a patient for the treatment of one or more chronic diseases. This approach is consistent with, and could be related to, the work that CMS and others are doing on medical homes. In addition, bundled payments should be developed for high-cost, high-volume DRGs, to include, at a minimum, the reimbursement for all physician services associated with the DRG and perhaps the hospital payment as well.

Ms Wilensky suggested the main problem with Medicare's current system for paying physicians is that the sustainable growth rate (SGR) forces reductions in physicians' fees whenever total payments to physicians grow faster than the optimal rate. However, she avoids discussing why those payments grow so fast.

Increases in Fees Paid for and Volume of Procedures

As we have discussed, the current system pays physicians much more to do procedures than provide "cognitive" services, and these discrepancies are increasing over time. The amounts it pays for particular procedures are frequently raised. Meanwhile, physicians increase the number of procedures they do, partially because they find ways to do procedures faster. Thus, the amount being paid for procedures increases rapidly over time. But then the SGR mechanism is used to cut fees across the board, including those for cognitive services, which did not contribute to the overall increase in costs.

Why does Medicare continue to behave seemingly so irrationally? As we have discussed before, it seems to do with the machinations of the shadowy RUC (RBRVS Update Committee).

The Shadowy RUC

As we have discussed, the US Medicare system determines what it pays physicians using the Resource Based Relative Value System (RBRVS). This system determines the pay for every kind of medical encounter according to a complex formula that is supposed to account for physicians' time and effort, physicians' practice expense, and the cost of malpractice insurance. The components of physicians' effort assessed are, in turn, technical skill and physical effort; the required mental effort and judgment; and stress due to the potential risk to the patient.

To keep the system, which was started in 1990, current, requires addition of new kinds of encounters, which means encounters involving new kinds of procedures, and updating of the estimates of various components, including physicians' time and effort. To do so, the Center for Medicare and Medicaid Services (CMS) relies almost exclusively on the advice of the RBRVS Update Committee (RUC). The RUC is a private committee of the AMA, touted as an "expert panel" that takes advantage of the organization's First Amendment rights to petition the government. Membership on the RUC is allotted to represent specialty societies, so that the vast majority of the members represent specialties that do procedures and focus on expensive, high-technology tests and treatments. However, the identities of RUC members are secret, as are the proceedings of the group.

This opaque and unaccountable process has resulted in increases outstripping inflation in fees paid for procedures, while fees paid for "cognitive"medicine, i.e., for primary care, and for services that involve diagnosis, management of acute and chronic disease, counseling, coordination of care, etc, but not procedures, have lagged inflation. The effects of the RUC have been amplified by the unexplained tendency of commercial managed care and health insurance to track the RBRVS system when making their own payments to physicians.

For further details about the RUC, see these posts on Health Care Renewal (here, here, here, here, and here) and important articles by Bodenheimer et al,(2) and Goodson.(3)

By the way, why the US Center for Medicare and Medicaid Services (CMS) relies de facto exclusively on the RUC to control the RBRVS system, and why the AMA made the RUC into a secret organization apparently beholden only to the organization's proceduralist members are unanswered questions.


What Wilensky Left Out, and Why?

Ms Wilensky, a distinguished health care policy expert, barely touched on the biggest problems with how the US fee-for-service payment system works, and why these problems occurred. Thus, it is not surprising that the few solutions she recommended seem irrelevant to these problems.

As an aside, her discussion is not atypical of what is seen in most writings about health care policy that have to do with costs. It appears that it is politically incorrect to say that incentives are skewed, that this skewing appears to have resulted from the acts of a few individuals, and that these acts occurred with little outside attention or accountability. Why do health care policy experts follow these dictates of political correctness?

I don't know, but one possible explanation is that they are themselves biased by their own incentives. So let us further consider the case of Ms Wilensky.

Ms Wilensky's Conflicts of Interest

The New England Journal of Medicine article identified Ms Wilensky as "a senior fellow at Project HOPE, Bethesda, MD, a former administrator of the Health Care Financing Administration (now the CMS), and a former chair of MedPAC." It also noted, "no potential conflict of interest relevant to this article was reported."

So it did not acknowledge the following relationships:

- Ms Wilensky is a member of the board of directors of Cephalon, which claims to be "one of the world’s top ten biopharmaceutical companies." According to the 2008 company proxy statement, her total compensation for this position was $347,395 in 2007, and she owned 65,000 shares of Cephalon stock or equivalent.
- Ms Wilensky is a member of the board of directors of Gentiva, which claims to be "the nation's leading provider of comprehensive home healthcare and related services." According to the 2008 company proxy statement, her total compensation for this position was $125,031 in 2007, and she owned 33,205 shares of Gentiva stock or equivalent.
- Ms Wilensky is a member of the board of directors of Quest Diagnostics Company, which claims to be "the world’s leader in diagnostic testing, information, and services." According to the 2008 company proxy statement, here total compensation for this position was $291,112 in 2007, and she owned 122, 224 shares of Quest stock or equivalent.
- Ms Wilensky is a member of the board of directors of SRA International, a multi-purpose consulting company which "provides health consulting services for global clients, both public and private." SRA International also has a subsidiary, SRA "Global Clinical Development [which] is a full-service, global CRO [contract research organization]" providing services to pharmaceutical, biotechnology and device companies. According to the 2008 company proxy statement, her total compensation for this position was $179,659 in 2007, and she owned 20,000 shares of SRA stock or equivalent.
- Ms Wiilensky is a member of the board of directors of the UnitedHealth Group, one of the largest US health care insurers/ managed care organizations. According to the 2008 company proxy statement, her total compensation for this postion was $322,591 in 2007, and she owned 312,560 shares of UnitedHealth stock or equivalent.

