Linda Ware wanted to stop smoking. Two years ago, she went to her doctor to get help, and began taking a new prescription medication aimed at fighting nicotine addiction: Chantix. She experienced hallucinations a few days later.
While driving in a remote area with her cousin she saw a vision of a sign in the distance that read, “God is in the realm.” Ware suddenly pulled off the side of the road, commanding the cousin to get out of the car. Then, just as abruptly, she broke out in laughter.
Although Ware suffered from depression, her daughter, Cary Ussery, said she had never acted like this. The next day a family friend found her slumped in front of her bed with a suicide note by her side. At the age of 57, Ware, a real estate agent from Cypress, Calif., overdosed on a lethal combination of pills.
Tragedy has plagued Chantix ever since it was approved in May 2006, even as the drug has helped some smokers kick the habit. By mid-2009, the U.S. Food and Drug Administration had received reports of nearly 100 suicides, 200 attempted suicides and close to 5,000 serious psychiatric events overall. Hundreds of reports of side effects have continued to stream in this year.
A review of the drug’s history shows that Pfizer Inc., the giant pharmaceutical company that makes Chantix, failed in its years of clinical trials to test the product on the mentally ill or those with a recent history of depression – even though millions of smokers suffer from psychiatric problems. Moreover, FDA regulators approved Chantix after a speeded-up “priority review” process, and did not request a follow-up study on mentally ill patients using the medication, even though the agency’s own safety reviewer reported that the exclusion of such smokers may have undermined the clinical trials.
It wasn’t until three years later, after thousands of reports of serious side effects, that the FDA told Pfizer to conduct trials including people with a history of mental illness. The agency then also slapped a so-called black box warning, the FDA’s strongest alert, on the medication.
The controversy over Chantix’s side effects, particularly for smokers with mental health issues, has triggered a torrent of lawsuits. About 1,000 such cases have been filed in federal court, and plaintiffs' lawyers say they anticipate bringing forward more than 1,000 additional suits. Plaintiffs in more than half of the cases claim the drug led to suicides or suicide attempts, and many say they suffered psychosis, blackouts, aggression, diabetes or other problems. No cases have yet been tried or settled.
The plaintiffs' lawyers argue that Pfizer, the world’s largest pharmaceutical company with sales this year of more than $60 billion, neglected to test Chantix adequately before its release, deliberately hid evidence of the drug’s potentially serious side effects and failed to sufficiently warn consumers about its risks.
Pfizer, for its part, defends Chantix and says it “acted responsibly and appropriately at all times in connection with the development, approval, and marketing” of the drug. The FDA, likewise, says it acted properly in approving the drug, despite the problems that emerged after it went on the market.
“The agency does not feel any mistakes were made,” said FDA spokeswoman Sandy Walsh. “We can never speculate as to what may happen with a drug once it goes into widespread use after approval.”
The FDA’s failure at the outset to require Pfizer to include the mentally ill in its research, however, points to a potentially serious flaw in the agency’s practices for regulating the safety of medications for these particularly vulnerable consumers. Although the mentally ill commonly are excluded from drug clinical trials, they account for a disproportionate number of smokers and are a key part of the target market for smoking cessation treatments.
Their exclusion leaves experts such as Dr. Karen Lasser, a Boston University researcher who has studied the link between mental illness and smoking, baffled. “You need to think about who is going to be taking the drug,” she said.
Back when Chantix was approved, Pfizer officials figured they had a potential major new star in their company’s portfolio. With nearly 70 percent of the estimated 45 million smokers in the U.S. hoping to quit, the market appeared to be vast. Sales quickly zoomed to $883 million in 2007, which turned out to be the drug’s peak year. (During the first nine months of this year, sales totaled $522 million.)
Chantix, which is sold as a pill, works by taking the pleasure out of smoking by interfering with the way nicotine ordinarily affects the brain. At the same time, it spurs the release of dopamine, which helps control the brain’s pleasure centers the way smoking usually does.
Pfizer launched the marketing of Chantix with a news release spotlighting the dire statistics on quitting smoking – less than 7 percent of smokers who try to quit on their own make it past the one-year mark. In contrast, clinical trials showed that about 22 percent of Chantix users who took the drug for three months were able to abstain from smoking for a year or more.
