Conflict of interest 2: Clinical practice guidelines and Deans

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My last blog post was about conflict of interest (COI) in medicine; there has been some recent literature on the subject, so I am providing a second posting on the topic.

In “Conflicts of interest in cardiovascular clinical practice guidelines”^[1], in the March 28, 2011 issue of Archives of Internal Medicine, Mendelson and colleagues reviewed the 17 most recent guidelines regarding the diagnosis and management of heart disease promulgated by the American College of Cardiology (ACC) and the American Heart Association (AHA), the most important issuers of such guidelines. These clinical practice guidelines (CPGs) are important, as not only do physicians use them as authoritative sources to inform their patient care, but increasingly payers – and courts -- are looking at whether they were followed to determine payment and bonuses, or culpability in malpractice cases. While thorough review of the published (and unpublished) evidence is required (indeed is a sine qua non) in the issuance of guidelines, these panels of experts are convened to allow their collective experience and knowledge fill the gaps where there is no evidence. The authors point to the 2009 Institute of Medicine (IOM, a group of distinguished physicians and medical scientists convened by the National Academies, which are private citizens gathered with federal support to advise on science and technology) report from its Committee on conflict of interest in medical research, education and practice, which states that there is insufficient study of COIs in guideline reporting, as the fact that both ACC and AHA have “recently placed restrictions on official participation in educational events and guidelines production”.

Using the concept of an “episode” to mean that 1 person participated 1 time in production of 1 guideline, there were a total of 651 episodes by 498 people in the production of the 17 guidelines. Overall, 56% of individuals (277) had some COI, and (coincidentally) a COI was present in 56% (365) of the total episodes, with a range among the 17 guidelines of 13% (2 of 15) to 87% (13 of 15). Interestingly, actual members of the guideline committees, as opposed to those who just reviewed the guidelines (“peer reviewers”) were more likely (63%, a level reaching statistical significance for those who care, p=.006) to have COIs, as were the chairs of the committees (or first authors) compared to committee members, 81% (p=.03). Only 6 of the 17 guideline committees reported whether the COIs were “modest” or “significant”; the authors found that of those 54% were modest and 29% significant. Perhaps more important, according to the authors, was that it was only a few companies, presumably those with the greatest economic stake in the outcomes, who were involved in most of the COIs. They also note that this is “a particular cause for concern given the fact that many of the newest ACC/AHA guideline recommendations are based more on expert opinion than on clinical trial data”.

Dr. Steven Nissen, commenting on the article in the same issue (“Can we trust cardiovascular practice guidelines?”^[2]), calls the “depth and breadth of industry relationships reported in this article…extraordinary,” in that they go beyond scientific collaboration to include significant stock ownership and serving as promotional speakers, and states that “no conceivable logic can defend [this] practice.” He continues “Such relationships are so antithetical to the academic mission that many medical schools have now forbid such relationships for their faculty. To allow such individuals to write CPGs defies logic.” I imagine his use of the word “extraordinary” is in the sense of “amazing”; since this is the first such study, we do not know if such COIs are indeed “extraordinary” in the sense of “well out of the ordinary”, or if they are, indeed, quite typical. Indeed, Mendelson et al cite a 2002 study by Choudry et al[3] in which the found that of the 52% of the authors of 100 CPGs for a variety of adult diseases who responded to their survey, 87% had “some type of relationship with the pharmaceutical industry” (and we would not imagine that the 48% who didn’t respond had fewer!) Dr. Nissen, who is from the Cleveland Clinic, reveals his own potential COIs, including research support from a number of companies and honoraria for speaking which he has turned directly over to charity. As covered in the New York Times (Duff Wilson, “Study finds conflict among panels’ doctors”, March 28, 2011), Dr. Nissen calls for “banning most of these conflicts rather than just disclosing them”.

