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F.D.A. Panel Endorses Inhaled Form of Insulin
  NY Times
Sept 9, 2005
The first inhaled form of insulin, a product that could reduce or eliminate the daily injections needed by millions of diabetics, moved closer to federal approval yesterday.
An advisory panel to the Food and Drug Administration voted 7 to 2 to recommend approval of the drug for adults with either Type 1 or Type 2 diabetes, despite some concerns about the long-term effect that inhaling insulin would have on users' lungs.
The product, called Exubera, was developed by Pfizer in partnership with Sanofi-Aventis of France and Nektar Therapeutics, a California biotechnology firm.
The full F.D.A., sensitive to criticism in the last year that it has been lax on drug safety, is still to rule on approval. The agency often, but not always, follows the advice of its advisory committees, which are made up of outside experts.
Because Exubera is a novel product that would be taken for years, it is conceivable the F.D.A. would ask for more data before approval, especially given the questions about its effect on the lungs and the fact that Exubera's advantage over injected insulin is mostly convenience. Data presented by Pfizer showed that Exubera was equivalent to injected insulin in controlling blood sugar, but not superior.
Pfizer and its medical consultants argued that approval of Exubera could enhance public health by encouraging more people to use insulin, which would improve control of their blood sugar. Keeping blood-glucose levels down has been shown to reduce long-term complications of diabetes like cardiovascular problems and kidney disease.
"There's resistance to use of insulin," at least partly because people fear injections, said Dr. William T. Cefalu, a professor at Louisiana State University who spoke on behalf of Pfizer. Fewer than a third of people with Type 2 diabetes use insulin, he said, but many more could benefit because two-thirds of diabetics do not control blood glucose as tightly as experts recommend.
Some 18 million Americans are estimated to have diabetes, although several million of them may not know it. At least 90 percent have Type 2 diabetes, which is often associated with obesity and usually begins in adulthood. The others have Type 1, formerly called juvenile diabetes.
Exubera would be inhaled from a device about the size of a flashlight that creates a cloud of powdered insulin. It would be taken at mealtimes and could replace the short-acting insulin typically injected then. But some diabetics would still need an injection of long-acting insulin at night or in the morning.
Rebecca W. Killion, a patient advocate on the advisory committee, said she took four injections of insulin a day and would be "thrilled" to cut it to one. "The siren call of that is almost irresistible," she said of inhaled insulin.
Still, Ms. Killion and many other panel members, as well as the F.D.A. staff, had many questions about the long-term safety of the drug.
Pfizer's application to the F.D.A. was delayed at least two years so that the company could conduct more safety studies after patients in earlier clinical trials experienced a small decline in lung function compared with those in the comparison group. The company also stopped testing the drug in children, with the result that Pfizer is not currently seeking approval for children's use.
The company said yesterday that after further study, the decline in lung function did not continue after several months and was not medically significant.
The advisory panel, made up largely of endocrinologists and pulmonologists, backed that finding in cases of people with healthy lungs. But in response to a question by the F.D.A., the panel voted 5 to 4 that safety had not been established for patients with lung diseases.
Oher questions involved whether patients would be able to use the device properly. "I am not at all convinced that the company has adequately thought out the training program," said the chairman, Dr. Paul D. Woolf, an endocrinologist at Crozer Chester Medical Center in Upland, Pa., who voted against approval.
Taking the drug will be somewhat complicated. Only about 10 percent of the inhaled insulin makes it into the bloodstream and the amount can vary depending on the patient's health and inhalation technique.
Inhaling three one-milligram packs of Exubera in succession produces a different effect than using one 3-milligram pack. Smokers tend to absorb several times as much drug into their bloodstream as nonsmokers. For that reason, Pfizer proposes that the drug not be approved for smokers. Some panel members urged more study on blood levels in those exposed to secondhand smoke.
Still, Pfizer and some committee members said patients could learn to use the device, as they have learned to use syringes and insulin pumps. Pfizer said that if the drug was approved, it would undertake various studies to detect side effects.
Analysts have estimated that Exubera sales could easily exceed $1 billion within a few years. Others are also developing inhaled insulin. Closest behind is Eli Lilly & Company, working with the biotechnology company Alkermes. Others include Novo Nordisk, the Danish insulin manufacturer, and MannKind, a California start-up. But Pfizer appears to be at least two years ahead of competitors.
After the panel voted to recommend approval, Pfizer shares closed yesterday at $26.51, up 21 cents. Sanofi fell 58 cents, to $41.37. Trading of Nektar, which initially developed the inhaled insulin, was halted.
Today, the advisory panel will discuss Pargluva, a pill for Type 2 diabetes developed by Bristol-Myers Squibb and Merck. A central concern of the F.D.A., according to documents released yesterday, is evidence suggesting that the drug can cause heart problems.
"It was shown to be as effective as current therapy, and it's an important new modality that will probably help some patients comply better" with treatment recommendations, said Talmadge King, a panel member who is a professor at the University of California at San Francisco. Rebecca Killion, a patient representative on the panel, said diabetics will find the new option appealing as an alternative to needles.
But the panel raised concerns about the effects on the lungs, voting 5-4 that Pfizer hadn't offered enough data to assess the safety of Exubera for patients with lung conditions such as asthma and chronic obstructive pulmonary disease. The drug was linked to a small reduction in lung function and to side effects that include coughing. James Stoller, a pulmonologist at the Cleveland Clinic, said he voted against Exubera because labeling wouldn't be enough to prevent patients with lung conditions from taking it. "There are many patients with these diseases in whom they are not diagnosed," he said.
The committee's chairman, Paul Woolf, an endocrinologist at the Crozer Chester Medical Center in Upland, Pa., voted against Exubera's approval because he "was not at all convinced that the company has adequately thought out the training program" to ensure patients take Exubera correctly.
The vote will be viewed as a reassuring sign that a drug without significant new treatment benefits -- Exubera simply replicates the effects of already-available insulin options -- can win a strong vote despite some safety worries.
Pfizer's Neville Jackson, a vice president and team leader for development of Exubera, said the amount of training for patients to use inhaled insulin "is probably no more than training patients to inject themselves." He said the company is working on approaches based on those used successfully during the clinical tests. During the meeting, Pfizer noted that it had made a commitment to continuing research about Exubera's safety if it wins approval. The company also defended the safety of the drug to the committee, arguing that the effects on lung function didn't continue to grow if Exubera was used over a long period of time, and often improved.
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