Allowing the pharmaceutical industry to determine the safety and effectiveness of its wares is like letting the foxes guard the henhouse.

This is amply demonstrated by the sordid and still-unfolding story of Chantix, a stop-smoking aid marketed by Pfizer. (The generic name for this drug is varenicline. Outside the United States, varenicline is marketed by Pfizer as Champix.)

Chantix was approved by the FDA on the basis of five studies, all funded by Pfizer and published in July and August of 2006. The designers of these studies seem to have pulled out all the stops in their efforts to stack the deck in Pfizer’s favor.

As many as one-third of prospective study participants were turned away for conditions including but not limited to a history of cancer, cardiovascular disease, chronic obstructive pulmonary disease, a history of alcohol or drug abuse, major depression, panic disorder, bipolar disorder, systolic blood pressure greater than 150 or diastolic pressure greater than 95, a body mass index of less than 15 or higher than 38, weight less than 45kg, those with "clinically significant abnormalities in the screening laboratory values…” The list goes on and on.  

The question is, why? It’s not as if these conditions are unknown among smokers. It’s hard to imagine an reason people with these conditions were excluded, unless the designers of these studies felt that these folks would have an especially difficult time quitting. But to whatever extent that is true, then their exclusion would cause the studies to overestimate the overall effectiveness of Chantix.  

If you are a smoker wanting to quit, and you have one or more of the above-mentioned conditions, how will Chantix interact with your condition, or with any medications you are taking for that condition? Who knows? 

The ads tease, "Ask your doctor if Chantix is right for you.” But how would she know? 

The studies also excluded those who were known to have relapsed after attempting to quit smoking with the aid of nicotine replacement therapy or another competing product. Common sense would tend to indicate that people who had already failed to quit with the aid of one product would be more likely than average to fail with Chantix.

Once again, to whatever extent that is true, their exclusion would cause these studies to overestimate the overall effectiveness of Chantix.  

There’s more. The designers of these studies created a clinical experience par excellence for would-be quitters. Study participants received all their varenicline for free. They also were treated to weekly one-on-one counseling sessions to assist in problem solving and training for relapse prevention. After varenicline was discontinued, the stop-smoking support continued in the form of extra counseling sessions as well as follow-up telephone calls for a total of 52 weeks. In addition, they underwent repeated complete physical exams, including taking the patient’s smoking history as well as an electrocardiogram, hematology, blood chemistry analysis, and urinalysis. Their weight, vital signs, and expired carbon monoxide were measured at each clinic visit – all opportunities to contemplate their health and mortality, to impress upon them the gravity of the matter at hand.

In short, they had available to them stop-smoking assistance probably beyond the wildest dreams of your rank-and-file smoker.

And what did the researchers find? Three of the studies – those by Gonzales et al. , Jorenby et al., and Onken et al. – assessed the effect of 1 mg varenicline administered twice a day for twelve weeks, in addition to intensive stop-smoking support that continued for a total of 52 weeks. Average results were very close for all three clinical trials: approximately 46% of study participants were smoke-free at the end of the first twelve weeks, and 22% were still smoke-free at the end of the 52 weeks. Flipping that around, that’s a 78% failure rate.

The study by Tonstad et al. found that 70.5% of those receiving varenicline for twelve weeks along with intensive stop-smoking support for a total of 52 weeks were smoke-free at the end of 52 weeks. That sounds pretty good, but wait a minute. 70.5% of what, exactly? It turns out that the study subjects were recruited from those who had already managed to emerge smoke-free from a previous twelve-week trial. Now let’s assume that the success rate for this trial at twelve weeks was the same as the average of that of the three above-mentioned trials, or 46%. Now 70.5% of 46% is 32%. Again flipping it around, we can deduce that after 24 weeks of varenicline as well as intensive stop-smoking support continuing for one year, the failure rate was something like 68%.

The last study, that by Nides et al., found that for subjects receiving varenicline for six weeks plus intensive stop-smoking support for a total of one year, the success rate at the end of that year was a dismal 14.4%. That’s a failure rate of 85.6%.

How will smokers in the real world, who cannot hope to call upon the kind of stop-smoking support these folks had, fare? We don’t know, but we can take a pretty good guess, in the light of previous experience with nicotine replacement therapy (NRT). Clinical trials of NRT, along with the kind of intensive stop-smoking support the varenicline trial participants received, reported spectacular success rates – in one case as high as 44%. But the twelve-month success rate for over-the-counter NRT is a dismal seven percent. For those attempting quitting for the second time, the rate is virtually zero.

In stark contrast to Pfizer’s diligence in stacking the deck in favor of Chantix in clinical trials is its downright lackadaisical behavior when it came to reporting untoward side effects.

Like suicide.

Chantix was approved by the FDA on 11 May 2006. A study published by the non-profit  Institute for Safe Medication Practices found that by the fourth quarter of 2007, Chantix surpassed all other drugs for serious events reported to the FDA, including but not limited to hostility/aggression, paranoia, homicidal ideation, hallucinations, psychosis, suicidal ideation, as well as 28 actual suicides.

The Institute notified the FDA, which on 1 July 2009 issued an alert and required Pfizer to include a black box warning – the strongest sanction possible short of banning a drug – on all packages of Chantix, cautioning users and health professionals to be on the lookout for changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide.  

It turned out that the situation was even worse than anyone thought. In the third quarter of 2010, the Institute found another spike in adverse events attributed to Chantix, and learned that the spike was due to a large number of adverse events which occurred in previous quarters but had not been tabulated by the FDA due to irregularities in Pfizer’s reporting system.  

These adverse events included 150 suicides, more than doubling the total number of suicides linked to Chantix.  

How did this happen? The FDA’s expedited review system requires drug companies to report within fifteen days adverse events that are both serious and unexpected. Less-serious and expected events are submitted quarterly, in so-called “periodic reports.” Pfizer was including suicides in the periodic reports.  

Moreover, Pfizer was lumping individual reports along with case summaries into a single text file, and these individual reports were not tabulated by the FDA.  

On 26 May of this year, the FDA sent a letter of warning to Pfizer, accusing them of a whole slew of irregularities in the company’s reporting of adverse drug experiences with respect to a wide variety of drugs. These include failure to submit adverse drug experience reports to the FDA as required, misclassifying and/or downgrading reports to non-serious without reasonable justification, inadequate written procedures for the surveillance, receipt, and reporting of adverse events… the letter goes on and on for six pages, detailing a pattern of alleged violations, many of which, the letter claims, had already been brought to Pfizer’s attention before.  

All this raises a number of disturbing questions.

Is suicide of Chantix users an “expected event?” 

And given that there is no data showing Chantix is any better than quitting cold turkey, outside of highly artificial clinical situations unlikely to be available to the average would-be quitter, why is the stuff allowed to remain on the market at all? 

And at this point, why should anybody believe ANYTHING the drug companies say?

Photo via Wikimedia Commons