On September 29, 2006, Pfizer issued a press release announcing European Commission approval of Champix, its new quit smoking pill. It boasts that "after one year, approximately one-in-five patients who received the 12-week course of varenicline [Champix] remained smoke-free."
What we do not know is whether Champix's modest 1 in 5 success rate is attributable to the effects of Champix, to the 16 clinical counseling sessions participants received, to the use of nicotine replacement therapy (NRT) following 12 weeks of Champix use, or to the fact that more than 1,000 hard to treat smokers who would likely have generated substantially higher failure rates were denied participation. What we do know is that Pfizer's clinical Champix studies were not blind as claimed.
Understandably, Pfizer wants to assign full credit for the results from its five varenicline studies to Champix. Understandably, it wants smokers to believe that, as in its clinical studies, 1 in 5 who purchase Champix will succeed. But if cessation pharmacology history teaches any lesson it is that clinical studies are engineered for victory, and unless real-world users can find a way to duplicate study engineering they should expect to experience dramatically lower success rates.
Champix's active chemical is varenicline. On May 11, 2006 Pfizer gained FDA approval to market varenicline in the U.S. as Chantix. Interestingly, the FDA refused to approve Pfizer's use of the name "Champix" asserting that from a promotional perspective, "it is overly fanciful and overstates the efficacy of the product" (PDF page 148).
Pfizer's five clinical trials of varenicline were published in July and August 2006. Three are comparable in that they involved a 12-week treatment period using 1mg of varenicline twice daily. The study headed by Gonzales produced a 21.9% one year Champix quit smoking rate, in Oncken the rate was 22.4% and in Jorenby 23% - an average of 22%.
But these rates were achieved under highly artificial clinic study conditions. Pfizer spared no expense in creating one of the most intense clinic quitting experiences in any smoking cessation study ever. Real-world quitters, alone with their Champix pills, or even participating in Pfizer's GetQuit support plan, will be fighting under entirely different battlefield conditions.
Varenicline study participants received a free 12-week supply of Champix, were reimbursed travel expenses associated with visiting their health provider to obtain it, attended 16 clinic visits involving one-on-one sessions lasting up to 10 minutes, with counselors trained in motivation and coping skills development, and received 8 follow-up telephone support calls from their provider.
The Impact of Motivation, Counseling and Support
How much of Champix's 22% one-year quitting rate is due to Champix and how much attributable to the 26 times in the Jorenby study that participants spent quality one-on-one time with their Champix provider, either in person or over the telephone?
Evidence tables in the June 2000 U.S. Tobacco Cessation Guideline combine and average similar smoking cessation studies and provide estimated six-month abstinence rates for a host of quitting methods and conditions. For purposes of comparison, varenicline's six-month rates were an identical 29.7% in both the Gonzales and Jorenby studies and involved up to 160 minutes of counseling time (10 minutes x 16 sessions) plus an additional 8 telephone calls of unknown duration.
Table 13 of the U.S. Guideline examines the impact of program contact time on cessation rates. It combines 16 different study arms and concludes that programs involving 91 to 300 minutes of total contact time should be expected to generate an average six-month quit smoking rate of 28.4%.
The only way smokers will ever know how much of varenicline's 29.7% six-month rate should actually be credited to Champix is for Pfizer to design and conduct studies which make varenicline stand on its own, without substantial contacts, counseling or ongoing support. Such studies were conducted when the nicotine patch and gum went from being prescription quitting aids to over-the-counter products.
A 2002 study by NRT pharmaceutical industry consultants combined and averaged the seven over-the-counter nicotine patch and gum studies and found that just 7% were still not smoking at six-months - a 93% six-month relapse rate. Although a well-kept industry secret, the one-year OTC NRT rate is likely a bit less than 5%. Yes, a 95% failure rate and near 100% failure for second time users.