But sometimes COIs are not even disclosed. The same issues of Archives of Internal Medicine contains a “research letter” titled “Failure by deans of academic medical centers to disclose outside income”^[4]. The authors, Freshwater and Freshwater, looked at holdings of deans of allopathic and osteopathic medical schools on the Morningstar directory of US corporate directors and executives, and EDGAR, the Securities and Exchange Commission database. They found that while there were only a few deans who served as directors of public companies involved in health care (9 of 161, with one serving as a director of 2 companies and one of 4), this information was not always disclosed on the schools’ websites, nor was the compensation received. This compensation for each directorship ranged from $11,250 to $386,439 with a mean of $217,454, with one dean who served on multiple companies receiving $640,038. “One dean’s official Web page disclosed the 2 directorships, but it did not disclose the compensation. Two medical schools’ Web sites disclosed 3 directorships, with one dean holding 1 and the other 2 directorships; however the Web sites underreported the deans’ compensation by 39%, 56%, and 80% compared with the compensation calculated from the companies’ EDGAR forms.” These deans are the same people who are expected to enforce the rules against COIs that Nissen refers to above. In a commentary[5], Lo (who was the chair of the 2009 IOM committee) et al, say that disclosure is not enough, and that “Some relationships need to be managed or even prohibited”. They do not go so far as to suggest that all should be banned, although I would note that 152 of 161 deans seem to do OK without serving as corporate directors.

So should all such conflicts, whether deans serving on boards of directors, guideline authors having financial relationships such as major stock holdings or speakers’ fees, or receiving grants from corporations, be disclosed or prohibited? I think that there is clear consensus that disclosure is the de minimis requirement. As I have noted before, without disclosure there is no way for the consumer of information in a research study to decide if their might be bias; this is at least as important for are those writing CPGs or presiding over our academic medical centers. But, as Nissen states explicitly and Lo hints at, disclosure is not sufficient. To extend the metaphor of the judge referred to by Howard Brody in his article Professional Medical Organizations and Commercial Conflicts of Interest: Ethical Issues and cited by me in The AAFP, Coca-Cola, and Ethics: Serving the public interest? August 20, 2010, knowing that a judge in a case you are party to owns large amounts of stock in the company you are suing is not sufficient to make you feel alright about her presiding in the case.

Mendelson et al note that “It has also been argued that relationships with industry may also bring a breadth of perspective and experience, especially if individuals have relationships with multiple different companies. Theoretically, these individuals may be less conflicted than those with fewer industry affiliations…”. Right. Taking graft from many sources makes you less beholden to any one of them. Unfortunately, if you buy this argument, then their study should disappoint you, as only a much smaller percentage of the CPG authors had more than one COI.

Come on. Prominent scholars take money from industry for the same reason that others do. They like the money. Perhaps they are eminent enough that their heads are so swelled that they can believe both that they are being paid solely for their wisdom, and not for any bias they might bring to the deliberations of academic groups like those writing CPGs or in the administration of medical schools, and that, in any case, they are so distinguished that there is no way they would demonstrate such bias. If so, they are deluded. No one else believes it, most especially the companies giving them money. These COIs need to be completely banned if we are to be able to trust their academic integrity and intellectual honesty.

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[1] Mendelson TB, et al, “Conflicts of interest in cardiovascular clinical practice guidelines”, Arch Int Med 28Mar2011;171(6):577-85. (only abstract available on line without subscription).

[2] Nissen SE, “Can we trust cardiovascular practice guidelines?” Arch Int Med 28Mar2011;171(6):584-5.

[3] Choudhry NK et al, “Relationships between authors of clinical practice guidelines and the pharmaceutical industry”, JAMA 2002;287(5):612-17.

[4] Freshwater DM and Freshwater MF, “Failure by deans of academic medical centers to disclose outside income”, Arch Int Med 28Mar2011;1717(6):586-7.

[5] Lo B, Kelch RP, Grady D, “Illuminating physicians’ financial relationship with industry”, Arch Int Med 28Mar2011;1717(6): 587-8.

