Drug Agency Weighs Role of Hormone Replacements

By GINA KOLATA

ETHESDA, Md., Oct. 24 — The Food and Drug Administration said today that it was still wrestling with questions about how to regulate hormone replacement therapy for postmenopausal women after a study raised questions about its safety.

The issues for the agency arose when a large federal study of what was the most popular hormone treatment, Prempro, made by Wyeth, was halted this year, five years after it began.

Investigators for the study, known as the Women's Health Initiative, found that there were small but important risks, including breast cancer, from taking the drug.

But there are dozens of hormone therapies besides Prempro on the market. Should the findings of the Women's Health Initiative, which tested Prempro, be applied to these other products? Should makers of new drugs for menopause be required to show they are safe in long-term studies?

At meeting here sponsored by the National Institutes of Health to discuss the future of hormone replacement therapy, Wyeth scientists and independent scientists said there was no reason to expect that the other products would not have the same risks as Prempro.

"It is making us re-evaluate the whole area," Dr. Janet Woodcock, who directs the F.D.A.'s Center for Drug Evaluation and Research, said. "The real question is, Where do we go from here?"

Dr. Daniel A. Shames, the director of the F.D.A.'s division that evaluates reproductive and Urologic drugs, asked the audience at the conference for guidance. Until now, he said, the agency has accepted data from studies lasting just 12 weeks to show that hormone therapies relieve the symptoms of menopause, with the women being followed for perhaps a year longer to assess the drugs' safety.

Now, he said, with the lessons of the Women's Health Initiative, what advice would the experts give?

"Is this adequate?" Dr. Shames asked. "If not, what should we do?"

At the same time, researchers at the National Institutes of Health said they must consider whether to sponsor large studies of other therapies for menopause and, if so, which ones to test.

The Women's Health Initiative study of Prempro, a combination of estrogen and progestin, involved 16,000 women and cost more than $600 million. But it addressed a question that was of vital importance to the 40 percent of American women who took hormone therapy after menopause. How safe is it to take a combination of estrogen and progestin? Estrogen unquestionably relieves symptoms of menopause, but the study asked whether it had other effects on health.

The study found that Prempro conferred slight risks of heart attacks, stroke, blood clots and breast cancer that were not balanced by its benefits, slight decreases in hip fractures and colon cancer.

Many of the researchers and doctors at the meeting here took issue with the study, criticizing its design and saying that the investigators did a disservice to millions of women. Many said that there are quality of life issues since without hormone therapy many women will suffer from hot flashes, vaginal dryness and night sweats.

Dr. Ginger Constantine, a Wyeth vice president, said that since the drug also slows bone loss that occurs at menopause, there could be an increase in osteoporosis if women stop hormone therapy.

"The reaction to a new scientific finding is really in proportion to the dogma it is upending," said Dr. Elias Zerhouni, the director of the National Institutes of Health. "We had a strong dogma" about hormone therapy, he added, so it should perhaps be expected that the reaction was swift and heated.

Some proposed that other menopause treatments be examined in studies as large and as rigorous as the Women's Health Initiative.

"We would love to think we could do more of those kinds of studies," Dr. Vivian Pinn, who directs the Office of Research on Women's Health at the National Institutes of Health, said. "But can we really justify spending the kind of money we spent on the Women's Health Initiative to study other preparations?"

In the meantime, Dr. Stephen E. Straus, the director of the National Center for Complementary and Alternative Medicine, said as many as 20 percent of menopausal women use herbal products, like soy or red clover or black cohosh to relieve symptoms. The risks, and benefits, of these products are unknown, he said.

"There are no long-term studies — not of safety, not of effectiveness." Dr. Straus said. Yet large rigorous studies will be a long time coming, he explained, because they require extensive preliminary scientific research before they could be justified. "We are not there yet," he said.