All these corporations benefit from how the health care system currently runs. In particular, our current procedure-heavy style of medicine, driven by the incentives dictated by the RUC, favors the extensive use of expensive pharmaceuticals, laboratory tests and devices. The companies Cephalon, Quest Diagnostics, and SRA International thus especially benefit from this style. As a member of the boards of these companies, Ms Wilensky has a duty to advance their financial performance. Thus, it seems that Ms Wilensky's legal responsibilities to these companies might tend to bias her against actively questioning how physicians are currently paid, or proposing solutions that might upset the status quo.

Ms Wilensky's leadership roles in US publicly traded corporations are public, but not easily found unless one knows where to look. (A previous post on Health Care Renewal did document Ms Wilensky's board relationships at the time, 2006, as they related to a report she helped author on pay-for-performance [P4P]). However, the New England Journal of Medicine did not choose to make these apparent conflicts of interest public.

Without the knowledge of these financial relationships, one might suppose Ms Wilensky's opinions are only based on her disinterested expertise as a well-known health care policy scholar. Without knowledge of these financial relationships, one might think that a secretive, opaque process skewing physicians' payments toward procedures is not an important problem for our health care system.

We have come to a critical time in the history of attempts to reform the US health care system. Whether reform occurs, and whether it does any good will depend on the quality of the debate that precedes it. Such a debate should be robust, but those involved ought to make clear where their biases and interests may lie.

Unfortunately, it may be that some of the most prominent voices in the debate are those of people with strong personal financial interests in having health care reform go in certain directions, not others. Furthermore, people with particular interests may not want certain issues to be even brought up. If these interests are not revealed, the debate becomes deceptive.

In a previous post, I said "I fear that much of the debate up to now has been deceptive, and will not lead to good outcomes." Since the current post is also about a prominent health care expert published in a leading international forum whose arguments seem to obfuscate a major cause of our health system dysfunction, possibly due to conflicts of interest which were not disclosed, my fear has become stronger.




References

1. Wilensky GR. Reforming Medicare's physician payment system. New Engl J Med 2009; 360: 653-655. Link here.

2.Bodenheimer T, Berenson RA, Rudolf P. The primary care-specialty income gap: why it matters. Ann Intern Med 2007; 146: 301-306. Link here.

3. Goodson JD. Unintended consequences of Resource-Based Relative Value Scale reimbursement. JAMA 2007; 298(19):2308-2310. Link here.

Post Title → What, The RUC, Again? - One of the World's Most Prominent Medical Journals Also Leaves Some Important Things Out

Another Misuse of EBM

We agree with Roy Poses' comment on the recent JAMA article about EBM, particularly regarding some of its unfortunate "misuses." In the article that stands as the defining credo of Health Care Renewal, Roy wrote:

Most physicians believe that medicine should be based on science. Evidence based medicine, (EBM) ‘‘the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients’’ [74], is a refinement of this view. Meanwhile, the scientific basis of medicine is under increasingly severe attack.

We'd like to take this opportunity to identify a misuse of EBM that, ironically, contributes to the attack on the scientific basis of medicine, and that authors Montori and Guyatt didn't consider--probably because they are unaware of it. We explain it in the following letter, submitted to JAMA in response to their article. We discuss it at more length on the other blog to which we contribute, Science-Based Medicine, referenced from the letter:

To the editor:

In their recent article, “Progress in Evidence-Based Medicine,” Drs. Montori and Guyatt include important caveats about misuses of EBM. They mention trials funded by industry. They list several, documented problems with such trials, and correctly warn that these can result in erroneous interpretations by “unsophisticated users of the medical literature.” They correctly worry about “abandoning appropriate skepticism.”

There is a related misuse of EBM that leads to erroneous interpretations even by sophisticated authors, and that calls attention to systematic problems in EBM: trials of highly implausible hypotheses. Thus, regarding the homeopathic preparation Oscillococcinum, the Cochrane Collaboration writes:

Though promising, the data were not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndromes. Further research is warranted…[1]

The data, however, are not promising, and further research is not warranted. The reason is that for highly implausible treatments, existing knowledge easily trumps modestly “positive” trial data. In the case of homeopathy, each of its tenets has been more than adequately disproved, and its claim that the potency of a “remedy” increases with each dilution of the original substance, continuing well past the point at which not a molecule of that substance remains in the preparation, contradicts physical reality.[2]

Such considerations reveal at least two, related problems with the evidence of EBM as it pertains to clinical trials. The first is explicit: by relegating “physiology, bench research or ‘first principles’” to Level 5 of its “Levels of Evidence” hierarchy, EBM fails to acknowledge that consistency with firmly established knowledge is a necessary, even if insufficient, basis for accepting a hypothetical treatment as effective.[2]

The second problem is part of the culture, if not the letter of EBM: by eschewing Bayesian in favor of “frequentist” statistics, its practitioners can excuse themselves from justifying estimates of prior probability, and erroneously conclude that trial data tell us more about reality than they do.[3-5]

In January, 2008, several colleagues began the blog Science-Based Medicine, referenced below.* The name, which could just as well have been “knowledge-based medicine,” is a frank recognition of the EBM weaknesses described above. Because of our interests, Science-Based Medicine’s content is predominantly, though not entirely, concerned with implausible health claims. Its larger message, however, is that these claims call attention to fundamental ways in which EBM can be improved, such as to justify its own claim to being an arbiter of real evidence.

Kimball C. Atwood, IV

Wallace I. Sampson

10/19/2008

* Steven Novella, David Gorski, Harriet Hall, Wallace Sampson, Kimball Atwood

[1] Vickers A, Smith C. Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001957. DOI: 10.1002/14651858.CD001957.pub3.

[2] Atwood K. Homeopathy and Evidence-Based Medicine: Back to the Future Part V. Science-Based Medicine 2008 (Feb. 8). http://www.sciencebasedmedicine.org/?p=42. Accessed October 19, 2008

[3] Atwood K. Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine.” Science-Based Medicine 2008 (Feb. 15). http://www.sciencebasedmedicine.org/?p=48. Accessed October 19, 2008

[4] Goodman SN. Toward evidence-based medical statistics. 1: The P value fallacy. Ann Intern Med. 1999;130:995-1004.

