Tuesday, January 13, 2009

New Study Shows that Nicotine Replacement Therapy is Ineffective for Gradual Smoking Cessation, But Concludes the Opposite

Severe Financial Conflicts of Interest are Present and the Resulting Bias is Apparent; Failure to Disclose Conflicts of Interest Also Appears to be a Problem

An article published in the February issue of the American Journal of Preventive Medicine concludes that nicotine replacement therapy - specifically, nicotine gum - is effective in achieving sustained smoking cessation (see: Shiffman S, Ferguson SG, Strahs KR. Quitting by gradual smoking reduction using nicotine gum: a randomized controlled trial. American Journal of Preventive Medicine, February 2009) (press release here).

This was a randomized placebo-controlled trial of nicotine gum for smokers who expressed a desire to quit using gradual reduction of smoking. The chief study finding was that the use of nicotine gum resulted in a three-fold increase in the proportion of subjects who achieved six-month continuous abstinence (OR = 2.86; 95% confidence interval, 1.93, 4.24). The study concludes that "smokers wanting to quit by gradual reduction can substantially increase their success by using nicotine gum to facilitate reduction and cessation. ... Offering this new way to use NRT may enhance the appeal and reach of a treatment that increases success, and thereby have positive public health impact."

The Rest of the Story

While the use of nicotine gum did result in a three-fold increase in the proportion of subjects who achieved six-month abstinence from smoking, the absolute proportion of these subjects was extremely low. Only 5.9% of subjects receiving nicotine gum achieved six-month abstinence, compared to 2.1% of those receiving placebo.

In my view, these results indicate that the use of nicotine replacement therapy was a dismal failure. The appropriate policy recommendation would be to encourage smokers who desire to quit to do so cold turkey. Cessation rates over six-months for cold turkey quitting are better than those observed here for quitting with the aid of nicotine gum. Thus, it is a very biased recommendation to encourage the national use of nicotine gum among subjects who express a desire to quit smoking gradually. From a policy perspective, it would be far more effective to encourage and stimulate smokers who desire to quit to do so cold turkey. This is what the scientific evidence, and the results of this paper itself, actually support.

The extreme bias in the conclusions of this paper would not be so problematic if it were not for the fact that two of the three authors have severe financial conflicts of interest with Big Pharma, and that at least three of the principal investigators in the study have financial relationships with pharmaceutical companies. More specifically, each of these authors and principal investigators have financial relationships with pharmaceutical companies that manufacture smoking cessation medications.

Two of the study authors - Dr. Saul Shiffman and Dr. Stuart Ferguson from the University of Pittsburgh - have financial conflicts of interest by virtue of their employment at a firm that consults for GlaxoSmithKline Consumer Healthcare on issues related to nicotine replacement medication. In addition, Dr. Shiffman has a financial conflict of interest because he has a financial interest in a venture to develop new nicotine replacement medications.

According to the article: "Through their work at Pinney Associates, Drs. Shiffman and Ferguson serve as consultants to GSKCH [GlaxoSmithKline Consumer Healthcare] on matters related to smoking control and/or nicotine replacement medications. Dr. Shiffman also has a financial interest in a venture to develop new nicotine replacement medications." These financial relationships are confirmed elsewhere.

Three of the principal investigators on the study at academic clinical sites also appear to have financial relationships with pharmaceutical companies:

Dr. David Gonzales (Oregon Health Sciences University): "Dr. Gonzales has received research contracts from Pfizer, Sanofi-Aventis, GlaxoSmithKline, Addex Pharmaceuticals, and Nabi Biopharmaceuticals and consulting fees and honoraria from Pfizer, Sanofi-Aventis, and GlaxoSmithKline and owns 5 shares of Pfizer stock."

