Loophole Part Two: The canary in the mine?

Part One here.

Should failings in the integrity of science and evidence-based clinical guidelines matter, regardless of the popularity of their proposals? Or, do we look the other way because we don’t want to appear to be endorsing politically incorrect unhealthy behaviors? Do the ends ever justify the means if it’s at the expense of science or lives?

How would you feel upon learning that an expert panel that had written clinical care guidelines issued by the Department of Health and Human Services had been commissioned and funded by a group which held the bulk of shares in the pharmaceutical companies whose products it had recommended as mandatory first-line treatment for all patients with this condition, and that the chairman and most of the hand-selected members of this expert panel had extensive financial interests with those same companies?

Do you feel it’s okay for clinical guidelines to be written by those who stand to benefit from their own recommendations? Or, do you feel that such financial connections should at least be disclosed?

How would you feel to further learn that the research and efficacy of the drug advised by this panel had been called into question by other medical professionals, had been linked to more adverse events than any other drug, and that the FDA had even issued public health advisories because of severe adverse effects with the drug? Would you still feel that you could trust the objectivity of these experts and their interpretation of the evidence? As a healthcare professional, would you want to be in the position of having to follow those clinical guidelines?

As has been repeatedly said by those behind the war on obesity, it would be tackled just like smoking by convincing the public that it is such a threat to society and so repulsive that the tiniest exposure is dangerous and intolerable. (We’ve moved from the era of Fred Astair to now hearing statements that even a brief whiff of second-hand smoke causes permanent heart disease. The soundest science is probably in between, given that the fundamental principle of toxicology is ‘the dose makes the poison.’) As the Washington Post wrote last week in the article, “Like smoking, like obesity,” the strategies used in the campaign against smoking could serve as a blueprint for anti-obesity initiatives.

Of course, no medical professional would recommend most people take up smoking for their health. That’s not what this situation is about. Smoking has come to be seen so negatively, though, that surprisingly little attention or concern has been given to conflicts of interest behind the clinical care guidelines for tobacco use issued by the HHS, even as it appears people are being hurt. Regardless of what you may personally believe about smoking, improper science and conflicts of interest, and a system that encourages and allows such breaches, should concern all of us... as we could be next.

Pharmaceutical treatments

Last November 20, 2007, the Food and Drug Administration had issued an Early Communication, warning the public and healthcare professionals that it was investigating serious adverse events from the drug, Chantix (varenicline), a drug made by Pfizer and marketed to help smokers quit. The FDA said it had received reports of “changes in behavior, agitation, depressed mood, suicidal ideation, and actual suicidal behavior” among users and had asked Pfizer to “elevate the prominence of this safety information to the warnings and precautions section of the Chantix prescribing information, or labeling.” [No specific mention of FDA issued warnings was found on the Chantix website.]

On February 1^st, the FDA issued a formal Public Health Advisory and a Medwatch alert, warning consumers and healthcare professionals about safety concerns with this drug, which it updated on May 16^th. By the end of the following week, the Federal Motor Carrier Safety Administrations had banned commercial driving licenses for anyone on Chantix and the Los Angeles Times published an investigative story on Chantix linked to dozens of highway traffic accidents. It profiled perfectly healthy people suddenly having seizures, losing consciousness and running their cars off the road (including a young man with his girlfriend and baby who found themselves in a murky river); and reported thousands of serious reactions involving Chantix had been reported to the FDA, including suicides.

In fact, according to a full report issued to the FDA from the Institute for Safe Medication Practices, which describes the adverse reactions in detail, this smoking cessation drug is associated with more serious adverse event reports than any other drug. “In the 4^th quarter of 2007, varenicline accounted for 988 serious injuries in the U.S. reported to the FDA, more than any other individual drug in this time period. By comparison the FDA received a median of 5 reports of serious injury” apiece for other drugs. In the U.S., 78 deaths were reported “in which varenicline was the principal suspect drug,” the report also found. While this doesn’t prove causality, this large number of cases in real-life settings warrant immediate safety concerns and it recommended doctors and patients exercise caution. [For those unfamiliar with the ISMP, since 1975, it’s been the country’s only nonprofit organization devoted solely to medication error prevention and safe medication use, and is funded only by charitable donations.]

