In its Annual Report to the Nation On the Status of Cancer, the NIH highlighted progress made on many fronts as cancer death rates continue to decline for women, men and children. While that’s good news, there’s still a lot of room for improvement, particularly with respect to lung cancer. Cigarette smoking is the driver for 90% of lung cancer diagnoses. Furthermore, as highlighted by the Centers for Disease Control and Prevention, smoking is also implicated as a cause for a dozen other cancers, including cancer of the esophagus, mouth and larynx. Getting people to quit smoking continues to be a national health priority.
There are drugs available to help smokers quit, most notably Pfizer’s Chantix (generic name varenicline), a nicotine partial agonist. Clinical studies with this drug showed that, after twice-a-day dosing for 12 weeks, half of patients on Chantix were able to stop smoking; 12 months later, half of those patients remained cigarette-free. The FDA approved this drug in 2007 and by the end of the year more than five million patients had taken it. However, routine post-marketing safety reports revealed that a small number of patients showed signs of neuropsychiatric symptoms including agitation, depressed mood, suicidal ideation and suicidal behavior. As a result of this information, the FDA slapped a black-box warning on the Chantix label to heighten the awareness of these potential side effects and to ensure that doctors closely monitor patients during Chantix treatment. Not surprisingly, new Chantix prescriptions dropped.
Ordinarily, this would be the end of the story. However, in early 2015 a paper appeared in the BMJ which indicated that Chantix’s neuropsychiatric adverse effects might be overstated. This study, a systematic review and meta-analysis of 39 randomized clinical trials with 10,761 participants, found “no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression or death with varenicline.” The authors did acknowledge that the drug could cause insomnia and abnormal dreams, side effects that were already well recognized.
As might be expected, Pfizer went back to the FDA to get the Chantix label changed. However, the FDA left the warnings about suicidal behavior and other psychiatric side effects unchanged. Part of its rationale was that meta-analyses are observational in nature and can at times be confounding. But, what the FDA really desired before ruling on this issue were the results of a clinical trial called EAGLES. This trial, which the FDA recommended and had a hand in designing, was intended to answer the suicidality issue not just for Chantix but also other smoking cessation products like GSK’s Zyban (bupropion) and the nicotine patch.
The results of the EAGLES trial are now available and the findings should provide comfort to those looking to quit. EAGLES enrolled 8,144 smokers who were equally divided into two groups: those with preexisting psychiatric disorders and those without. For 12 weeks they were treated with either a placebo, a nicotine patch, Zyban or Chantix, then they were followed up for another 12 weeks. The researchers found that, for those without psychological problems, moderate to severe side effects were found in 2.4% on placebo, 2.5% on the nicotine patch, 2.2% on Zyban and 1.3% on Chantix. Those with psychological problems experienced higher rates of neuropsychiatric side effects: 5% on placebo, 5.2% on the patch, 6.7% on Zyban and 6.5% on Chantix. Consistent with previous results, Chantix was more effective than the other treatments in getting smokers to quit. The authors concluded that there was no “significant increase in neuropsychiatric disorder events attributable to varenicline or bupropion relative to nicotine patch or placebo.”
So, what happened to the earlier fears about increasing suicidal tendencies with Chantix? Post-marketing safety reports are especially important when a new drug is launched, as far more people are likely to be prescribed a drug once it is marketed than are able to be studied in clinical trials. This early monitoring is important as more patients get exposed to a new drug. But false positives can also be found using such surveillance. When statins were first launched, the FDA required periodic tests to monitor liver function as there was a potential worry about the impact of statins on the liver. Over the years, that worry proved unfounded and such tests are no longer required. This is a similar situation. As data are accumulated, more is understood about the risk-benefits of a new medicine and its use can be modified as needed.
Despite the fact that the EAGLES trial was rigorously designed in conjunction with the FDA, not all find the study convincing. Thomas Moore, a senior scientist with the Institute of Safe Medicines Practices, had this to say about EAGLES:
It would be a mistake to claim this study proves that severe psychiatric effects don’t occur with Chantix….Given that this is a manufacturer-sponsored study conducted in 140 centers in 16 countries, it would benefit from an independent event review.
Moore’s comments are unfortunate. He implies that studies sponsored by a manufacturer should be viewed with suspicion. The vast majority of clinical trials are, in fact, sponsored by manufacturers, including all of those that have failed, such as studies in Alzheimer’s disease, heart disease, etc. No one seems to question manufacturer sponsorship when drugs fail. To attack EAGLES for this reason is insulting. Furthermore, all of the data from EAGLES will be submitted to the FDA for their independent and in-depth review.
There continues to be a big debate about the cost of new medicines, particularly breakthrough cancer therapies. Of course, one can avoid such expensive medicines by preventing this disease in the first place. A month of Chantix treatment costs a mere $300, or less than $1,000 per full course of therapy. This is a small price to pay to reduce the incidence of lung cancer as well as the other cancers caused by smoking.
By removing the black box label for Chantix, the FDA will encourage the broader use of this drug and enable more and more people to quit. It is an action that needs to be taken.
(The author is the former head of Pfizer R&D.)
