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FDA Oncology Committee Debates Iressa's Status Following Negative Trial Results

Renee Twombly

Serious questions about the fate of the lung cancer drug Iressa (gefitinib) were asked last month when the U.S. Food and Drug Administration's Oncology Drugs Advisory Committee (ODAC) met for the first time since the drug's maker AstraZeneca announced that Iressa, the first targeted cancer therapy to receive accelerated approval, failed its phase III randomized, placebo-controlled confirmatory survival trial.

Because a complete analysis of the data from that 1,692-patient trial, including an examination of patient subgroups that appeared to respond to the drug, was not yet available, the focus of the meeting was narrowed to a discussion of whether AstraZeneca provided "transparency of process" by adequately informing physicians and patients about the results. With only one negative vote, the committee agreed that the company had communicated promptly and thoroughly. "I got more notice about this drug than I have credit card applications," said committee member Michael Perry, M.D., from the University of Missouri. "I can't think of another time in my practice when I was inundated with information about a negative outcome."

Some committee members as well as FDA staff discussed whether new labeling restrictions are needed to spell out to physicians that a rival drug, Tarceva (erlotinib), has shown a survival benefit in the treatment of non–small-cell lung cancer. Citing the side effects of Iressa and its high cost, committee member Maha Hussain, M.D., from the University of Michigan, said it was "unethical to keep it available for people who are not likely to benefit." Those patients should be prescribed "the stuff that works," she said.

FDA officials at the committee table seemed to agree, acknowledging that revising Iressa's packaging insert to reflect the fact that new patients should be given Tarceva is being discussed within the agency. The issue of whether Iressa is being prescribed for new patients is "where we feel very uncomfortable," said Richard Padzur, M.D., director of the FDA Division of Oncology Drug Products.



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AstraZeneca announced in December that Iressa (gefitinib) did not improve survival in a phase III randomized trial. So far, the U.S. Food and Drug Administration has taken no further action on the drug.

 
A labeling change "doesn't force doctors to make a decision one way or the other, but [it] encourages them," said Robert Temple, M.D., director of the FDA Office of Medical Policy. But acting ODAC chair Silvana Martino, D.O., from the University of Southern California, resisted such a move, suggesting it was coercive. "How do you sit in my office and look over my shoulder?" she asked.

The committee also discussed the implications of the data that AstraZeneca presented at the meeting. In December, the company reported that preliminary data from the treatment arm of the Iressa Survival Evaluation trial failed to show a statistically significant survival benefit (5.6 months) compared with placebo (5.1 months), but briefing documents given to ODAC shortly before the March meeting said that statistical significance could be reached if a different statistical analysis had been used. The company also said that unvalidated secondary endpoint data of objective response rates and time to treatment failure suggested significant improvements in Asian and nonsmoker subgroups.

Temple called this analysis "post hoc" and said he was "worried about what AstraZeneca was telling people." But others on the committee argued that the trial barely missed statistical significance, and that the drug clearly works for some patients, an observation that was echoed by three of four public speakers who addressed the committee to support Iressa.

Peter Lurie, M.D., deputy director of the consumer watchdog group Public Citizen's Health Research Group, said that Public Citizen had just filed a petition asking FDA Commissioner Lester Crawford, D.V.M., Ph.D., to permanently remove the drug from the market. Lurie pointed out that Iressa had failed in two mortality endpoint studies even before being granted accelerated approval and that it has now failed a third such study. "If ever there was a drug that was eligible for removal from the market under Subpart H [the accelerated approval program], this is it," said Lurie. Not to do so "would make an absolute mockery" of the program, he said.

Committee member Otis Brawley, M.D., from the Emory University School of Medicine, expressed contrition, saying that the FDA and ODAC got themselves into the "pickle" they are in today and that patients are owed an apology.

"The development of this drug has been mishandled by AstraZeneca and mishandled by this committee," said Brawley, who acknowledged that he had voted for approval 2 years ago. "The fact remains that this drug has been available for 7 years and we still haven't figured out how this drug should be used in the treatment of lung cancer," he said. "Perhaps if we had held off getting it available to patients 2 or 3 years ago, those studies would have been done."



             
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