[5] Goodman SN. Toward evidence-based medical statistics. 2: The Bayes factor. Ann Intern Med. 1999;130:1005-13.

Post Title → Another Misuse of EBM

Commercial Funding of CME, and Distinguishing Babies from Bathwater

There has been quite a bit of discussion lately about how industry funding influences continuing medical education. One of our industrious scouts pointed out one of the most recent entries in this discussion, an article on this subject by the Editor-in-Chief of the Journal of the American College of Cardiology, Dr Anthony N DeMaria [DeMaria AN. Continuing education, industry, and physicians. J Am Coll Cardiol 2008; 52: 1035-1036. Link here.]

Dr DeMaria confessed to "very mixed feelings" about the move to end commercial support of CME. He felt that such commercial support did some good.

This support has been estimated to amount to nearly $1 billion per year and has enabled us to have the breadth and depth of learning opportunities we currently enjoy.

Although he acknowledged that commercial support "sometimes appeared to primarily serve the interests of the supporters," he felt that full disclosure would allow physicians to be properly skeptical of that support.

I have a further, even more basic, reservation about the proposal to end commercial support for CME. Inherent in such an action is the idea that physicians are like sheep: easily led and without the ability to recognize biased or slanted information. I find this demeaning to the profession. In my experience, physicians are more skeptical than naïve; by nature they are not anxious to accept, but rather are waiting to be convinced. Given the competitive demands entailed in becoming a physician, we are likely intelligent enough to recognize bias when it is present.

Thus, he also felt that terminating commercial support would be bad.

I worry that termination of all commercial support is a major overreaction.

I view the proposal to eliminate all industrial support of medical education as throwing the baby out with the bath water. I agree that certified CME should be objective and free of all bias, and I am not naïve enough to think that this has been fully achieved. However, I think there are other ways to accomplish this goal, and that we have the structure in place to be successful in the ACCME, medical societies, and academic institutions. Tightening existing guidelines and greater diligence to adherence should be adequate. Equally important, I think physicians are intelligent, savvy, and independent enough to know bias when they see it, and to resist recommendations that are not based on firm data. Physicians may not be perfect, but in pursuing continuing education, we have set an example for other professions to follow. Industrial support has helped to make this possible; let's think long and hard before we upset the cart.

First, note that this is yet another argument that physicians ought to be offended by the notion that they can be influenced by commercial relationships. I agree that maybe few physicians consciously alter their decisions and judgments according to their financial relationships with companies that have vested interests in selling health care products or services. But, common sense and experimental psychology suggests that such relationships can influence judgments and decisions even without conscious awareness of their effects.

Second, note that Dr DeMaria makes yet another argument that full disclosure can resolve conflicts of interest. However, there is also evidence from experimental psychology that disclosing conflicts may give people a license to further exaggerate their communication and actions in favor of their personal financial interests, and that recipients of disclosure may not know how to adjust for it adequately (see post here.)

I disagree with Dr DeMaria. I do not think the current approach, based on full disclosure as an adequate way to manage the conflicts caused by industry funded CME, and to manage conflicts of individual continuing medical educators, is adequate.

Finally, it appears that Dr DeMaria did not disclose his own financial relationships with commercial suppliers of health care goods and services. A bit of searching revealed that he serves or has served on medical advisory boards for CardioNet, Cardiodynamics International, and ResMed, on the scientific advisory board of BSP, and on the board of directors of Biosite. A disclosure for the American College of Cardiology ACCEL program also stated he has gotten modest (<$10,000) consulting fees or honoraria from "all echocardiography and ultrasound companies." He did not disclose these relationships in association with the article cited above, nor did he disclose them in conjunction with his role as editor-in-chief of the journal. A disclosure for a 2006 CME program included "Stock Options: Resmed, Biosite, Targe GW. Consulting Fees: Resmed, Targe GW, Vasomedical. Research Grants: Resmed, Acoufiant. Speaker: Acoufiant. Employment: Resmed. Ownership/Partnership: Resmed. Officer/Trustee: Resmed, Biosite. Receipt of Royalties: Resmed."

Although Dr DeMaria asserted that physicians are smart enough to recognize bias when they see it, it is not clear they could recognize the effect of financial relationships which are not disclosed to them at all. Dr DeMaria did not give his physician readers an opportunity to judge whether his defense of commercially sponsored CME might have been influenced by his own relationships with industry, nor did he give his readers an opportunity to judge whether his actions and writing as the editor in chief of a major medical journal were otherwise influenced by these relationships.

In my humble opinion, as I have said before, those who advocate particular health policy positions have the same obligation to disclose relevant conflicts of interest as do those who advocate particular approaches to clinical problems. Policy positions ought to be skeptically evaluated taking into account whether those expressing them stand to gain personally from what they advocate. Failure to adequately disclose conflicts of interest ought to inspire even more skepticism.

I fear much that today much of the health policy debate amounts to stealth health policy advocacy.

Furthermore, in my humble opinion, those who exercise editorial control over health care and medical journals have the same obligation to disclose relevant conflicts of interest as do authors of clinical research articles.

Finally, based on the experimental psychology study to which I alluded above, I doubt that even full disclosure of all conflicts in detail will allow adequate management of the conflicts of interest that now pervade medicine and health care.

Post Title → Commercial Funding of CME, and Distinguishing Babies from Bathwater

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

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

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

Recall how the story began, with the publication in the New England Journal of Medicine by Nissen and Wolski of a meta-analysis focused on cardiac adverse effects of rosiglitazone (Avandia, by GlaxoSmithKline) (see post here). The main achievement of the Nissen and Wolski meta-analysis [Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here] was to be the first published article to combine data from all relevant clinical trials of rosiglitazone completed to date. Although two major trials of Avandia had been published, its manufacturer, GlaxoSmithKline, had performed many other smaller trials of the drug, most of which have not been published to date. They did eventually appear on a web-site run by GSK. However, this web-site was relatively obscure, and it was not created voluntarily, but in response to a settlement of legal action that alleged GSK had suppressed clinical research about its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link here and our post here). Nissen and Wolski found it, compiled the results of trials on Avandia, and combined their results with those of the few published trials in their meta-analysis.