Other studies have demonstrated that Chantix has helped some smokers, but often is no better than other options for quitting. For instance, a study published in in the journal “Thorax” in 2008 showed that Chantix works better than the nicotine patch for some people, but not for others. Other researchers have concluded that nicotine gum is just as effective as Chantix.
Still, experts such as Lirio Covey, a professor of clinical psychology at Columbia University who worked on early studies of Chantix, say the FDA’s approval of Chantix made sense. “Some people really have a hard time stopping smoking. Chantix does have some utility,” Covey said. “I would say that it’s a pretty good drug, but it’s not the first resort” for treatment.
For Covey, who said she has received close to $80,000 from Pfizer this year to study the effects on mood of smoking cessation, the key facts are these: millions have taken Chantix to stop smoking, and the number of people who suffered severe side effects is relatively small. In her estimation, the benefits of the drug outweigh the risks. She also said it’s still not clear if the side effects are the result of the drug or nicotine withdrawal.
But questions about why Chantix’s safety wasn’t fully evaluated extend back at least to May 2006, when the FDA’s safety reviewer for the drug, Dr. Howard Josefberg, submitted his report to the agency. He endorsed approving Chantix, but found that Pfizer’s clinical trials may have been “too carefully screened.” He noted that the studies excluded people treated for depression over the previous 12 months as well as “those with histories of panic disorder, psychosis or bipolar disorder.”
“The patient population studied, then, may not represent the true target population should varenicline be approved,” added Josefberg, using the generic name for Chantix.
The routine exclusion of mentally ill subjects from clinical trials, researchers say, is justified in certain cases. Sometimes the subjects are too sick to consent to participate. Mentally ill patients may also fail to follow the proper dose regimens or other instructions. In addition, including people with mental or other health problems in drug research can complicate evaluating the results of a medication.
Yet many experts argue that excluding the vast numbers of Americans who are mentally ill from the trials leaves in doubt the real world effects of drugs on many people who may be vulnerable to a medication’s side effects. According to the National Institute of Mental Health, 26 percent of Americans 18 and older, or close to 60 million people, suffer from a diagnosable mental disorder in a given year. About 6 percent suffer from a serious mental illness.
Beyond that, the mentally ill account for a big proportion of American smokers. A report this spring from the U.S. Centers for Disease Control and Prevention found that 43 percent of adults with depression smoke, versus 22 percent of other adults.
Raymond Lorenz, the author of a recent paper on Chantix and the mentally ill and a faculty member at Auburn University’s pharmacy school, said more research is needed to gauge the risks that psychiatric patients face when they take the medication. Still, he wrote that excluding the mentally ill “seems to be a glaring oversight” in Pfizer’s trials before the FDA approved Chantix.
The FDA could have, but didn’t, ask Pfizer to conduct additional research – in this case, research including mentally ill smokers – immediately after Chantix was approved. The agency sometimes does that as a compromise, to ensure that medications reach patients without extra years of delays, while keeping an eye on a drug’s side effects after it comes into widespread use.
By late 2007, the parade of Chantix warnings and restrictions by federal authorities had begun. That November the FDA issued a warning that some patients taking Chantix reported having suicidal thoughts. Two months later, the agency ordered revised labeling indicating that Chantix’s safety for mentally ill patients was not established. Other federal agencies also took action, including the Federal Aviation Administration, which banned pilots and air traffic controllers from using Chantix.
Finally, in July 2009, the FDA came around to fully embracing testing Chantix on the mentally ill. “There is a disproportionate amount [of them] that smoke and they would be potentially exposed to this drug,” said Dr. Curtis Rosebraugh, an FDA drug evaluation official, in a media briefing. "We have no idea if that subgroup population is at higher risk or not and so we do want to get some sense of that.”
People like Brandon Campbell, though, already have a first-hand sense of the risks. About three years ago, Campbell, 33, an information technology technician at Duke University Hospital, gave Chantix a try after enrolling in an employee wellness program to quit smoking. Though Campbell had a history of depression, at the time there was no indication that the safety of the drug had not been established in people like him. Soon after finishing a course of treatment, Campbell said, he experienced severe symptoms, including thoughts of suicide.
This summer, Campbell said, he sat in his garage in Durham, N.C., with the doors shut tight and the car running, hoping to die from carbon monoxide poisoning. Then the cops started beating on the door, and he was rushed to the hospital. Still a smoker, Campbell would like to quit, but is wary of using a pharmaceutical drug again. “It’s like playing Russian roulette,” he said.