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New York Times
U.S. Weighs Early Release of Experimental AIDS Drug
GINA KOLATA,
July 19, 1991

In a highly unusual meeting, an advisory committee to the Food and Drug Administration today began deliberating on whether to approve for marketing a drug that has not been completely tested in normal clinical trials.

The drug is an experimental AIDS remedy, and if it is allowed to go on the market it could establish new standards for the approval of drugs for life-threatening illnesses.

The drug is didanosine, or DDI, manufactured by the Bristol-Myers Squibb Company. The company said data from the early testing showed that about half the patients who took DDI had clinical improvements.

Unlike any other new drug application in recent memory, the DDI application does not include data from the standard tests to establish safety and efficacy. Instead, the manufacturer, with the support of the Federal agency, is relying on preliminary data and findings from a program in which patients are given the drug by doctors who keep track of their progress.

The advisory committee's meeting is to continue Friday, at which time it could reach a decision. The Federal agency must ratify the committee's decision before it takes effect but it is rare for the agency not follow the advice of an expert panel.

The agency has made a massive effort to gather data on DDI and to analyze it for the company, using its most creative statisticians and data analysts.

In an interview in the hallway outside the packed ballroom where the panel was deliberating, Dr. David A. Kessler, Commissioner of the F.D.A., said the agency was taking the unusual steps because new drugs to treat people with AIDS are so desperately needed. He said it was acting to hasten this drug to the market.

The agency called in data from Bristol-Myers Squibb in late December, more than three months before the company submitted its new drug application, and began anaylzing the data. It convinced the National Institues of Health to give it an unusual early look at data from clinical trials in progress. The agency put scores of staff members on the DDI project and set up weekly meetings with officals from the National Cancer Institue and the National Institue of Allegery and Infectious Diseases to study the data.

"More than with any other new drug application, the F.D.A. is part of the drug development process," Dr. Kessler said. But he said this sort of effort would also be appropriate for drugs for cancer and Alzheimer's disease.

Many of the advocates for people with Acquired Immune Deficiency Syndrome, who were quietly listening to the detailed presentations, said they were delighted with the agency's role. "The F.D.A. has become an advocate for the public health," said Martin Delaney of Porjcet Inform, a San Fancisco advocacy group. "In the past, the F.D.A. was just a gatekeeper."

But the Federal agency and Bristol-Myers Squibb are also taking a risk. The advisory committee is a fiercely independent group that asks sharp questions and is acutely aware that its advice could change the nature of drug approval.

"The committee is a wild card," said Dr. Daniel Hoth, director of the division of AIDS at the National Instiute of Allergy and Infectous Diseases.

The data that Bristol-Myers Squibb hopes will get its drug approved came almost entirely from two sources. The company has data from several preliminary studies that were designed to look for dangerous side effects, but not to look for efficacy. And it has data from a massive program it initiated in September of 1989 in which it provided DDI free of charge to people with AIDS who could not tolerate or no longer responded to AZT, the only drug marketed for the treatment for AIDS.

Bristol-Myers Squibb has provided DDI to as many as 20,000 people in this expanded access program, but only 8,000 have been evaluated so far and the program was designed to gather safety data only, not to determine how effective the drug was against AIDS.

Of the patients evaluated, the company said some had increased numbers of a type of disease-fighting white blood cell, CD4, that is destroyed by the AIDS virus that cripples the immune system. Others who took the drug had diminishing traces of an AIDS-virus protein that is a sign of viral infection, p24 antigen; other patients gained weight, and still others had increased numbers of a vareity of white and red blood cells, a sign that the drug could be counteracting the virus's infection of the bone marrow. Many patients had more than one of these signs of improvement, the company said.

The company also said the drug could cause pancreatitis, a potentially deadly complication, in about 5 percent of patients and could cause peripheral neuropathy, an excruciating pain in the nerves of the feet, in about 20 percent of patients.

The difficulty in using data from the expanded access program rather than traditional data that were designed to study efficacy is that the studies did not include, for comparison, people who did not receive the drug. That can make it difficult or imposible to decide whether changes in patients' health are because of DDI or whether they would have occurred without the drug.

To get around this hurdle, the company, with the help of sophisicated analyses by F.D.A. staff, is comparing the fate of people who took DDI in the preliminary studies or in the expanded access program to the fate of people who were in control groups from previous studies of other drugs.

But Dr. Paul Meier, a member of the advisory committee and a statistician at the University of Chicago, said such historical controls can be extremely complicated to evaluate.

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