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

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

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

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

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

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

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

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

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

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

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

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

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

Furthermore, in the NY Times article,

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

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

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

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

Furthermore, an article in the Philadelphia Inquirer noted,

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

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

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

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

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

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

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

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

BLOGSCAN - Suppressing Research on Occupational Disease

On the Scientific Misconduct Blog, Dr Aubrey Blumsohn summarizes a fascinating and disquieting case of suppression of research, involving occupational disease, a giant computer company, and a huge publishing company.

Post Title → BLOGSCAN - Suppressing Research on Occupational Disease

Did Conflicts of Interest Affect a Review of Anti-Coagulants to Treat Blood Clots?

In an article published last week on Medscape [Cundiff DK. Evidence-based medicine and the Cochrane Collaboration on Trial. Medscape Gen Med 2007; 9(2):56, link here] are allegations that conflicts of interest affected the Cochrane Collaboration review of the use of anti-coagulants for pulmonary embolism and deep venous thrombosis. Here are the main points of the article:

In 2001, I volunteered to help conduct a review for the Cochrane Collaboration of the evidence base for the use of anticoagulants (warfarin [Coumadin] and heparins) for blood clots in the lungs (pulmonary emboli, or PE) and legs (deep venous thromboses, or DVT), as recently affected Vice President Dick Cheney. Dr. Juliet Manyemba, a physician from England, and John Pezzullo, PhD, a retired biostatistician formally from Georgetown University School of Medicine, were my coauthors. I disclosed to the Cochrane editor that my research interest in anticoagulants for DVT and PE originated because of a malpractice case against me concerning a DVT patient that resulted in the loss of my medical license.

Warfarin, heparin, and other anticoagulant drugs have been used to treat blood clots since the 1940s based on unscientific anecdotal evidence and observational studies with historical controls. Subsequently, countless RCTs involving blood thinners for venous thromboembolism (VTE) patients have included no un-anticoagulated control subjects. According to anticoagulation researchers contracted or employed by drug companies, the rationale is that it would be "unethical" not to give anticoagulants to clinical research subjects with blood clots in their legs or lungs. After reading over 1000 studies on the topic, I found 1 randomized and properly controlled trial of DVT patients. Patients in the study received either standard treatment (warfarin and heparin) or phenylbutazone (an anti-inflammatory drug like aspirin). From this single well-designed study of anticoagulants came a startling result: The anticoagulants did not prevent deaths.

Cochrane archivists turned up 2 other RCTs of anticoagulation therapy in DVT patients. Neither trial found any benefit due to anticoagulants. Summing the results of the 3 trials, 66 DVT patients received anticoagulants and 6 of them died; 60 DVT patients did not receive anticoagulants, and 1 of them died. None of the 3 trials had been referenced in any journal articles or reviews of anticoagulant therapy that I read.

Although these 3 trials show a trend suggesting that warfarin and heparin do harm, there were too few patients to show with statistical significance that anticoagulants increase deaths. But they contain enough subjects to show that anticoagulants do not reduce mortality. Based on the complication rate of anticoagulation for DVT or PE in much larger observational studies, anticoagulants kill 1000-4000 Americans with VTE each year due to internal bleeding, mostly in the brain.

The Cochrane peer reviewers (at least 4 out of 7 of which had undisclosed financial ties to the drug companies that make anticoagulants) delayed four years over releasing this review for publication. When the only 3 RCTs discovered showed no benefit and possible harm from anticoagulants, the editor and peer reviewers directed us to include 8 additional lines of evidence supporting anticoagulation from about 50 other studies in the medical literature. When my critique of those 8 lines of evidence showed that they were all faulty, the peer reviewers did not rebut a single point. Instead, the editor demanded that we delete the additional lines of evidence from the review, because they were not from RCTs.

When the author of one of the randomized trials discovered by the Cochrane archivists refused to cooperate and clarify to us his method of randomizing patients in his study, the Cochrane editor and/or peer reviewers invented a reason to disqualify the trial from inclusion in our review. The editor told us to accept the edits or the review wouldn't be published. The 'authors' conclusions,' written into our article by the Cochrane editor and peer reviewers, were these: 'The limited evidence from randomized controlled trials of anticoagulants versus nonsteroidal anti-inflammatory drugs or placebo is inconclusive regarding the efficacy and safety of anticoagulants in venous thromboembolism (DVT and PE) treatment. The use of anticoagulants is widely accepted in clinical practice, so a further randomized trial comparing anticoagulants to placebo could not ethically be carried out.'

In our final draft of the review, we authors said that a placebo-controlled trial would be impractical and suggested a 'noninferiority trial' with anticoagulants vs a nonsteroidal anti-inflammatory drug. One of the peer reviewers, with no conflict of interest that I could find, commented, 'Note that it is ethically possible to conduct a study to determine if anticoagulation therapy is harmful. If nothing else, dose reduction studies could determine if lower doses or weaker therapies (aspirin or NSAIDS?) are equally effective" (ie, a noninferiority trial).'

At the suggestion of Dr. [Kay] Dickersin [the Director of Cochrane's US Center for Clinical Trials], I issued a complaint to the Cochrane Collaboration publication arbitrator in September 2006.

Dr. Dickersin recently told me that she cannot estimate when the Cochrane investigation will be completed. A recent similar investigation took 2 years. The publication arbitrator has resigned, and she has no guarantee of finding a replacement anytime soon.