Dr. Stephen Rennard (University of Nebraska Medical Center): "Dr. Rennard has had or currently has a number of relationships with companies who provide products and/or services relevant to outpatient management of chronic obstructive pulmonary disease. These relationships include serving as a consultant (for Adams, Almirall, Altana, Array Biopharma, AstraZeneca, Aventis, Biolipox, Centocor, Dey, Critical Therapeutics, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Ono Pharma, Otsuka, RJ Reynolds, Roche, Sankyo, Schering-Plough, Scios, and Wyeth), advising regarding clinical trials (Altana, AstraZeneca, Aventis, Centocor, GlaxoSmithKline, Novartis, Pfizer, and Philip Morris), speaking at continuing medical education programs and performing funded research at both basic and clinical levels (Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Novartis)."

Dr. Nancy Rigotti (Massachusetts General Hospital): "In the past 5 years, Dr Rigotti has received research grant funding from Pfizer, GlaxoSmithKline, Sanofi Aventis, and Nabi Biopharmaceuticals and has consulted for Pfizer and Sanofi Aventis. These companies have investigational or marketed smoking cessation medications."

There are a number of problems with the disclosure of these financial conflicts of interest. First, while the financial conflicts of interest of the study authors are revealed in the paper itself, they are not disclosed in the press release, so far as I can tell. Thus, reporters and members of the public who read these results and conclusions in the press release, but do not read the full article are not aware of the severe financial conflicts of interest of Dr. Shiffman and Dr. Ferguson.

Second, even in the article itself, the financial conflicts of interest of the study site principal investigators are not disclosed. I was able to find out about these financial conflicts only after hours of research using databases that are not publicly available. I think readers of this article would be shocked to find out, for example, that the principal investigator of this study at the University of Nebraska Medical Center has reported having consulted for GlaxoSmithKline, manufacturer of nicotine gum, as well as for 20 other pharmaceutical companies. This type of information, especially because it is not disclosed, really puts the validity of the study findings and conclusions in question.

The study does not even mention how smoking status was ascertained, who asked the question, who recorded the result, and whether the individual conducting the assessment was blinded as to the subject's intervention vs. placebo status. To have principal investigators of a clinical trial who are financially conflicted and not to reveal this in a manuscript summarizing the findings is extremely problematic. In my view, it violates ethical standards of conduct, since I believe all such financial relationships should be disclosed in the paper.

Beyond the apparent failure of disclosure of financial conflicts of interest of several of the study site principal investigators, an additional problem is the fact that principal investigators at academic institutions were allowed to serve in that capacity in the first place, given that this was a clinical trial in which an actual drug being marketed by the company of interest was being tested in human subjects, and among whom there was a risk of adverse events, which were monitored in the study.

At my institution, it would be extremely unlikely that we would allow an individual with this type of conflict of interest to serve as the principal investigator on a clinical trial such as this. When human subjects are involved in research, conflicted principal investigators are generally not acceptable, unless there is a major compelling reason to make an exception. It would be interesting to know whether conflict of interest advisory committees at the University of Pittsburgh, Massachusetts General Hospital, University of Nebraska Medical Center, and Oregon Health Sciences University reviewed these cases, and if so, what their justifications were for allowing individuals with financial relationships with pharmaceutical companies that manufacture smoking cessation products to serve as principal investigators on a clinical trial involving potential significant risks to human subjects.

It would also be of interest to know whether the human subjects at these institutions were informed of these conflicts of interest of their site principal investigators.

Also of interest would be knowing whether there were procedures in place to ensure that the conflicted principal investigator had no role in collecting or analyzing data in the study. This point, however, is almost moot since by definition, the principal investigator is the primary person with responsibility for the collection and analysis of the data, even if others are performing the primary tasks.

Readers may want to note that the fact that the study was funded by GlaxoSmithKline Consumer Healthcare is not of primary concern to me. My concern is over the financial conflicts of interest of study authors and principal investigators, not with the overall funding by a pharmaceutical company. The funding itself does not represent a financial conflict of interest. The conflict of interest comes from the fact that the study authors and some of the site principal investigators appear to have signficant financial relationships with pharmaceutical companies, including the company that manufacturers nicotine gum and others that manufacture other nicotine replacement therapy or smoking cessation medications.

I do find it problematic that the University of Pittsburgh apparently allowed Dr. Shiffman and Dr. Ferguson to serve as principal investigators of the overall study (which they appear to be since they are the authors of the summary article), since they have significant financial conflicts of interest and because this is human subjects research.

