FDA, Pfizer Told of Chantix Safety Concerns a Year Ago

June 12, 2008— -- A physician and top smoking cessation researcher says U.S. regulators and a drugmaker brushed aside his concerns a year ago about possibly dangerous side effects from longer-term use of the stop-smoking drug Chantix.

Now a new report from the nonprofit organization Institute for Safe Medicine Practices cites nearly 1,000 adverse event reports associated with Chantix. That report, released late last month, has prompted the Federal Aviation Administration to ban the drug's use among commercial pilots.

The report was the first time many people had heard of the possible pitfalls of a drug considered largely safe for the treatment of nicotine addiction, and for which over 6 million prescriptions have been written. The controversy over Chantix and the persistence of the complaining doctor, John Spangler, director of Tobacco Intervention Programs at the Wake Forest University School of Medicine in Winston-Salem, N.C., points up loopholes and gaps in the way drugs are declared to be safe to use in the United States. Spangler has contributed articles to ABCNews.com in the past.

Spangler as early as May 2007 raised questions over the adequacy of the long-term safety of Chantix. He raised concerns about heart and vision effects in people who took the drug for at least one year. He brought them to the attention of the medical community, the U.S. Food and Drug Administration and Pfizer, the company that manufactures the drug.

At the center of these concerns was a study that purported to record side-effects of the drug, also known as varenicline, when used for an entire year.

Spangler says the safety study by researchers employed by Pfizer and published in a relatively obscure medical journal looked at far too few subjects — a total of only 251 taking the drug — to determine whether or not the drug is safe when used over that duration.

Yet, the conclusion of the study reads, "Varenicline 1 mg BID can be safely administered for up to 1 year" — a conclusion, Spangler says, that is not supported by the data.

"[Making this conclusion] would be like me balancing my checkbook without looking at any of the checks I wrote or the deposits I made," Spangler says. "They've got to look at the data."

Furthermore, Spangler says when he analyzed the data in the Pfizer study, he found that the authors ignored possible signals of safety concerns.

"When I did the inferential calculations, I found a relationship [to serious adverse effects]," he says. "They had the data, but they didn't crunch the data at all."

The authors failed to mention that study subjects who took the drug were 2.5 times as likely to experience a serious adverse event, Spangler says. The FDA defines an adverse event as including such problems as hospitalization, a persistent or significant disability or incapacity, or congenital anomaly or birth defect.

While these serious medical events could be due to chance, the small size of the study makes it impossible to draw any firm conclusion, he added. So until a larger study of the same duration proves otherwise, medical professionals must consider the possibility that this increased risk exists.

Pfizer officials counter that even though the study concludes that it is safe to take the drug for 52 weeks straight, the package labeling suggests a course of 12 weeks to help smokers quit, followed by another 12-week course to help patients continue their abstinence.

"It is very important to separate what's in the scientific literature from what's in the label," said Dr. Ponni Subbiah, Pfizer's vice president of medical affairs. "Where [doctors] should get prescribing information is from the label."

Pfizer, like other drug companies, pays doctors to give talks and study their products. ABC News contacted two of these doctors, both of whom defended Chantix.

Mike Cummings, director of the Department of Cancer Prevention at Roswell Park Cancer Institute in Buffalo, N.Y., called Spangler's response to the Pfizer study "alarmist."

"Dr. Spangler's recommendation that varenicline should be restricted until additional objective safety data are available seems extreme to me," says Cummings.

Another doctor who received money from Pfizer, in this case to study the drug, said he sees no concerns about the safety of varenicline when prescribed according to the label. "I try to keep up with this stuff because I prescribe [Chantix]. I have not seen anything that makes me feel like something is going on here," said Dr. Joseph DiFranza, professor of family medicine and community health at the University of Massachusetts Medical School in Worcester.

The authors of the ISMP report, however, say that Spangler's concerns about Chantix should have been viewed as a "red flag" that safety questions surrounding the drug needed additional attention.

"We found a dramatic increase in the number of reported serious adverse events with Chantix," said Dr. Curt Furberg, professor of public health sciences at Wake Forest and a co-author of the ISMP report.