The AAFP, Coca-Cola, and Ethics: Serving the public interest?

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Last fall, the American Academy of Family Physicians (AAFP) (full disclosure: the organization of family physicians, to which I belong) entered into a partnership agreement with the Coca-Cola Company for support of its patient information website, FamilyDoctor.org. The amount of the funding is uncertain, but it is reputed to be in the “mid-six-figures”. The arrangement came in for a great deal of criticism, both within and outside of the family medicine community, and several members of the organization resigned in protest. I addressed this as a small part of a larger blog, Harvard Medical School limits outside income: a good start, on January 21, 2010.

The debate has not gone away, and has been highlighted by two articles in the recent (July-August 2010) issue of Annals of Family Medicine, the research journal sponsored by all the family medicine organizations in the US and Canada. The first is by Howard Brody, the family physician and medical ethicist from the University of Texas Medical Branch at Galveston, “Professional Medical Organizations and Commercial Conflicts of Interest: Ethical Issues”, and the second is response by Lori Heim, President of the AAFP, “Identifying and Addressing Potential Conflict of Interest: A Professional Medical Organization’s Code of Ethics.” Brody’s essay is a clearly written review of the ethics of conflict of interest, addressing both whether the relationship between AAFP and Coke is a conflict of interest (COI) and whether it is ethically worrisome, and an analysis of the reasons and defenses put up by AAFP and Coke. In the first, he notes that a conflict of interest can, and often does, exist even when no “bad” outcome can be identified; it is simply a conflict between the primary set of responsibilities (in this case, of physicians and their organizations’ social responsibility for looking out for the best interests of their patients’ health; in other settings it might be awarding of government contracts or foundation grants) and a second, usually financially motivated set of interest.

Brody distinguishes between two strategies for addressing COI, a Management Strategy in which COIs are divulged so that others (presumably in this case, patients and the public) can take them into account, and the Divestment Strategy, in which organizations rid themselves of COI relationships. He dispenses with the conflation of COI with intellectual conflicts (that an investigator might want to show that his/her “pet hypothesis” is correct and put it in the best light) because readers will always be aware of the latter, but will not know of commercial relationships unless they are divulged. He notes that the Divestment Strategy is favored in most recent ethical literature (and in increasing numbers of medical schools, as per my January 21 blog), although not by the AAFP.

He then addresses the counterarguments and justifications that the AAFP has put forward in this case. These include:

· “Premature Accusation”, in which the AAFP says “you can’t know that we have a conflict until you see the content. He notes the conflict exists regardless, and offers this “crude” analogy: “imagine that a judge who is sitting on a case involving a contract dispute between two companies is discovered to own $100,000 worth of stock in one of the companies. The judge cannot divert criticism of this conflict of interest by saying, ‘But you haven’t waited until I delivered my verdict—how do you know that I won’t rule against the company in which I own stock?’ In the AAFP case, if the final educational material includes a strong statement against sugary soft drinks, we will never know whether, absent the Coca-Cola funding, the statement would have been even stronger. That such questions will inevitably be raised shows the conflict of interest is both present and serious, quite apart from the eventual contents of the educational materials."

· “Other Party not Evil”, in this case Coca-Cola. The issue, of course, is not whether they are evil, but whether their interests may lie in opposition to the interests of the health of doctors’ patients; “The physician has a duty to prescribe medications or make dietary recommendations based on scientific evidence. The companies have an interest in selling more beverages, or more drugs, regardless of the evidence.”

· “Wrong not to Engage” with organizations such as Coca-Cola. “Schafer[1] noted the propensity for engagement with industry, in such discussions, magically to convert itself into accepting large sums of money from industry.…No one is suggesting that the AAFP not engage Coca-Cola if the engagement avoids conflicts of interest and the result of the engagement would be improved public health.” [my bold]

Brody also addresses the similarities and difference between this and the 1997 relationship in which the American Medical Association (AMA) actually endorsed products made by Sunbeam. He notes that the relationship is called a “Consumer Alliance”, when it is more properly a corporate alliance. (I had missed this Newspeak usage in my January 21 blog, where I mistakenly called it a “corporate partnership”!)