Contrasting Early NRT Studies
Compare the over-the-counter patch and gum's approximately 5% one-year rate with rates generated in early nicotine gum studies which, like Pfizer's Champix studies, were often loaded with education, counseling and support elements.
Varenicline's 22% one-year rate is actually lower than the 1976 nicotine gum study headed by Russell in which 23% were still not smoking at one year. It also fails to measure up to the 1980 Raw study which produced a whopping 38% one-year rate, to the 1982 Jarvis study's 31%, the 1983 Schneider study with 30%, the 1984 Hialmarson study at 29%, the 1986 Daughton study at 31%, the 1987 Kornitzer study at 32%, or the 1989 Tonnesen study which boasted a 44% one-year quit smoking rate.
Diverse Study Site Evidence
Online FDA varenicline documents raise serious concerns that factors other than Chantix or Champix impacted performance. The Medical Review shows striking contrasts at a number of study sites in four week continuous quitting rates (CQR) during the final weeks of varenicline treatment, weeks 9 to 12.
At the University of Massachusetts Medical School, 46% of the 22 member placebo group were still not smoking at 12 weeks compared to 50% for the 22 member varenicline group. Hardly an impressive victory. New York's Medical and Behavioral Health Research witnessed 35% of the 17 member placebo group still smoke-free at 12 weeks compared to only 6% of the 16 member varenicline group.
Did counseling sessions at these study sites place greater emphasis on front-end quitting tips such as the importance of stabilizing blood sugar, overcoming time distortion, handling alcohol, understanding elevated blood serum caffeine levels, and recognizing emotional loss? Would doing so have allowed a far greater percentage of placebo group members to successfully navigate the up to three days needed to rid their body of all nicotine and endure the worst of withdrawal?
Did sites generating dismal placebo group rates fail to counsel participants on the fact the reason they could skip meals while still smoking and not experience wild blood sugar swings is because nicotine was their spoon, with each puff pumping stored fats and sugars into their bloodstream?
Were placebo group counseling concerns totally ignored at Tulane University where 0% of 8 placebo group members were still not smoking at 12 weeks, in San Francisco where 0% of 10 survived, in central Kentucky with 0% of 12, and at the University of Mississippi with 0% of 9?
What possible explanation is there for the tremendous diversity in 12-week quitting rates among Champix users? In Brooklyn only 18% of 12 varenicline users were still smoke-free at 12 weeks, at New York's Central Park just 6% of 16 remained quit, and in Jackson, Mississippi only 14% of 15 were still healing.
On the flip side, Champix users did amazingly well at the University of Nebraska where 67% of 18 users were still free at 12 weeks, at Newport Beach, California where 64% of 28 remained quit, at Palo Alto with 69% of 13, and the Mayo Clinic with an amazing 81% of 21 users were still standing.
Did counselors at some sites strongly encourage Champix users to endure and persevere through medication side effects while counselors at other sites were not as persistent?
Adverse events among the 692 varenicline users in the two identical studies (Jorenby and Gonzales) included 199 participants reporting nausea, 51 reporting flatulence, 50 with constipation, 81 reporting abnormal dreams, and 36 reporting sleep disorders. Did symptoms contribute to researcher awareness of participant group assignment and failure of the study's blind?
Were counselors at some clinical sites - such as the Mayo Clinic -- better trained than others? Were their backgrounds primarily in pharmacology cessation counseling or in behavioral cessation counseling? How will Pfizer's boast of a 1 in 5 Champix / Chantix one-year success rate be affected by the fact that almost all real-world quitters will use it without the benefit of sixteen one-on-one counseling sessions?
Nicotine Replacement Therapy Use During Champix Studies
The brain's dopamine pathways not only produce a neurochemical "aaahhh" reward sensation surrounding species survival events such as eating, drinking, reproduction and accomplishment but also generate powerful and salient reinforcing memories that ensure we return for more.
