Wednesday, April 06, 2011

Rest of the Story Calls for Removal of Chantix from the Market: FDA, Pfizer, and Anti-Smoking Groups Have Done Enough Damage to People's Lives

Today, I am calling for the FDA to remove Chantix from the market and for anti-smoking groups and researchers to demand that the FDA take such action.

It has become clear to me that the current black box warning is simply insufficient to protect the public from the significant and severe adverse side effects of Chantix.

The FDA responded to the more than 100 reports of suicides, more than 400 reports of violence, and more than 11,000 other cases of severe side effects associated with Chantix by requiring Pfizer to place a "black box" warning label on the medication. The label warns physicians to monitor their patients for adverse psychiatric effects, such as severe depression, violent behavior, and suicidality.

However, it has become clear to me that this black box warning is simply not sufficient. The severe and often deadly effects of Chantix can occur quickly and without warning. Many of the individuals who have died as a result of Chantix use committed suicide suddenly, without warning, and within just days after initiating therapy with this medication. Clearly, the black box warning was not sufficient. With a drug that can have such severe adverse effects in such a short time, it is simply impossible to appropriately monitor and prevent these effects from becoming lethal through physician monitoring. The effects appear too quickly and medical practice is not set up to conduct psychological testing every day for a one- to two-week period following initiation of medical therapy for smoking cessation.

Evidence published in January demonstrates that Chantix is most definitely not a safe drug. A study published in PLoS One reported that Chantix is the worst drug offender in terms of being associated with suicidal behavior and violence towards others. According to the research, Chantix has been associated with more than 400 cases of violence and more than 11,000 serious adverse effects. Chantix was associated with 18 times the number of violence cases as one would have expected by chance.

The study controlled for the possible increased tendency towards aggression among the population being treated with Chantix and the relationship between varenicline use and violence was still enormous. Thus, these effects seem to be a real side effect of Chantix use.

The article concludes: "Acts of violence towards others are a genuine and serious adverse drug event associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and antidepressants with serotonergic effects were the most strongly and consistently implicated drugs."

This research has led some to conclude that: "the message is clear that while Chantix can prove to be an effective weapon for chronic quitters (smokers who try various magic bullets to kick the habit, only to fail…), the costs to some in terms of Chantix aggression and other Chantix side effects can be potentially devastating."

According to a news article published in the March 2009 issue of the Journal of the American Medical Association (JAMA), evidence was already mounting at that time supporting the conclusion that use of the smoking cessation drug varenicline (Chantix) is associated with suicidal ideation and behavior in a substantial number of treated patients (see: Kuehn BM. Studies linking smoking-cessation drug with suicide risk spark concern. JAMA 2009;301(10):1007-1008).

According to the article: "A new analysis by the US Food and Drug Administration (FDA) adds to evidence that varenicline might be associated with an increased risk of suicidal thoughts and behavior, including among patients with no psychiatric history. The results, which were published in January, follow warnings from the agency that such a link is likely, as well as label changes noting a possible risk. ... An analysis of adverse event reports submitted to the FDA between May 2006 (when varenicline was approved) and November 2007 found 116 cases of suicidal ideation and 37 cases of suicidal behavior, more than half resulting in death. Half of the patients reporting either suicide ideation or suicidal behavior had a history of psychiatric problems, 26% had no such history, and 24% had an unknown psychiatric history."

Because there are many other treatments available for smoking cessation with similar effectiveness, I believe that the cost-benefit ratio for Chantix is now clearly on the side of the costs to society - even with the black box warning - and the drug should therefore be pulled from the market.

According to an article in Lawyers USA, there are now at least 200 lawsuits that have been filed by the families of plaintiffs who allege that their loved ones committed suicide as a result of taking the smoking cessation drug Chantix (varenicline) or by plaintiffs who attempted suicide after starting Chantix. These cases were filed by a single law firm, which is investigating another 1,200 cases. Another firm is investigating 175 similar cases.

The plaintiff's attorney was quoted in the article as describing the cases as follows: ""Tragically, almost without explanation, these people commit suicide, often without any prior diagnosis of family or individual history of depression, psychosis or any other type of psychological conditions."

According to the article: "On Feb. 1, 2008, the Food and Drug Administration issued an alert that 'serious neuropsychiatric symptoms have occurred in patients taking Chantix.' The symptoms include 'changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicides.' 'It appears increasingly likely that there is an association between Chantix and serious neuropsychiatric symptoms,' the FDA stated. ..."

