Wednesday, July 02, 2008

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.


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.


Anonymous said...

Cathryn M Clary, vice president for external medical affairs for Pfizer, "fears too much transparency will cause confusion."


This is a revealing statement regarding the elitist views of pharma.

Too much truth is bad? That's Orwellian at best, Stalinist at worst.

Don't let those stupid patients know the truth; it's bad for them.

My God.

Anonymous said...

Here are some posts from Gooznews on this and related topics:

Anonymous said...

From my business prospective this appears to be just another scam. I would define a scam as having a number of common traits, some of which follow:

Extreme confidence. This is why they are called confidence men. People perpetrating these scams are able to speak and argue with extreme confidence, challenging anyone who disagrees to exhibit the same level of confidence. This is often accompanied with the statement that "you would only be confused" with all of the information.

Reversing the argument: The old prove me wrong statement. This is effective since we often intuitively know something is wrong but do not have the information at hand. This is followed by a never ending stream of questions to keep the challenger off balance while the person making the original statement does not have to defend their position.

Group dynamics. You do not need everyone in a group to buy into an argument, only a few who will defend, with confidence, a speakers position. We have all heard of a "shill." KOL's seem to fill this position in this new variation of a very old game.

Denial. When all else fails we simply deny a problem exist. How do you then argue with someone who will not, at the very least, recognize a counter opinion exist? Me influenced by money? How dare you question my integrity! (See extreme confidence and reversing the argument.)

This list is obviously short and not inclusive. Troubling is we see these behaviors being repeated time and time again by those in the medical community. Health Care Renewal has done an excellent job of exposing those involved with these scams with the only defense available: A well crafted, fact based argument, brought to the table before those who wish to argue can muster their minions to overwhelm the argument with noise.

I am once again reminded that "Facts are the enemy of truth."

Steve Lucas

Bruce Grant said...

As usual, incisive and thoughtful...but the generic name for Chantix/Champix is varenicline, not verenicline. Keep up the good work.

Anonymous said...

Thanks for the studies. I knew that I had read about the long-term efficacy of Chantix compared to other methods, but couldn't find them. No matter how many crutches you use, in the end you have to walk on your own.

Anonymous said...

For the real story click on:

or google keywords:
healthline Foulds influence

Anonymous said...

Looks like you didn't read reference 2, 10, 11 or 13 of the original paper that all give evidence on the safety and efficacy of treatment beyond the labelled duration.

More importantly, the new Public Health Service Guideline specifically states that some patients may require longer duration treatment (just as for numerous other medical conditions, the severity varies and so the intensity and duration of treatment should vary accordingly).

Roy M. Poses MD said...

Re the last anonymous comment about references 2, 10, 11, or 13.

I should make a rule for comments that anyone trying to make a point by citing evidence from the clinical research literature needs to explain how the particular studies cited support that point.

Reference 2 is a clinical practice guideline. It summarizes some clinical data, but contains no new data. Its reccomendations are a matter of opinion. Some of the people involved in writing the guideline had conflicts of interest. Thus, it provides no original evidence about safety or efficacy.

Reference 10, the Mayo Clinic study, randomized patients for a maximum treatment duration of 12 months, if I read it correctly. (It is difficult to follow in some places.) The study did follow people after the completion of treatment, but strictly speaking, it did not involve treatment for more than one year. Its validity was threatened by a high rate of loss to follow-up. It did not demonstrate that the study drug, bupropion, produced a signficantly higher abstinence rate at 12 months, or 3 months after completion of treatment. It did not report safety data. So this study did not provide any good evidence about the safety of bupropion vs placebo, or of the efficacy of bupropion used for one year vs placebo. It provided no evidence about the drug used for more than one year.

Reference 11 was a report of the follow-up of a cohort of patients originally part of the treatment group in an unblinded study of a complex intervention on smokers with COPD. Some of the patients in this group continued to take nicotine chewing gum for varying periods of time, up to 5 years. The study did not show any obvious increase in cardiovascular events in patients who continued to use the gum. It also had complex data on a variety of symptoms, presented in a way that made it difficult to attribute the symptoms to the gum. This was not a report of a controlled trial, and did not include data about the efficacy of nicotine replacement therapy using nicotine gum for inducing abstinence. At best, this study provides suggestive data about the safety of nicotine gum used for more than one year, but because it did not report data from a controlled trial, was subject to various study biases. This study provided no evidence about efficacy.

Finally, reference 13 was a controlled trial comparing bupropion to placebo. All patients who were abstinent on bupropion for 7 weeks were randomized for an additional 45 weeks of therapy. Patients were followed after the conclusion of therapy at one year. The trial did not assess therapy for more than one year. The study did not show a significant difference in abstinence over the entire time period of observation by proportional hazards regression, or in continuous abstinence at the end of a year. The study reported some safety data, with no significant difference in overall adverse events between bupropion and placebo over one year, although there were two deaths in bupropion group (and none in the placebo group.) This study did not provide data about safety or efficacy of treatment used for more than one year. It did not provide evidence that bupropion was efficacious at one year.

I didn't see how any of these references provided evidence that long-term treatment with any drug is efficacious for inducing patients to stop smoking. One reference provided very limited and difficult to interpret evidence that nicotine gum may be safe if used more than one year. None of these references provided much data about safety, and none provided data beyond that just mentioned about long-term safety of any drug used to induce abstinence.

The next time someone would like to comment that reference x challenges what I or someone else) said), please describe the evidence and explain how it might support the point.

Anonymous said...

Roy said: I didn't see how any of these references provided evidence that long-term treatment with any drug is efficacious for inducing patients to stop smoking.

Combine this with Steve's fine explanation of a scam . . . and voila--you have 'last anonymous' proving both of your points. (I suspect 'last anonymous' is either a pharma insider--attempting to perform damage control--or a Chantix sales rep--attempting to alleviate guilt and complicity in promoting this questionable product.


Anonymous said...

When I was with Big Pharma, companies were known to pay 1500 dollars or more to one of them for a 10 minute presentation, normally consisted of basic disease state stuff and the presentation was of a monotone and apathetic oration.

In any given year, I'd spend tens of thousands of dollars on such speaker programs. Do the math. That's a lot of wasted money. We never measured the effect of the speaker afterwards. It's a psychotic process of no monetary benefit for the sponsor, in my opinion.

Dan Abshear