The conflict of interest calls into question the integrity of the process by which study site data were collected, combined, and analyzed. This is not because of any suspicion of anything less than honorable character and intent among the authors. It is because a financial conflict of interest can create an unconscious bias which may be perceived as affecting the conduct of the study and the reporting of the study results.

Let me also take this opportunity to emphasize that I am not accusing anyone of intentional wrongdoing or any lack of individual integrity. Bias related to conflicts of interest can be completely subconscious. But that is precisely why they need to be eliminated or managed properly.

There is little doubt in my mind that the financial conflicts of interest inherent in this research led to a bias (albeit unconscious) in the interpretation and presentation of the study findings and conclusions. Obviously, it led to a much more positive reporting of the findings than was warranted. In fact, I would go so far as to state that the study conclusion is unsupported by the study findings. Nicotine gum should not be recommended for these patients; they should be encouraged to quit smoking cold turkey.

While differences of opinion are appropriate and expected, when one opinion that is being widely disseminated with an eye towards affecting national policy is influenced by a financial conflict of interest - and especially when that conflict is not adequately disclosed - this is problematic.

Finally, while Dr. Shiffman's conflict of interest is disclosed in this article, it does not appear to be disclosed in another article he wrote about women's success in smoking cessation (see: Shiffman S. How when matters for quitting and relapse [commentary]. Addiction 2008; 103:822-823).

That article discusses factors that relate to the success of smoking cessation among women and treatment for smoking cessation and prevention of relapse. Thus, it would seem that Dr. Shiffman's conflict of interest by virtue of his consulting for GlaxoSmithKline and his venture to develop new smoking cessation medications would be relevant. However, this conflict of interest does not appear to be disclosed in the article. The declaration of interest statement says only: "The author is a co-founder of invivodata, inc., which provides electronic diaries for clinical trials."

If anything, I would think that the conflict of interest with a pharmaceutical company that manufacturers products for treatment of nicotine dependence and the interest in a venture to develop new such treatments would be of even more relevance than the interest in electronic diaries, which actually don't seem to be particularly relevant here. But the point is, if electronic diaries were thought to be relevant, then why weren't the pharmaceutical conflicts of interest disclosed?

It's always possible that I'm missing something here. I've examined the full text of the articles mentioned as well as the press release in detail.

The rest of the story is that this research appears to be an example of: (1) Failure to disclose relevant financial conflicts of interest in a study press release; (2) Failure to disclose some relevant conflicts of interest in the study itself; and (3) Inappropriate conflicts of interest among principal investigators on human subjects research.

That these issues are arising in tobacco control research does not come as a surprise to me.

For a previous discussion of the inappropriate role of conflicts of interest in tobacco control research and policy, see the following posts:

Executive Director of Campaign for Tobacco-Free Kids Violates President-Elect Obama's New Rules for Lobbyists on Transition Team

New Report Warns of Serious Risk Profile of Chantix; Recommendation of Chantix by Anti-Smoking Researchers with Conflicts of Interest is Unacceptable

International Tobacco Control List-Serve and Discussion Site Now Sponsored by Big Pharma

Chantix Lawsuits Piling Up; Dangers from Severe Financial Conflicts of Interests of Tobacco Control Researchers and Institutions Revealed

With $50,000 in Annual Resources from GlaxoSmithKline, Chair of Expert Panel on Smoking Cessation Should Have Recused Himself, or Been Removed

Press Release on Smoking Cessation Guidelines Fails to Disclose Financial Conflict of Interest of Expert Panelists

NIH Expert Panel Recommends Smoking Cessation Pharmaceuticals for Every Smoking Patient; Panel Chair and 8 Members Have Financial Ties to Big Pharma

Financial Conflict of Interest Not Disclosed in Article on Smoking Cessation; Another Example of Failed Disclosure in Tobacco Control Research

Weill Cornell Medical College Again Defends Researcher's Failure to Disclose Tobacco Funding and Financial Conflict of Interest

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