Medscape General Medicine published my entire review, including the evidence from the 8 lines other than the 3 RCTs included in our Cochrane VTE review.[Cundiff DK. Anticoagulation therapy for venous thromboembolism. MedGenMed. 2004;6(3):5. See link here.] The Medscape VTE review concluded, 'Anticoagulants have not been shown to be efficacious in reducing morbidity or mortality or safe in venous thromboembolism treatment.' Medscape Chief Editor, George Lundberg, MD (former Chief Editor of JAMA), wrote the accompanying editorial, entitled 'Is the Current Standard of Medical Practice for Treating Venous Thromboembolism Simply Wrong?' [MedGenMed. September 9, 2004;6(3):36. See link here.]

While I concur with Dr. Healy that relying solely on evidence-based medicine to determine medical guidelines better suits the needs of governments and insurance companies for cost control than the needs of patients for optimal medical treatment, I agree for a different reason. While evidence-based medicine is absolutely essential to comprehensive healthcare reform, it has been profoundly corrupted by money.

This article has received no attention in the press, as far as I can tell. Note that the main benefit of warfarin after DVT is supposed to be prevention of extension and new clots, not postponement of death. However, Cundiff is certainly correct that the use of warfarin entails the risk of major, sometimes disabling or fatal bleeding, so that mortality should be assessed in any trials of this drug.

Note further that the article did not disclose the identity of the reviewers with alleged conflicts of interest, nor the nature of their alleged conflicts. Nonetheless, add this to other cautionary tales about how financial entanglements can influence the design, execution, and in this case, dissemination and discussion of clinical research.

ADDENDUM (22 June, 2007) - This post on Notes from Dr RW reminds us that blog first posted about this story in 2005.

Post Title → Did Conflicts of Interest Affect a Review of Anti-Coagulants to Treat Blood Clots?

Annals of Internal Medicine Shows Appropriate Skepticism About a Commercially Sponsored Clinical Trial

The Annals of Internal Medicine just published a clinical trial that compared a new type of anti-diabetic drug, exenatide, (Byetta, from Eli Lilly & Co, and Amylin) an incretin mimetic, to placebo for patients already being treated for Type 2 diabetes. [Zinman B, Hoofwerf BJ, Garcia SD et al. The effect of adding exenatide to a thiazolidinedione in supoptimally controled type 2 diabetes: a randomized trial. Ann Intern Med 2007; 146: 477-485.]

The article was typical of the commercially sponsored clinical trials that appear in many journals. The Annals, however, made a publishing decision that was atypical of how many journals handle such articles. It included an accompanying editorial that was appropriately critical of the study design and methods, and appropriately attuned to how commercial research sponsors, such as pharmaceutical companies, biotechnology companies, and device manufacturers, may manipulate how research is designed, carried out, analyzed, and reported to serve their vested interests.

We have blogged about such research manipulation before. See our posts about Richard Smith's catalog of manipulation strategies, about specific strategies used in a study of muraglitazar, about David Healy's description about manipulation strategies used for studies of SSRIs (selective serotonin reuptake inhibitors), and Wally Smith's summary of the creation of pseudoevidence. But commercially sponsored articles whose design, execution, and analysis have been manipulated to serve their sponsors interests slip into print regularly, unaccompanied by any notice of how they serve commercial purposes.

The Clinical Trial of Exenatide

In summary, the trial by Zinman et al compared exenatide to placebo in patients already received either rosiglitazone (Avandia, by GlaxoSmithKline) or pioglitazone (Actos, by Takeda Pharmaceuticals), sometimes also metformin, but who were not necessarily trying to modify their lifestyles (either their diet or exercise schedule). A total of 233 patients were randomized, and followed for 16 weeks. Patients in the exenatide group had a statistically significantly lower hemoglobin A1c level, a measure of overall control of blood sugar, at the end of the trial. They also had statistically significantly greater rates of nausea and vomiting, and greater rates of dropping out due to adverse events.

The Editorial

Accompanying the trial was an editorial [Malazowski S. Exenatide in combination therapy: small study, big market, and many unanswered questions. Ann Intern Med 2007; 146: 527-528.] The editorial amounted to a rigorous critical review of the trial. It pointed out most of the trial's many design and methodologic problems, and explained why its results were less than earth-shaking.

These problems included:

• Difficulty determining to whom the results would apply - The patient population consisted of people who did not have their diabetes under excellent control, but were not on optimal medication regimens, and were not trying to improve their diets or increase their exercise. Thus, "we simply don't know whether patients optimally treated with diabetes education, diet, TZDs, [thiazolidinediones] and metformin will receive as much benefitfrom exenatide as the paper reports," since such patients were not included in the study. Nor could the study predict whether adding exenatide would work better than simply increasing the doses of conventional medication, or starting a diet modification or exercise program.
• Short duration - Although diabetes is a chronic problem, the study did not assess the new medication in long-term use. Thus, it was not designed to tell whether it would work in the long run, whether it would affect the patients' longevity, development of complications, symptoms or health status in the long run, and whether it would lead to adverse effects in the long run that did not occur in the short run.
• Small sample size - "Small and short studies provide a false sense of safety, because common severe drug reactions may not occur in the condensed timeline and the limited number of patients." Even so, patients who received exenatide had a relatively high rate of nausea and vomiting, often leading to discontinuation of the drug. So the study did not suggest that any benefits of the drug clearly outweighed its harms. [Note that the editorial did not mention that patients on exenatide also had higher (but not statistically significantly higher) rates of hypoglycemia, low blood sugar, than did patients given placebo. Hypoglycemia, which can be serious, is the main hazard of aggressive treatment of blood sugar. One patient on exenatide also developed an unusual, possibly allergic reaction, allergic alveolitis. The study was clearly too small to predict the rates of these effects that would occur if the drug were used in large numbers of patients. Thus, there is suspicion that the benefit/ harm ratio of this drug is even less favorable.]

Furthermore, the editorial pointed out the relationship between the study's commercial sponsorship and its flawed design. Malozowski stated, "the study was designed, conducted, and analyzed by employees of the manufacturer in collaboration with academicians...." (Note also that the three academicians who contributed to the study all worked part-time for the manufacturers as consultants and/or speakers.) So, "the design and reporting of Zinman and colleagues' study reminds us that the manufacturers control the flow of information about its product. By virtue of FDA approval for the combination of exenatide and TZDs, the data obtained in the study can lead to enormous financial benefits to the sponsor. Millions of patients received TZDs and metformin - now physicians may consider adding exenatide. Great power requires great responsibility. Physicians and patients need answers to the many questions raised by this small study."