Heim’s response states that Brody misses the point, and goes on to make the same arguments that AAFP has made before, that Brody has addressed and debunked, offering nothing new to the discussion. It refers to the AAFP Code of Ethics, and creates the disturbing sense that “we want the money, we don’t think we are doing anything unethical with the money, and so stop criticizing us.” In other words, it purposely and deliberately misses the point.

Does the AAFP’s relationship with Coke go beyond a conflict of interest (which it clearly is) to actually providing unhealthful material? Some authors believe so; public health attorney Michelle Simon, in her blog Appetite for Profit, addresses the issue on July 22, 2010. She notes that FamilyDoctor.org contains the disclaimer “This content was developed with general underwriting support from The Coca-Cola Company,” and comments “That makes it sound as if the Coca-Cola is just paying someone else to do the writing. But it appears the company is directing the substance of the content as well, since the verbiage is pretty similar to that found on Coca-Cola's own website on these very topics. (See for example, the company's page on sweetener ‘facts and myths’.)”

Simon quotes Dr. Heim’s article, “To gauge an individual or organization’s ethics, one must view its behavior over time, define the goal of that behavior and compare the outcome with the mission and values. Within this context, one can determine whether the assumption or appearance of conflict of interest or ethical lapse was, in fact, correct.” And comments: “What? She lost me somewhere between outcome and values. Taking money from Coca-Cola is not a science experiment that you watch over time, gather data, and then publish the analyzed results. But if one were to approach the issue that way, there's no shortage of evidence of Coca-Cola's 'ethical lapses.' Whether your concern is marketing to children, labor abuses, or contaminating water supplies in developing nations, Coca-Cola would be the one company you'd not choose as a partner. Journalist Michael Blanding has written an entire book called The Coke Machine: The Dirty Truth Behind the World's Favorite Soft Drink, due out in September, which chronicles these misdeeds and more.”

Certainly, the AAFP is not the only organization that has potentially undermined its public trust. For another big one, the American Dietetic Association (ADA) has a partnership (I don’t know if they’ve dared to call it a “consumer alliance”) with – Hershey! (see ADA’s press release at its own website; also see the Fooducate blog).

Maybe the ADA’s partnership is more outrageous, but as a family doctor and educator, I take the AAFP’s relationship with Coke more personally because it undermines me. At the time of this deal, several of the other family medicine organizations, including the Association of Departments of Family Medicine (ADFM, academic department chairs, to which I also belong) expressed serious concerns about this relationship to the AAFP leadership. These concerns related particularly to the fact that, to the public, family medicine is family medicine, and when the largest family medicine organization, AAFP, does something the entire discipline is affected; for example, medical students, or faculty in other departments, who may be distressed by the relationship express that concern to the faculty of family medicine. AAFP, the big dog on the block, listened. It didn’t change its policy, though. Money talks, of course, but if AAFP’s 55,000 active members (not including students, residents, and retirees) each sent in $10, it would be about the same amount as they received from Coke. Are we that cheap? As far as the content on FamilyDoctor.org is concerned, check it out for yourself. You can start by clicking on the benign (but somehow familiar) logo at the top of its web page.

Brody concludes his essay with: “Family physicians are widely trusted by their patients and communities. Merely by having chosen our specialty, family physicians have demonstrated a commendable commitment to putting the health needs of their patients ahead of personal financial gain. They deserve to be represented nationally by an organization that fully reflects those high ethical commitments and standards.” I couldn’t agree more.