"A study in May 2008 by the Institute for Safe Medication Practices, a prescription drug watchdog group based near Philadelphia, reported that in the fourth quarter of 2007, varenicline accounted for 988 serious injuries reported to the FDA, more than any other single drug. ... The Federal Aviation Administration has banned pilots and air traffic controllers from using Chantix; the drug has also been banned for use by commercial drivers." ...

"On Feb. 1, 2008, Pfizer strengthened its Chantix labeling to include stronger warnings about neuropsychiatric symptoms. In May 2008, it revised the warning again, advising physicians to discontinue Chantix immediately if patients become agitated, depressed or suicidal."

However, discontinuing Chantix as a result of patients becoming suicidal is ineffective. If patients are suicidal and they commit suicide, it is too late to withdraw the medication. No physician's office is equipped to conduct the kind of day-to-day, intensive psychological monitoring that would be needed to make Pfizer's recommendation effective in preventing these severe adverse side effects.

The FDA cannot allow this black box warning to remain the only protection for patients, as it is woefully inadequate. The time has come to pull Chantix from the market.

The Rest of the Story

How ironic it is that the FDA is spending more time trying to ban electronic cigarettes - which have not caused a single reported death or severe adverse effect in the U.S. - but is sitting on its hands with regards to Chantix, which continues to kill people due to its effects on violence, aggression, depression, and suicidality.

And ironically, while five anti-smoking groups have called for the removal of electronic cigarettes from the market, none have called for the removal of Chantix, although the latter drug is actually killing people while the former is not.

For this reason, I argue that both the FDA and the anti-smoking groups bear major responsibility in the tragedy of Chantix-related suicide.

Also bearing responsibility, I believe, are the anti-smoking researchers who have been recommending the use of Chantix as part of a national smoking cessation strategy, but who had or have severe conflicts of interest by virtue of their receiving money from pharmaceutical companies that manufacture smoking cessation drugs, in particular - from Pfizer, the manufacturer of Chantix.

The Chantix experience serves as a poignant (and tragic) reminder of exactly why it is that financial conflicts of interest are not to be tolerated in the formation of national clinical treatment policy. The presence of financial conflicts of interest produces a bias (even if subconscious) that is unacceptable when recommendations are being made that affect people's lives (i.e., clinical practice).

The bias in the Clinical Practice Guideline panel's analysis is apparent when one considers the research documenting that the overwhelming majority of successful quit attempts are unplanned. The planning of quit attempts by patients with medication provided by their physicians is, on a population basis, one of the least effective methods of smoking cessation.
Planned quit attempts are actually less successful than attempts that are unplanned. National smoking cessation policy and treatment of patients should therefore be based on efforts to motivate patients sufficiently to quit cold turkey, rather than to plan quit attempts for them.

The bias created by financial conflicts of interest with Big Pharma in tobacco control continues and can be seen in numerous research articles. For example, in response to the article documenting that unplanned quit attempts are the most successful, a researcher from the University of Vermont challenges the conclusions of that study. What is not disclosed is the fact that in 2006, the same researcher "accepted honoraria, fees or travel expenses from Academy for Educational Development, Atrium Healthcare, Cambridge Hospital, Celtic Pharmaceuticals/Xenova, Concepts in Medicine, Cowen and Companies, Cygnus, Edelman Bioscience, Exchange Supplies Ltd., Fagerstrom Consulting, Free and Clear, Health Learning Systems, Healthwise, JSR, Insyght, LEK Consulting, Maine Medical Center, Nabi Pharmaceuticals, New York Association of Substance Abuse Providers, Nabi Biopharmaceuticals, National Institutes on Health; Pfizer/U.S., Pfizer Canada, Pinney Associates, Sanofi-Aventis, Shire Health London, Temple University of Health Sciences, University of Wisconsin and ZS Associates."

What at first glance might appear to be an unbiased assessment of the state of the research turns out instead to be written by someone who has received money from a large number of pharmaceutical companies, including several that have a direct financial stake in consumers making planned rather than unplanned quit attempts.

Not long ago, an NIH expert panel released a 2008 update of the clinical practice guideline regarding the treatment of tobacco use and dependence (see: Fiore MC, JaƩn CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. May 2008).

The guideline recommends that every patient who wishes to quit be treated with pharmaceuticals, unless medically contraindicated. The guideline also recommends the use of Chantix, despite concerns about its potential suicide risk.

Far from being an objective review and assessment of the best possible strategy to enhance smoking cessation among smokers in the United States, the guideline is a heavily biased analysis that is plagued by the presence of severe financial conflicts of interests among the panel's chair and at least 8 of its other members.