As doctors who’ve examined the research have cautioned, the safety profile for Chantix is incomplete as it’s a relatively new drug with only short-term trial evidence. While it appears somewhat better than other cessation interventions, “it appears to have more risk,” according to Dr. Sidney Wolfe, M.D., with Public Citizen. “That part of the risk-benefit equation is missing, and it’s changing rapidly,” he told Associated Press. As AP reported:

Lois Biener, a researcher of tobacco use and control efforts at the University of Massachusetts in Boston, said most people who quit do so without smoking-cessation drugs. There's little evidence that these drugs are superior in the long run to quitting without help, and while a few studies have shown some benefit, it's “way less than what is claimed” by medication advocates, Biener said.

Since September 2007, the Public Citizen has been warning the public not to use Chantix. The May 2008 issue of the British Drug and Therapeutics Bulletin also reported concerns about the psychiatric complications with Chantix, saying that the “marketing claims of a ‘favourable safety and tolerability profile’ are questionable.”

Suzanne Danforth, writing in SeaCoastOnline, described the controversy surrounding this drug and the various theories being advanced how it could be responsible for so many systemic reactions, from suicidal impulses to heart attacks and diabetes. As she explained, there are no “nicotine receptors” in your brain. So, this drug is believed to block all of your pleasure receptors, and those resulting warm fuzzy chemicals that allow our sense of contentment and pleasure, “whether it comes from kissing your kid or smelling a flower or smoking tobacco.”

“[W]hy wouldn't the world turn gray and dispiriting? But how to account for aggression, psychosis, heart attacks, diabetes?” Perhaps, she said, brain chemistry is more complicated and there’s a delicate balance that influences everything in our body and our interactions with the world. For now, the science isn’t known and “we’ll just have to use our common sense.”

New HHS clinical care guidelines

Yet, despite even the FDA communications and numerous medical concerns raised in the medical community since last year, the HHS just issued the new smoking cessation Clinical Practice Guidelines, “Treating Tobacco Use and Dependence, 2008 Update” ... which specifically recommends Chantix.

According to the guidelines, the use of medications should be encouraged for all patients (except where medically contraindicated, such as pregnant women) attempting to quit smoking. The “seven first-line medications” include: Bupropion SR, Nicotine gum, Nicotine inhaler, Nicotine lozenge, Nicotine nasal spray, Nicotine patch, and Varenicline (Chantix). Chantix is given its highest recommendation, an “A=Strength of Evidence.”

This update differs from the original 1996 and the 2002 versions of these clinical guidelines, specifically in highlighting and emphasizing more medications as being effective (including both controversial over-the-counter and this prescription drug). According to this update, pharmacological tobacco dependency treatments, especially when combined with counseling, are “both clinically effective and highly cost-effective.”

The guidelines also note that in 1997, only 25% of managed care health plans covered tobacco dependence treatment, but 90% offered coverage by 2003, adding weight to the impact of these guidelines. This provides extra incentives for recommending covered treatments.

Anytime we encounter research or guidelines that appear to depart from the strength of the scientific evidence, we turn to those financial disclosures to better understand what might have influenced the conclusions. In Appendix A of the 2008 clinical guidelines (page 223), the financial disclosure section specifically notes that all of the panelists were required to complete exhaustive disclosures in accordance with those ORI policy regulations. It reveals that 9 of the 24 members on this expert panel have received pharmaceutical moneys, most of which stand to benefit from the clinical guideline recommendations. The chair of the panel, Michael Fiore, M.D., is listed as having no financial interests, but, as has been reported, such as Kevin Hilliker’s article in the Wall Street Journal, Dr. Fiore oversees an academic center that is funded in part by drug companies that make smoking cessation products and “he personally has received tens of thousands of dollars in speaking and consulting fees from those companies.”

According to Dr. Fiore’s testimony on May 9, 2005 in the Department of Justice tobacco lawsuit: “GlaxoSmithKline gave a grant to the University of Wisconsin that established a chair for the treatment of tobacco dependence. That donation by GlaxoSmithKline was to the University. Named chairs at the University of Wisconsin provide the person who sits in that chair to access to the revenue generated from the investment on the initial grant. So in this instance, I have access to up to $50,000 per year to support my University approved and sanctioned educational, research, and policy activities.” He also stated: “Over the past five years, my outside consulting work on an annual basis has ranged between about $10,000 and $30,000 or $40,000 per year.”

The 18-member panel that developed the earlier 2000 guidelines had also been headed by Dr. Fiore. “He and at least eight others on it had ties to the makers of stop-smoking nicotine,” wrote Hilliker. However, looking at the actual financial disclosure statements in the earlier 2000 guidelines, I count 13 with extensive pharmaceutical connections, including those reported by the chair. [See below*.]