And even DiFranza admits that the Pfizer study published last year may have been too small and too underpowered to affirm the safety of Chantix when taken for a year.

"What [Spangler's response] says is that the study was underpowered," DiFranza says. "It means the study's too small … That's a valid point.

"I would think that the FDA would look at this and demand a larger study before approving Chantix for long-term use; I would be surprised if they were given the go-ahead to market Chantix for 12 months based on this study."

Yet, to date, the FDA has demanded no such study. Pfizer has not yet sought FDA approval to change its label to allow long-term use. But at least eight subsequent studies on Chantix — appearing in such high-level medical journals as Annals of Internal Medicine and the Proceedings of the National Academy of Sciences — have cited this study by Pfizer in support of the drug's safety for long-term use.

What Are the Risks?

Varenicline, which received FDA approval in May 2006 after being granted a priority review, has been touted as one of the most effective medicines available today to help smokers kick the habit.

Chantix helped 33 percent of smokers who used it avoid tobacco use for six months after quitting, according to a federal review of previous studies. By comparison, only 14 percent of smokers taking placebo pills were able to abstain from tobacco for as long.

The safety of the drug came into question with last month's release of the ISMP report, which found that by the last quarter of 2007, the FDA received 988 reports of serious injuries in those taking the drug.

Among the "adverse events" were 224 cases of potential heart-rhythm disturbances and 148 reports of vision disturbance.

In the commentary he submitted last year to the FDA which was also published in the journal Current Medical Research and Opinion — the same one in which the Pfizer study appeared — Spangler cited one case of cataracts and cases of heart problems in study subjects among his concerns.

"On active drug, one patient developed bilateral subcapsular cataracts (deemed to be drug related by the investigators, including the investigator who actually examined the patient); and two patients developed coronary artery disease events," Spangler's May 2007 commentary reads.

Moreover, Spangler notes that additional cardiac events were mentioned by the study's researchers — but they did not elaborate on the nature of these other adverse events.

"In this situation in particular, we're talking serious adverse events — cardiovascular events," Spangler says. "If you're putting someone on a drug that causes cardiac effects — especially if they're already at higher risk of such effects — you're doing them harm. You then have to do a risk-benefit study to see if the harm is greater than the benefit."

In addition to contacting the major medical journals, Spangler also sent several e-mails to the FDA at the time. In a May 2, 2007 e-mail Spangler outlined his concerns with the size of the study and the authors handling of their data. But it remains unclear what action, if any, the FDA took.

"The FDA has been taking a close look at the reports of adverse events that have been coming in," said FDA spokesperson Susan Cruzan. She added that any study done by Pfizer on Chantix would have had to have been sent to the FDA for review at the time that it was published, according to FDA policy regarding studies done by drug manufacturers.

Even with the new report, DiFranza says it would be premature to sound the alarm bell, particularly on a drug that he says has shown a great degree of effectiveness in helping smokers quit their deadly habit.

A spike in adverse events could be the results of lawyers soliciting for those who say they have been harmed by the drug. Plus, he adds that the rate of reported adverse events remains low, considering that 6 million prescriptions for the drug have been written so far.

And Subbiah notes that, when considered alongside other, larger safety studies that have been done on Chantix, the rates of adverse events were fairly comparable. She adds that the study is only one of numerous safety studies on Chantix, which when combined have looked at a total of more than 3,500 patients.

But last year's relatively small study is thus far the only one to look at safety in patients taking the drug for a year. And Spangler says his biggest concern is how this study is being used.

"I think it reveals that it is easy to put studies in low-level journals and say something just wrong, not true, that has no statistical basis whatsoever or scientific basis whatsoever," he notes. "The authors were making a false claim that was not justified by the data that had been published under the title of long-term safety."

And he says that the lack of response to his concerns by Pfizer and the FDA underscores what could be a hidden public health threat when it comes to drug safety.

"It turned out my only recourse was a letter to the editor in an obscure journal with no press coverage," Spangler says. "It's wrong, because I turned out to be right.

"There needs to be some way for the dissenting voices to be heard and for the FDA to respond much more proactively."