In my experience, rarely have I seen a commercially sponsored study whose flaws all seemed to increase the likelihood of finding results favoring the sponsor's vested interests published with an accompanying commentary that pointed out these flaws and their relationships to these vested interests.

Given the great efforts commercial sponsors make to get studies with results favorable to their products published, it would be nice if all journals accompanied such articles with appropriately critical accompanying commentaries.

Kudos to the Annals of Internal Medicine for showing the way forward.

Post Title → Annals of Internal Medicine Shows Appropriate Skepticism About a Commercially Sponsored Clinical Trial

Won't Get Fooled Again, Again, Again

In mid-July, there were three well-publicized cases in which authors of scholarly articles in prominent medical journals failed to disclose important financial arrangements that may have affected what they wrote. In fact, each case was so well-publicized that I thought it did not need additional comment from Health Care Renewal.

The cases were:

• An article published in JAMA in February found that withdrawing anti-depressants from pregnant women was associated with relapse of depression [Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295:499-507.]. A letter published in JAMA in July revealed that "all 9 0f the physician coauthors have been paid by antidepressant manufacturers, while only 2 reported disclosures." (See coverage from the Wall Street Journal, available through the Pittsburgh Post-Gazette here.)
• An article was published in Neuropyschopharmacology in July about vagus nerve stimulation as a treatment for depression [Nemeroff CB, Mayberg HS, Krahl SE. VNS therapy in treatment-resistant depression: clinical evidence and neurobiological mechanisms. Neuropsychopharmacology 2006; 31, 1345–1355.] The Wall Street Journal discovered that eight of the article's nine authors had financial ties to Cyberonics Inc, the manufacturer of the device. The ninth author is an employee of the company, which was disclosed." (See previous post on Cyberonics here.)
• An article published in JAMA in July found an association between migraine headaches and the risk of cardiovascular disease and stroke for women [Kurth T, Gaziano JM, Cook NR et al. Migraine and the risk of cardiovascular disease in women. JAMA 2006; 296: 283-291]. The editor of JAMA then discovered that all six authors of the study had financial ties to makers of treatments for migraines or heart-related problems, but did not disclose these relationships, (see the JAMA corrections here, AP here, and PharmaGossip here.)

What has been remarkable is the editorial response to these cases in two of the US most widely-read newspapers.
By Jennifer Washburn in the Los Angeles Times,

Most of us place enormous faith in our universities. We trust that they are autonomous, independent institutions committed to education, scholarship, academic freedom and the production of knowledge free from the influence of special interest groups. Right?

Wrong. In the last 25 years, the United States has given birth to a market-model university, one where professors increasingly work 'for hire.'

Each university is afraid to tighten its rules for fear that this might drive talented faculty (and industry dollars) to other schools with more lax policies. But until the top U.S. research universities collectively adopt one rigorous, uniform policy, their autonomy will continue to erode.

By an anonymous editorial writer in the New York Times, (via the Houston Chronicle),

Leading medical journals seem to be having a difficult time disentangling themselves from the pharmaceutical and medical device industries. If they cannot stop printing articles by scientists with close ties to these businesses, they should at least force the authors to disclose their conflicts of interest publicly so that doctors and patients are forewarned that the interpretations may be biased.
It seems imperative that more muscle be put into forcing disclosure and publication of conflicts of interest. If all leading journals agreed to punish authors who fail to reveal their conflicts by refusing to accept further manuscripts from them, a lot more authors would be inclined to fess up. Better yet, journals should try much harder to find authors free of conflicts. That is the best hope for retaining credibility with doctors and the public.

And by Benedict Carey in the New York Times,

Companies don’t just hire doctors to do research — a practice that in theory ought to help keep businesses scientifically honest — they also trade on the researchers’ names. Like producers shopping a new a movie, they go for star power, an A-list cast with names that themselves sell a product, and pull other doctors along, even when the evidence for a treatment is not strong.

One of the supposed strengths of American science is that it is decentralized and diverse: there are dozens of top researchers who are competitive and critical, enforcing a high standard. But when many or most of the leading figures are playing for the same team — an all-star team — that lineup itself may carry the day, regardless of the science.

With this topic finally getting widespread notice in medical journals and in the main-stream media, I hope it is not hopelessly naive to expect some action. At the very least, we need much more rigorous disclosure requirements for authors of articles in medical journals, and generally for people who bill themselves as academics writing or speaking about medical and health care issues in any venue. In addition, we need broadly based rules about conflict of interest that apply to all people who make decisions in health care.

[For the theme music, go here.]

Post Title → Won't Get Fooled Again, Again, Again

British Medical Journal Highlights Conflicts of Interest

The latest issue of the British Medical Journal featured several articles on conflicts of interest and the integrity of the evidence base for health care.

WHO Obesity Task Force Linked to Pharmaceutical Companies

The main points of this article [ Moynihan R. Obesity task force linked to WHO takes "millions from drug firms. Br Med J 2006; 332: 1412.] were:

The International Obesity Task Force has relied heavily on funding from the drug industry for a decade, despite being widely seen as an independent think tank and having ties to the World Health Organization.

Set up in the mid-1990s with help from grants from three drug companies, the task force aims to portray obesity as a 'serious medical condition' and to promote better prevention and management strategies.

It has a high media profile and is highly influential. A senior US member and a well respected authority on obesity, William Dietz, is currently one of the driving forces behind a controversial change in definitions of childhood overweight and obesity, which some researchers believe may exaggerate the problem and unnecessarily label children as diseased.

Although the task force has at times disclosed the names of drug company sponsors, the exact amount of that sponsorship remains secret.