But by happenstance the nicotine molecule fits the brain's nicotinic type acetylcholine receptors responsible for generating dopamine. Chronic nicotine use causes the brain to fight back and attempt to diminish nicotine's impact by growing or activating millions of extra acetylcholine receptors in at least eleven different brain regions - a process known as up-regulation.
The larger receptor playing field creates a tolerance cycle of escalation in which the smoker often must gradually use more nicotine in order to overcome additional brain up-regulation and de-sensitization. Any attempt to quit using nicotine will briefly leave the dependent user de-sensitized during the brief period of time needed for the brain to down-regulate and restore natural receptor counts.
The theory behind NRT was that it allowed dopamine flow to continue while buying the smoker time to extinguish psychological nicotine feeding cues and conditioning. Its downfall has been that, outside of extremely supportive clinical studies, few quitters have the self-discipline and motivational stamina needed to engage in a lengthy period of gradual stepped-down withdrawal on their own.
Dismal real-world NRT success rates have resulted in the industry actually blaming quitters for not using it properly. But proper use often results in the quitter getting hooked on the cure. In 2004 GlaxoSmithKline consultants noted that nearly 40% of nicotine gum users are dependent upon it, or, as the consultants like to put it, they've become "persistent users."
A May 2005 study found that varenicline causes alpha4 beta2 type acetylcholine receptors to produce 30 - 60% of the dopamine flow that nicotine would produce if sitting on the same receptor site. Not only does this raise ongoing nicotine-type dependency concerns, which Pfizer asserts only impact about 3% of users [Note: 2006 archived WayBack document for historical reference only], but concerns over permitting NRT use during varenicline studies once the 12-week treatment period was complete.
Although Pfizer's studies acknowledge keeping records of nicotine use during the 40-week post-treatment monitoring period, that data has not yet been made part of the public record at the FDA. As stated in the Oncken study, "During the follow-up period, use of nicotine replacement therapy did not disqualify subjects from being considered abstinent."
The obvious question becomes, what percentage of the 1 in 5 of Champix users reported as have successfully quit for one year were still chemically dependent upon nicotine? In that almost all varenicline users will purchase Champix or Chantix with the goal and dream of breaking nicotine's grip upon their mind and life, do they have a right to know the actual percentage that Pfizer counted as success stories, who were in reality still solidly hooked?
Champix and Chantix's real-world performance rates are likely to be further eroded by the fact that a substantial percentage of difficult to treat smokers applied to participate in each study but were denied. In Gonzales 1,843 smokers were screened and 458 were excluded (25%), in Oncken 980 were screened and 333 excluded (34%), and in Jorenby 1,413 were screened and 386 excluded (27%).
Excluded from participation were those suffering from cardiovascular disease, alcohol abuse, major depression, panic disorder, systolic blood pressure greater than 150 or diastolic pressure greater than 95, a history of cancer, a body mass index (calculated as weight in kilograms divided by height in meters squared) of less than 15 or higher than 38; weight less than 45kg, those with a "clinically significant medical disease," those over age 75 or younger than age 18, those smoking fewer than 10 cigarettes per day, and those known to have recently relapsed during NRT or Zyban/Wellbutrin quitting attempts.
Most within these groups reflect populations that have historically been extremely challenging to assist in quitting, including youth who often smoke fewer than ten per day. Real-world conditions will not bar them from using varenicline.
Their use of Champix or Chantix has not yet been studied and we have no idea how their status and conditions will impact outcome. What we do know is that their exclusion from Pfizer's studies has likely resulted in a significant overstatement of varenicline's true one-year effectiveness.
European Commission and FDA Must Demand Solid Science
Will government medicine approval authorities continue to allow pharmaceutical companies to design and conduct chemical studies guaranteed to produce clinical efficacy but which result in approval of products that in real-world use perform no better than quitting without them?