[1] Schafer A. Biomedical conflicts of interest: a defence of the sequestration thesis—learning from the cases of Nancy Olivieri and David Healy. J Med Ethics. 2004; 30(1):8–24

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Statins and scientific integrity

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“Statins” are a class of drugs that lower lipid levels, especially low-density lipoproteins (LDL, “bad” cholesterol), and raise high-density lipoproteins (HDL, “good” cholesterol). Since we know elevated LDL levels are associated with higher risk for a number of vascular diseases, mainly coronary heart disease but also stroke, it made sense that these drugs would be beneficial for preventing recurrences in people who had prior heart attacks and strokes (“secondary prevention”) as well as preventing a first attack in those who had the risk factor of elevated LDL (“primary prevention”). Indeed, studies have shown the former; that is, that the use of statins reduced the risk of both a second attack and dying. However, most of the studies that have been done, and showed benefit, studied both groups, people who had already had a coronary event and those with elevated LDL who had not, and combined the results. The first big study that presumed to show benefit of these drugs for primary prevention was the JUPITER study (“Justification for the Use of Statins in Primary Prevention” – all these studies have cute, if often tortured, eponyms). It specifically looked at the drug rosuvastatin, marked as Crestor ® by its manufacturer, AstraZeneca, who also happened to fund the JUPITER trial.

Two articles that just appeared in the Archives of Internal Medicine (V 170, #2, June 28, 2010) raise serious questions about the use of statins for primary prevention. But they also raise serious questions about research ethics, particularly when trials are industry funded, and the strategic manipulation (not falsification) of the data that is presented to make drug therapy look better – this can mean billions of dollars in sales for the manufacturer. They also point out the danger of looking at intermediate, or “surrogate”, outcomes (in this case, lowered cholesterol and LDL) rather than the ones of real interest to patients, which are, essentially, death (mortality) and the quality of life (morbidity). I have discussed this previously (“Quality and Chronic Disease Management,” Feb 24, 2009, and “Physician conflict of interest” Dec 8, 2008; see also the article by GY Gandhi, et. al., “Patient-important outcomes in registered diabetes trials”, JAMA. 2008 Jun 4;299(21):2543-9.)

The first article, “Statins and all-cause mortality in high-risk primary prevention”, by KK Ray, et. al. (Arch Int Med, 28 Jun 2010; 170(12):1024-31) is a “meta-analysis”. This is a type of study that looks at a group of previously-done studies to try to determine if there is a consistent conclusion that is stronger because it includes more patients than any one study, or weaker because the various studies contradict each other. The authors’ goal was to tease out the results for primary prevention from studies that had looked at the use of statins for both primary and secondary prevention. There were 11 studies that met their criteria, which had a total of 65,229 (= “a lot”) of participants. Their Conclusion (verbatim from the abstract): “This literature-based meta-analysis did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up.” This is not to say that the statins did not lower LDL; they did, and significantly, but in the population of people that had not yet had a coronary event or stroke, they did not prevent mortality. It is important to note that they did also, to a small degree, decrease the risk of having a heart attack, although not of dying. The reduction in risk was about 1.5%; that is, if 200 people are treated for 5 years, 3 will not have heart attacks (NNT=67 over 5 years). The previous studies, by mixing up those who did have a prior event and did have lower mortality (secondary prevention), with those who had not, showed, on net, a benefit. This study demonstrates that there is no reduction in mortality from using statins as primary prevention; whether the small reduction in MIs and their associated morbidity and cost is worth the administration of statins in high-risk patients is at least questionable, and may be an issue for each patient to decide with their doctor.