In 2002 the International Obesity Task Force officially merged with another group called the International Association for the Study of Obesity. The most recent annual report of the newly merged group highlights close ties with WHO but also shows that two drug companies, Roche and Abbott, are primary sponsors, supplying around two thirds of its total funding. Roche makes the antiobesity drug orlistat (Xenical), and Abbott makes sibutramine hydrocholoride (Reductil).

A senior member of the merged group who has seen funding documents but did not want to be identified told the BMJ that over recent years sponsorship from drug companies is likely to have amounted to 'millions.'

Tim Gill, a representative of the task force and executive officer of the Australasian Society for the Study of Obesity, said that although the task force focused mainly on prevention rather than treatment, drug companies benefited anyway from raised public awareness....

My comment is that ideally, organizations that claim to speak with the authority of the WHO ideally should be free from conflicts of interest, but practically, at a minimum should fully disclose all potential and actual conflicts of interest. Thus, the International Obesity Task Force (IOTF) ideally should operate without financial ties to organizations and firms that might financially or ideologically benefit from promotion of certain anti-obesity measures. If it must continue such ties, they should be clearly revealed, so those reading the IOTF pronouncements may know where they come from.

CONSTRUCTIVE SUGGESTION

Any readers who know someone on the WHO Executive Board should consider contacting them suggesting a more rigorous policy to govern conflicts of interest that may affect WHO affiliate organizations.

Conflicts of Interest and Journal Editors and Publishers

A commentary discussed how editors and owners of medical journals may be affected by conflicts of interest [Lexchin J, Light DW. Commercial influence and the content of medical journals. Br Med J 2006; 332: 1444-7.] Its main points were:

• Although government and organizations may influence medical journals, "we think the greatest potential for biases comes from commercial influences."
• A minority of major journals have stated policies on editors' conflicts of interest.
• Income that could constitute institutional conflicts of interest for journals may come from publishing supplements, which are often heavily supported by pharmaceutical companies; selling reprints, which journals may heavily market to pharmaceutical companies; and from advertising.
• Journals rarely report their sources of revenue.
• There is anecdotal evidence that journals' publishing decisions may be affected by concerns about effects on advertising.
• Recommendations for change included disclosure of all sources of funding; adherence to international guidelines on conflicts of interest; editorial disclosure of personal conflicts of interest; banning editors from having any financial ties to companies that advertise in the journal; development of a classification of all possible financial ties among authors and commercial firms, which should then be fully disclosed using this system; publishing manuscript drafts and reviewers' comments on the internet; and a thorough external independent investigation of the issues.

Holding Out Against Conflicts of Interests

A personal essay by Joe Collier [Collier J. The price of independence. Br Med J 2006; 332: 1447-9.] focussed on independence, a positive term for the absence of conflicts of interest and external influence. Collier made a strong plea for the importance of independence for journal editors.

What has emerged over the years is that my views have needed to be much more than independent. To be of real value, they have needed to be delivered in a way that the message was clear, pertinent, honest, and unambiguous. Advice that can be misinterpreted or leaves room for misunderstanding is often unusable and may be dangerous. In my experience, people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult.

Independence in itself does not make the advice right, and, conversely, partisan advice is not necessarily wrong. Similarly, an adviser's bias will not necessarily colour all of their judgments adversely. A chief executive of a large drug company could give unbiased and invaluable guidance on how to increase business success. But the same executive's advice on the best drug for headache is unlikely to be helpful. What independence does is to improve clarity.

I attempt to live in a way that is consistent with the Nolan principles, which were developed as a set of standards of behaviour for ministers, members of parliament, civil servants, and other senior public servants. But even these are incomplete and would benefit from strengthening by the addition of sections of the recently introduced Duties of an Expert Witness:

Selflessness—No advice should be influenced by the possibility that it might result in financial gain or other material benefits for the advisers, their families, their friends, or other interested third parties.
Integrity—Independent advisers should not place themselves under any financial or other obligation to outside persons or organisations that might influence them inappropriately.
Objectivity and openness—Independent advisers must be able to explain why they have reached their conclusion and what reasoning led to their opinion.
Accountability—Independent advisers must be fully accountable for the advice they give and be prepared for their advice and their methods to be scrutinised.
Honesty—Independent advisers must declare each and every one of their competing interests that might have a bearing on the advice. It is for the recipient of the advice, not the adviser, to decide what that bearing might be.

But even these principles and the notion of proportionality are not enough. There are two additional requirements: advisers should respond if their position is challenged—silence is not a real option—and if an error has been made, the adviser is duty bound to point it out (preferably being the first to do so) and offer an apology and a correction.

Collier's statement about the personal cost of being independent was striking:

For me, independence has meant saying what I mean and often being seen as rude and uncaring; holding no favours; deciding on each issue on the basis of the evidence rather than blindly following the majority; risking being seen as inconsistent (a loose cannon); not necessarily being able to support friends and colleagues; giving advice that runs counter to my personal interest; and criticising employers or senior members of the establishment. Perhaps predictably, the positions I have taken have often caused me difficulties. I have lost friends, been ostracised by the establishment, and had my career advancement undermined.

Much of this must seem familiar to those who have blown the whistle about health care mismanagement, conflicts of interest, and corruption.

But there is an up-side:

But the freedoms and intellectual satisfaction gained by being allowed to be an independent thinker giving unfettered advice have far outweighed these burdens. Moreover, for each of the friends I have lost, I believe I have gained professional colleagues who value and trust my judgments. My career progression is not necessarily what one would advise for someone starting out in medicine, but for those who put independence of thought high in their hierarchy of values, the stance is worthwhile and rewarding.

Summary

Finally, there was a nice editorial summary [Godlee F. What price integrity? Br Med J 2006; 332: ], which included an assertion that the BMJ is currently following most of the reccomendations set forth by Lexchin and Light, and may consider full disclosure of all sources of revenue.

It's nice to report some positive news now and then. The increasing emphasis by major medical journals on the problems causes by conflicts of interest has to be a positive development.