The FDA and European Commission knew or should have known that both NRT and varenicline studies were not blind as claimed, and that resulting odds ratio victories have little or no foundation in science. Instead of exposing known blinding failures they remain quiet and allow horribly flawed science to be used to exploit the dreams of smokers dying to break free.
Nicotine is a psychoactive chemical producing a powerful dopamine/adrenaline high. Those addicted to it are dependent upon prolonged dopamine aaahhh" reward sensations accompanied by central nervous system stimulation. It gets the heart pounding faster, their senses perked, their fingers and toes growing cold, and energizes the addict as nicotine causes the release of stored fats and sugars into the bloodstream.
Smokers who have attempted quitting know what their withdrawal syndrome feels like - a rising tide of anxiety which breeds irritability, impatience, anger and depression. They joined NRT and varenicline clinical studies after being promised the "chance" of receiving free medicine, which they hoped would diminish their withdrawal syndrome.
Pfizer's studies indicate that eighty to ninety percent of varenicline study participants had attempted quitting at least once previously and failed. In the case of both NRT and varenicline, the expectations of withdrawal syndrome reduction were frustrated by assignment to the placebo group, or fulfilled by assignment to the active group, with the arrival of nicotine or varenicline in the brain.
A June 2004 study by Mooney reviewed 73 allegedly double-blind NRT studies and declared that the limited number of studies assessing blindness were not generally blind as claimed in that "subjects accurately judged treatment assignment at a rate significantly above chance."
Mooney warned researchers that, "to determine the prevalence of failure, clinical trials of NRT should uniformly test the integrity of study blinds. Moreover, if blindness failure is observed, subsequent efforts should be made to determine if blindness failure is related to study outcome and, if so, to provide an estimate of treatment outcome adjusted for blindness bias. Without these methods and analyses, the validity of NRT clinical trial results could be questioned."
Were blinding studies conducted in association with any of Pfizer's five varenicline studies? If so, the results have not yet been made public. Using Mooney's warning, smokers have legitimate reason to question the core validity and integrity of Pfizer's five studies.
The blinding analysis in a 2005 study by Dar found that 3.3 times as many placebo group members correctly guessed that they had received placebo (54.5%) as guess nicotine (16.4%). Although the Dar study focused on smoking reduction, Tonnesen's 1993 nicotine inhaler quitting study produced strikingly similar placebo group findings with 3.8 times as many in the placebo group correctly guessed placebo (58%) as guessed nicotine (15%). Among inhaler users, Tonnesen found that 3.5 times as many correctly guessed inhaler (46%) as guessed placebo (13%), while 42% on active and 27% on placebo did not know which treatment they had received.
The FDA and European Union knew that placebo group expectations and frustrations in NRT studies are identical to those experienced in varenicline studies. They sought some degree of reduction in their withdrawal syndrome and none occurred. It was no secret to Pfizer that roughly 80% of the placebo group would relapse within two weeks, handing the active group victory by default.
Smokers join clinical studies in hopes of receiving promised medications that result in withdrawal symptom reduction. Their expectations differ from the 80 to 90% of annual quitters who attempt quitting cold turkey, who fully expect to sense and navigate withdrawal.
It is an important distinction because government authorities continue to turn their heads while Pfizer proclaims to smokers that its nicotine replacement products competed against and defeated cold turkey quitters. Those wanting to quit cold turkey were never invited to clinical NRT studies. The representation is false and extremely deceptive.
Although it may be impossible to randomize alternative expectations of fully enduring or dramatically diminishing physical nicotine withdrawal, the pharmaceutical industry can and should recruit and fully serve both expectations from the same general population when conducting clinical studies. Subgroups with similar traits could then be compared and odds-ratio victories would at last have some validity. If education or counseling is to be included we must accept the variance that its intensity, duration, focus and content should be tailored to each group's differing cessation needs.
But pharmaceutical industry financed studies will likely never pit "real" cold turkey quitters against those wanting to sense a diminished withdawal syndrome as the expected results would likely destroy more than one golden goose.