Key Opinion Leaders, Drugs for Smoking Cessation, and Transparency as a Cause of "Confusion"

A perspectives article from the April 1 issue of the Annals of Internal Medicine has provoked a slowly growing controversy. (1) Let me summarize the main points of the article before getting to the controversy.

As the title, "the case for treating tobacco dependence as a chronic disease," suggests, the authors argue "for some smokers, long-term pharmacotherapy [which] is the difference between tobacco abstinence and lifelong smoking," based on the argument that smoking is like a chronic disease.

They called for long-term use of pharmacologic treatments for tobacco addiction, including nicotine replacement therapy (NRT), buproprion, and verenicline, asserting that these drugs are safe and effective, and have "proven benefits." Such proven treatments, therefore, ought to be used long term.

Although long-term use is considered off-label, patients should be encouraged to remain smoke-free, and if extended courses of pharmacotherapy will assist them, treatment should be continued, encouraged, and reimbursed.

Rather than considering cessation medications as a short-term aid in smoking cessation, these medications should be covered in the same manner as the treatment of other long-term illnesses and conditions, such as asthma, depression, and diabetes....

However, their enthusiasm for pharmacologic treatment for smoking cessation, even in the short-term, seems to go beyond the evidence. That evidence shows that the "proven benefits" of these treatments do not accrue to the majority of patients receiving them. For example, in one widely disseminated study comparing verenicline, buproprion and placebo, the proportions of patients who were abstinent for one year (the duration of follow-up) were 21.9% for verenicline, 16.1% for bupropion, and 8.4% for placebo. Although the most effective drug, verenicline, more than doubled the continuous abstinence rate compared to placebo, the large majority of patients treated with that drug, 78.1%, did not achieve continuous abstinence, even for one year.(2) In another recent study, patients given verenicline were somewhat more likely to be abstinent at the end of a year (26.1%) than those treated with nicotine patches (20.3%), although the difference did not reach statistical significance.(3) However, again the great majority of patients treated with either medicine were not continuously abstinent, even for one year.

Thus, most smokers treated with drugs will not remain abstinent from smoking, even for one year. Furthermore, I am aware of, and Steinberg et al did not cite any data from controlled trials about the safety or effectiveness of any pharmacologic treatments of tobacco addiction for patients followed for more than one year. There is no reason to suspect that these drugs' effectiveness over the long-term would be any better than their rather marginal effectiveness when when used short-term.

In my humble opinion, Steinberg et al might have been able to make a case for controlled trials of these drugs' use that would follow patients for more than one year. But they presented no evidence to support the clinical use of these drugs, much less insurance company reimbursement for them, for time periods longer than those found in the published trials.

So why did these authors make arguments that went beyond the evidence?

Soon after the article came out, Adriane Fugh-Berman and Douglas Melnick, writing in the Bioethics Forum, noted:

The most important section of this article is the conflict of interest statement. The two authors who have advanced degrees are on the speaker’s bureau of Pfizer and are consultants to Pfizer, Novartis, GlaxoSmithKline, and Celtic Pharma. Pfizer makes varenecline (marketed under the brand name Chantix) and Nicotrol, a nicotine nasal spray. GSK makes Nicorette gum, Commit nicotine lozenges, Nicoderm nicotine patches, and Zyban (buproprion, which GSK also sells as an antidepressant under the name Wellbutrin). Novartis makes Thrive, a nicotine chewing gum ('thrive,' which means to prosper or flourish, seems a rather peculiar association for a delivery system for an addictive drug.) And Celtic Pharma is developing TA-NIC, a nicotine vaccine.

Furthermore, last week, an article in BusinessWeek provided more information about the financial ties of two authors of the Steinberg et al paper.

In 2006, Pfizer recruited Foulds to serve on its paid national advisory board for Chantix. The company also selected Foulds and Steinberg to be 'key opinion leaders,' sending them to talk to doctors about Chantix over fancy dinners and paying them each $900 per presentation. Foulds and Steinberg say that between them they have made a total of about a dozen appearances.

Steinberg received a $30,000 grant from Pfizer in April 2007 to study the effect of Chantix on patients forced to forgo cigarettes while hospitalized for other illnesses. He says this was his first research grant from a drug company. (The Robert Wood Johnson Foundation separately provided $300,000 for the hospital study.)

Steinberg, according to BusinessWeek, denied that he is influenced by his ties to Pfizer:

Adamant that his work for Pfizer and other drug companies poses no problem, he adds: 'We look at the data, and we look at our own clinical experience.'

While the authors disclosed the nature but not the effect size of their financial relationships in the Annals of Internal Medicine article, they were not so forthcoming to their patients. Per BusinessWeek,

Both doctors stress that it's not standard practice to tell patients about potential conflicts.

On the Web site for UMDNJ's smoking clinic, it's not easy for a layman to find disclosures. There is no clearly labeled list of companies that pay Foulds and Steinberg that is directly accessible from the home page. There are links to journal articles, some of which reveal industry ties. But getting the information takes effort. The online version of the Annals article requires a viewer to have a paid subscription for full access. Their twice-a-year newsletter, The Nicotine Challenger, doesn't disclose their work for Pfizer, even in articles that speak highly of Chantix.

Foulds includes a broadly worded disclosure on his blog, but doesn't name companies for which he consults.

Finally, neither author saw the need to provide more disclosures to patients.

Telling patients more about industry ties 'would just puzzle them,' Foulds says.

Steinberg sees no need to be more forthcoming. His passion for helping people quit is fueled by treating numerous cases of high blood pressure and other problems precipitated by smoking.

To add a final touch, Cathryn M Clary, vice president for external medical affairs for Pfizer, "fears too much transparency will cause confusion,"

The more information that's out there, the more difficult it will be for patients to process

There has been a good deal of discussion about drug, biotechnology and device companies paying "key opinion leaders" to help market these products (for example, see these posts here and here). And there has been a good deal of indignation that it is an affront to physicians to judge the content of medical education they provide based on who paid for it (see this link.)

Although the case of the Annals article is essentially only an anecdote, it does suggest an association between payments to key opinion leaders, and opinions that are more enthusiastic about the payers' products than the evidence seems to warrant.

Furthermore, it suggests that key key opinion leaders and the companies who sponsor them may dismiss transparency about their financial relationships as a cause of "confusion." If patients really are too naive to understand the implications of payments by drug and other commercial firms to key opinion leaders, would the KOLs and their patrons prefer that government step in to protect these poor, naive patients from such relationships they cannot understand? That is what their attitude seems to invite.

References

1. Steinberg MG, Schmelzer AC, Richardson DL, and Foulds J. The case for treating tobacco dependence as a chronic disease. Ann Intern Med 2008; 148: 554-556. Link here.
2. Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB et al. Verenicline, and alpha-4-beta-2 nicotinic acetylcholine receptor partial agonist, vs sustained release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006; 296: 47-55. Link here.
3. Aubin HJ, Bobak A, Britton JR, Oncken C et al. Verenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 2008. Link here.