Post Title → British Medical Journal Highlights Conflicts of Interest

A Former Editor Cites Foucault

A while back, we posted about the firing of the editors of the Canadian Medical Association Journal (CMAJ), noting this seemingly unfortunate example of a power struggle within a medical organization. However, the firing of Dr Hoey has generally been presented in terms of abuse of power as a violation of editorial independence.

For example, in 2005, Hoey wrote an unsigned editorial in CMAJ that started with the premise, "freedom from interference in editorial decisions stands at the heart of the credibility of any reputable journal." He then announced "we have a transgression to report," and then went on to recount how "a CMA [Canadian Medical Association] executive objected strenuously to a news article we were preparing on behind-the-counter access to levonorgestrel (Plan B)."(1) Similarly, the editor of the British Medical Journal responded to Hoey's firing, "this is a sorry tale that shows how little the CMA (its officers and - since there is no sign of a concerted outcry from them - its members) understands what it means to be the custodian of an international academic medical journal."(2)

There has been much more discussion of the firing of Hoey and then the departure of many other CMAJ editors. The New England Journal of Medicine ran a commentary in March.(3) Last week, it ran another, this time written by Dr Hoey, himself.(4) Would this more clearly delineate what happened?

Hoey's article, however, took an unusual stance. He chided "owners [who] may wish to limit to limit the scope of their journal, to restrict its editorial perspective to matters of bedside medicine and the narrower interests (as perceived by the usually nonphysician publishers) of their physician readership." He then denied this "vision." Instead, he proclaimed, "for Foucault, medicine is a political act."

That is where he lost me, decisively. The Foucault he cited, assuredly is Michel Foucault, one of the "postmodern vanguard," authorities repeatedly cited to justify the fashionable post-modern concepts that have swept through the academic humanities and social sciences. Foucault is cited:

• For his hostility to the Enlightenment. For example, he wrote, "it is meaningless to speak in the name of -or against - Reason, Truth, or Knowledge."(5) Hicks explained, "Postmodernism rejects the entire Enlightenment project. It holds that the modernist premises of the Enlightenment were untenable from the beginning and that their cultural manifestations have now reached their nadir. While the modern world continues to speak of reason, freedom, and progress, its pathologies tell another story. The postmodern critique of these pathologies is offered as the death knell of modernism: 'The deepest strata of Western culture' have been exposed, Foucault argues, and are 'once more stirring under our feet.'"(6)
• To support the self-contradictory and ultimately meaningless assertion that there is no external reality, that reality is "socially constructed." "Foucault at times suggested that underlying what counts as objective knowledge is a power relation, one category of people benefiting at the expense of another category of people. The radicals thus see the social construction of reality...."(7)
• To support totalitarianism. "As part of the attack on the Enlightenment, the critique of truth suffers from a tendency to reinforce pre-enlightenment despotism. The Enlightenment replaced individual and institutional power with more objective measures of validity, and it is no surprise that the rejection of objectivity collapses back into power as a means for defining absolute truth."(8) Foucault's belief that "liberal democracies are actually more oppressive than medieval despots or even modern totalitarians,"(9) was consistent with his occasional embrace of totalitarian rulers. In 1971, he said, "when the proletariat takes power, it may be quite possible that the proletariat will exert toward the classes over which it has triumphed a violent, dictatorial, and even bloody power. I can't see what objection could possibly be made to this."(10) Similarly, he extolled the 1978 Iranian revolution, "exulting in the 'intoxication' of revolution and the violent expression of 'collective will,' and praised its leaders 'political spirituality,' which he thought reflected a health 'religion of combat and sacrifice.'"(11)

In my humble opinion, citing Foucault as an authority suggests a sympathy for post-modernism that would not be helpful to a journal editor. Most of editing is about science, and science does not fit with the notion that external reality does not exist. Readers of Health Care Renewal are certainly aware that medicine and health care are influenced by politics. But the notion that politics is all of medicine, or a totalitarian world view will not help us address concentration and abuse of power.
But perhaps Hoey's citation of Foucault was a mistake, or misinterpretation. After citing Foucault, Hoey admonished journal editors not to discuss or even divulge editorial decisions to their publishers, for that would "gut the editorial independence of a journal." However, the editor's outlook and assurance should include "an eager propensity to poke a stick into something or somebody." That proclamation suggests that Hoey's reliance on Foucault was not some mistake. Characterizing an ideal journal editor as an undisciplined trouble-maker fits Foucault's fascination with "limit experiences."(12) Yet editors whose main joy is in poking sticks into something or somebody without restraint or accountability will only add to concentration and abuse of power.
Thus, it still seems like our original characterization of the dispute at CMAJ was apt, "A classic power struggle within medicine's increasingly less-hallowed halls. Here it seems drearily familiar." That's too bad.
References
1. CMAJ. The editorial autonomy of CMAJ. Can Med Assoc J 2006; 174: 9.
2. Godlee F. A big mistake. Brit Med J 2006; 332:
3. Shuchman M, Redelmeier DA. Politics and independence - the collapse of the Canadian Medical Association Journal. N Engl J Med 2006; 354:1337-1339.
4. Hoey J. Editorial independence and the Canadian Medical Association Journal. N Engl J Med 2006; 354: 1982-3.
5. Hicks SR. Explaining Postmodernism: Skepticism and Socialism from Rousseau to Foucault. Tempe: Scholargy Publishing, 2004. P. 2. (Link here)
6. Hicks, P. 14.
7. Farber DA, Sherry S. Beyond All Reason: the Radical Assault on Truth in American Law. New York: Oxford University Press, 1977. P. 24. (Link here)
8. Farber, Sherry. P. 106.
9. Farber, Sherry, P. 29
10. Lilla M. The Reckless Mind: Intellectuals in Politics. New York: New York Review of Books, 2001. P. 150. (Link here.)
11. Lilla. P. 154.
12. Lilla. P. 150.

Post Title → A Former Editor Cites Foucault