For those unfamiliar with smoking cessation products, here’s a quick overview. GlaxoSmithKline is one of the world’s largest over-the-counter product companies and distributes the leading smoking cessation products: Nicoderm CQ, a nicotine patch; Nicorette gum; and Commit, the only approved nicotine lozenge. Pfizer is the manufacturer of Nicotrol, a nicotine patch, as well as Chantix. Johnson & Johnson’s family of companies includes the ALZA Corporation which developed NicoDerm CQ and Clear NicoDerm CQ nicotine patches; McNeil Consumer Healthcare which manufactures the Nicotrol nicotine patch, licenses sales of Nicoderm nicotine patches and Nicorette gum, and markets the Nicotrol inhaler; and McNeil Pharmaceuticals which markets Nicotrol nasal spray. J&J’s nicotine products, alone, bring in $500 million a year for the company. In June 2006, J&J bought Pfizer's Consumer Healthcare business for $16.6 billion dollars, which includes the entire Nicorette line of smoking cessation products. [Readers may remember that, as of 2006, RWJF held 55,983,308 shares of J&J common stock, valued at $33.4 billion dollars.]

Dr. Michael Siegel, M.D., a professor at Boston University School of Public Health who specializes in preventive medicine and public health, and whose research focus has been on smoking and the health effects of second hand smoke, wrote of these conflicts:

While there is room for debate about issues such as whether Chantix should still be prescribed for smoking cessation and about whether a pharmaceutical-based or a cold turkey-based approach would be more effective for smoking cessation on a population level, what I don't think there is room for debate about is whether decisions about these issues should be made for the nation by experts who have severe financial conflicts of interests with Big Pharma.

While having experts writing clinical care guidelines who also have connections with the very drug companies whose products they are recommending is disturbing, regardless of the health issue, if we stop here, we miss even more serious issues raised in this incident: that greater potential influences come from nonprofits.

RWJF isn’t just the largest funder of anti-obesity programs and legislation efforts, but anti-tobacco, too. Yet, being a foundation, it’s not only exempt from taxes, it doesn’t have to file disclosure reports required of other lobbying organizations. Going down the list of members on the 2008 expert panel that developed the tobacco clinical guidelines, finds 15 members with extensive ties and funding from RWJF, including a number serving on a variety of RWJF programs such as Prescribe for Health (advances behavioral counseling interventions for tobacco cessation and obesity), Addressing Tobacco in Managed Care (working to get smoking cessation products and interventions covered by healthplans), Smoke-free Families, and its Smoking Cessation Leadership Center.

To get an idea of the significance of these ties, Susan Curry, for example, is director of smoking cessation programs at the University of Illinois in Chicago which has received active grants from RWJF of $2,996,867 in 2005-2008 and $1,240.783 for 2007-2009. Her university program was also awarded an $8 million, 4-year grant from RWJF in 2003 for a smoking cessation program. She’s also served on the Board of the American Legacy Foundation (a lead agency for the 2008 guidelines) which received a $720,000 grant from RWJF for smoking cessation programs.

According to the University of Wisconsin’s website, Dr. Fiore founded and has served as director of the University of Wisconsin Center for Tobacco Research and Intervention (UW-CTRI) since it was established in 1992. He is also co-director of the RWJF national program, Addressing Tobacco in Managed care. In 2003, RWJF awarded UW-CTRI, with Fiore as project director, $300,000 to translate tobacco dependence research into policy. Another $400,000 was granted in 2005 to evaluate a national quit line. RWJF granted another $400,000 from 2005 through July 2008 to build a network to fund tobacco-related research. In September, 2007, RWJF granted $99,316 to increase Medicaid recipient demand for tobacco dependence treatment. And in December 2007, Dr. Fiore and UW-CTRI was granted $100,000 to update, test and disseminate the 2008 tobacco clinical guideline.

Yet, he and the other panelists didn’t see this money as a conflict and didn’t recuse themselves from serving on the clinical guidelines panel. But, there are not required to even disclose these financial interests.