What about the JUPITER trial? This is the subject of the second article, “Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy”, by M deLorgeril et.al. (Arch Int Med 28 Jun 2010;170(12):1032-36. In a scathing “critical reappraisal” the authors note a slew of flaws in both the conduct and reporting of the JUPITER study. These include ending the study early, after only 2 years, at a time when it appeared that there was mortality benefit from the patients treated with rosuvastatin but when the curves were beginning to come together (i.e., maybe with more time the apparent benefit to rosuvastatin treatment would have disappeared and there would have turned out to be no difference in mortality rate), publishing reports in which the end of that curve was truncated, to not show the coming together, and publishing “subgroup” analyses that seemed to show benefit (by gender) but not where they didn’t (patients with diabetes). Most surprisingly, JUPITER had what seemed to be an extraordinarily low rate of fatality from myocardial infarction. The authors note that, to be able to get meaningful data to look at, they had to do calculations from the data presented by the JUPITER authors. For example, to know how many people died from heart attacks (myocardial infarction, MI) they had to subtract “nonfatal myocardial infarction” from “any myocardial infarction. This is not falsification, but it is very unusual for authors to present the data in a way that readers are required to make such calculations in order to get very important information. The rate of fatal to non-fatal MI was extremely low compared to studies from the World Health Organization, that show it to be 40-50%; in JUPITER it was 8.8% in the placebo group and 29% in the rosuvastatin group. First of all, it seems, if this data is correct, the fatal to non-fatal MI rate was 3 times as high in the group treated with rosuvastatin as in the group that was not treated (surely not the a point the authors and sponsoring company wanted to emphasize). Moreover, everyone in the study was “…unexpectedly – and inexplicably – highly resistant to acute ischemia and infarction.” The authors of this article suggest that there are many inconsistencies and implausabilities in the JUPITER data.

They then go on to discuss at length the roles of the sponsor (the drug company) and conflict of interest in reporting the data both by the sponsor and the principal investigator, who is co-holder of a patent for a test that is used to show “risk” for coronary artery disease (called “C-reactive protein, or CRP). They refer to other industry-sponsored flawed studies, including those about rofecoxib (Vioxx ®) and gabapentin (Neurontin ®), which I have discussed previously (“The ‘Neurontin Legacy’”, Jan 22, 2009). A superb editorial by Lee Green, “Cholesterol-lowering therapy for primary prevention: still much we don’t know” (Arch Int Med 28 Jun 2010; 170(12):1007-8) summarizes these issues.

Think about this. We have a bunch of studies that seem to show that statins are effective for prevention of cardiovascular events (heart attack and stroke) and prevent death. Turns out that they do this for those who have already had a heart attack, but for those who haven’t, the reduction in heart attack is small and there is no reduction in mortality. The use of statins in the much larger group, people with elevated cholesterol who have not yet had a heart attack, means big money for the drugs’ manufacturers. Studies that mixed the two groups blurred the distinction.

Then we have a big study (JUPITER) that purports to show that statins ARE effective for primary prevention, but that study is funded by the drug company and is seriously flawed. We know elevated cholesterol is associated with heart attack and we presume lowering cholesterol would help prevent those heart attacks, but, amazing and very important, when the study is actually done, the data doesn’t show it. (In studies looking at another such indicator, homocysteine, it was shown that, while elevated homocysteine levels are associated with heart attack, and folate – a cheap drug – lowers homocysteine levels, this did not decrease the rate of MIs. Too bad for the makers of the expensive homocysteine level test.)

I assume that I do not have to review the conflict of interest in the study being funded by the drug company and having the principal investigator a patent holder of a test that is highly used for assessing MI risk. The obvious concern is not that this was a potential conflict in the JUPITER study, but that it in fact led to selective interpretation and presentation of data (and the answers to how they had such a low rate of fatal MIs is still not in). This certainly challenges the claim we sometimes hear that just because there is a potential conflict of interest, it doesn’t mean that there is bad science being done. Of course, intrinsically it doesn’t, but this is one more example – with Vioxx and Neurontin and others – to show that it often does. And it also makes it harder for those who would argue that accepting industry gifts (whether lunch or fancy vacations) is benign. All these issues make a great example for teaching students, about conflict of interest, surrogate measures, scientific integrity, and how, from big issues to small ones, self interest colors our perceptions (see J Dana and G Lowenstein, “A Social Science Perspective on Gifts to Physicians From Industry”, JAMA. 2003;290:252-255).
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