Nine of the panel members have received, or are currently receiving, funding from pharmaceutical companies. Most of the involved companies stand to gain from the clinical practice guideline's recommendations, because these companies manufacture drugs recommended by the panel.

Here is the long list of financial conflicts of interest among this supposedly objective panel of expert scientists:

Michael C. Fiore (panel chair): "reported that he served as an investigator on research studies at the University of Wisconsin (UW) that were supported wholly or in part by four pharmaceutical companies, and in 2005 received compensation from one pharmaceutical company. In addition, he reported that, in 1998, the UW appointed him to a named Chair, which was made possible by an unrestricted gift to the UW from GlaxoWellcome."

William C. Bailey: "reported significant financial interests in the form of compensation from three different pharmaceutical companies in 2006 and two in 2007 for speaking engagements."

Timothy B. Baker: "reported that he has served as a co-investigator on research studies at the University of Wisconsin that were sponsored by four pharmaceutical companies."

Neal L. Benowitz: "reported significant financial interest in the form of compensation from one pharmaceutical company for each of the years 2005-2007, as well as stock ownership in one pharmaceutical company."

Michael G. Goldstein: "reported that his employer received support from Bayer Pharmaceutical prior to 2005 and that he was employed by Bayer Pharmaceutical Corporation prior to January 1, 2005. His organization received payments for his professional services from two pharmaceutical companies and one commercial Internet smoking cessation site during the period 2005-2007."

Harry A. Lando: "reported serving on an advisory panel for a new tobacco use cessation medication and attending 2-day meetings in 2005 and 2006 as a member of this panel."

C. Tracy Orleans: "reported significant financial interests in the form of a dependent child who owns pharmaceutical stock... ."

Maxine L. Stitzer: "reported participation on a pharmaceutical scientific advisory panel for a new tobacco use cessation medication."

Sally Faith Dorfman: "reported her employment by Ferring Pharmaceuticals, Inc., a company whose business does not relate to treating tobacco dependence."

GlaxoWellcome, which apparently endowed the Chair position that the chair of the panel enjoys, is the manufacturer of Wellbutrin, Commit lozenge, Committed Quitters, NiQuitin/Nicoderm, Nicabate, and Nicorette. The use of all of these drugs is recommended by the panel.

What this means is that we basically have a group of experts who are largely financially linked with pharmaceutical companies, and who stand to gain personally if they recommend the use of pharmaceuticals as part of their smoking cessation guidelines. The more use of pharmaceuticals they recommend, the more they stand to gain.

While I find it objectionable that these agencies would allow experts with these type of financial conflicts of interest to serve on the panel, I find it equally troubling that such individuals would agree to serve. I believe that based on these conflicts, these experts should have recused themselves from service on the panel.

This is a conflict of interest in the ugliest way that I can imagine. It is precisely the type of thing that needs to be stopped.

Perhaps the most troubling conflict of all is that of the expert panel's chair - Dr. Michael Fiore. Dr. Fiore has reported "that he has lectured and consulted for Pfizer and has served as an investigator on research studies at the University of Wisconsin (UW) that were supported by GlaxoSmithKline, Nabi, Pfizer, and sanofi-aventis." Pfizer is the company that markets Chantix.

That this panel made a national recommendation that all physicians use Chantix (and other drugs) to treat every smoker without specific contraindications and that this recommendation was made by a panel whose Chair had received money from Pfizer, is inexcusable. It is even more troubling that the panel has not issued any kind of update or warning to modify its recommendation that Chantix be used as a smoking cessation drug in light of the many reports of the deadly side effects that this medication has had.

The rest of the story is that the many Chantix-associated suicides are truly a tragedy, and they are even more tragic because the deaths that have been caused by Chantix would possibly have been prevented had the national panel not consisted of members with such severe financial conflicts of interest. Any kind of objective review of the data, in my opinion, would have precluded a national panel from recommending the use of this drug, given the many alternatives available that have similar effectiveness. At very least, an objective panel would have returned to this issue after - at the latest - the January 2011 report and issued a modification of the Clinical Practice Guideline retracting the recommendation that patients be treated with Chantix.

The central tenet of medicine and public health is "to do no harm." Sadly, this is a story in which physicians and public health practitioners have caused harm. While mistakes occur, and are excusable because people are only human and cannot predict the future, clouding scientific and policy issues by financial conflicts of interest that result in poor national recommendations is not acceptable. We owe the public a greater degree of scientific, medical, and public health integrity.

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