What you may have realized is that not only these latest clinical guidelines, but the 1996 and 2000 versions, were co-sponsored by RWJF, as is described on its website and the Executive Summary of the guidelines themselves. RWJF also funded numerous grants to disseminate the guidelines, established and funds the Addressing Tobacco in Managed Care program, and assembled the expert panel members developing the clinical guidelines. “Seventeen of the 18 panel members who developed the original Guideline reconvened to produce the update,” said RWJF. “The final version was sent to RWJF” before being “submitted to the US Public Health Service” for publication. Also, the “University of Wisconsin Comprehensive Cancer Center paid the project director's salary [Dr. Fiore] during part of the project.”

We are so quick to condemn ties to pharmaceutical companies, but when even stronger financial connections and potential influences come through a foundation or nonprofit professional organization tied to a pharmaceutical company, those go unquestioned. This leaves open any pharmaceutical company or special interest to be able to buy influence and weaken the integrity of science and medicine simply by setting up a nonprofit or working through one. You may not think that this example has influenced the public messaging about the deadliness of cigarettes or that this applies to you. But it does. It illustrates that the groundwork has been laid to make it possible for stakeholders to influence clinical practice guidelines for obesity and other preventive health measures, as well as the public policies that follow.

If you feel that financial disclosures are important for helping to preserve the integrity of science and evidence-based medicine and public health policies, then financial disclosure statements should include all moneys, including those from nonprofits.

© 2008 Sandy Szwarc

* Clinical Practice Guideline Treating Tobacco Use and Dependence
U.S. Department of Health and Human Services, Public Health Service
June 2000

Appendix C: Financial Disclosures for Panel Members, Consultants, and Senior Project Staff

Panel Members

Michael C. Fiore has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Ciba-Geigy, SmithKline Beecham, Lederle Laboratories, McNeil, Elan Pharmaceutical, and Glaxo Wellcome.

William C. Bailey has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Glaxo Wellcome, SmithKline Beecham, Schering-Plough, 3M Pharmaceuticals, Pfizer, and Sepracor.

Stuart J. Cohen has not served as a consultant for, given lectures sponsored by, or conducted research sponsored by any pharmaceutical company.

Sally Faith Dorfman has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by various pharmaceutical companies.

Michael G. Goldstein, in addition to being an employee of the Bayer Corporation, has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Glaxo Wellcome, McNeil, Ciba-Geigy, SmithKline Beecham, Boehringer Ingelheim, Sano Corporation, Dupont Pharmaceuticals, and Eli Lilly.

Ellen R. Gritz has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Bristol Myers Squibb, SmithKline Beecham, and Glaxo Wellcome.

Richard B. Heyman has not served as a consultant for, given lectures sponsored by, or conducted research sponsored by any pharmaceutical company.

Carlos Roberto Jaén has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Glaxo Wellcome Pharmaceuticals.

Thomas E. Kottke has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by McNeil Consumer Healthcare.

Harry A. Lando has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Glaxo Wellcome and SmithKline Beecham.

Robert Mecklenburg has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by SmithKline Beecham and GlaxoWellcome.

Patricia Dolan Mullen has not served as a consultant for, given lectures sponsored by, or has conducted research sponsored by any pharmaceutical companies.

Louise M. Nett has not served as a consultant for, given lectures sponsored by, or conducted research sponsored by any pharmaceutical company.

Lawrence Robinson has not served as a consultant for, given lectures sponsored by, or conducted research sponsored by any pharmaceutical company.

Maxine L. Stitzer has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by McNeil and SmithKline Beecham.

Anthony C. Tommasello has not served as a consultant for, given lectures sponsored by, or conducted research sponsored by any pharmaceutical company.

Louise Villejo has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Ortho Biotech.

Mary Ellen Wewers has not served as a consultant for, given lectures sponsored by, or conducted research sponsored by any pharmaceutical company.

Consultants

Timothy Baker has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Elan Pharmaceutical, SmithKline Beecham, Glaxo Wellcome, and Lederle.

Victor Hasselblad has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by CorTheraputics, Skinceuticals, Merck, Novartis, AstraZeneca, AstraCharnwood, The Medicines, Pfizer, Daiichi, Hoffman-LaRoche, RhonePolenc Rorer, Alexion, SmithKline Beecham, Dade, Quad-C, and Centocor Lilly.

Marc Manley has not served as a consultant for, given lectures sponsored by, or conducted research sponsored by any pharmaceutical company.

David L. Schriger has served as a consultant for, given lectures sponsored by, or has conducted research sponsored by Pfizer Corporation and the MedAmerica Corporation.

David W. Wetter has not served as a consultant for, given lectures sponsored by, or conducted research sponsored by any pharmaceutical company.