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September 26, 2002

SCIENCE 2002: The shifting sands of scientific consensus in clinical research

Last summer, many women and their doctors were shocked to learn that hormone replacement therapy (HRT) — once thought to forestall osteoporosis and heart disease while relieving menopausal symptoms — is not the panacea that it had seemed to be.

An eight-year clinical trial, conducted by the National Heart, Lung and Blood Institute, was stopped after five years when researchers found an increased risk of breast cancer, coronary heart disease, stroke and pulmonary embolism among women using HRT.

The study concluded that HRT reduced rates of hip fractures and colon cancer and may prevent memory loss and the onset of dementia but that "on balance, the harm was greater than the benefit" for most women.

At the time, an estimated 6 million American women were using HRT, a combination of estrogen and progestin, making it one of the most commonly prescribed treatments in the United States. (Progestin helps to prevent uterine cancer, a side effect of estrogen therapy.) HRT prescriptions are reported to have plummeted since the clinical trial results appeared in the July 2 Journal of the American Medical Association.

How could researchers, gynecologists and others in the medical community have been so wrong about HRT?

Incomplete research, a misguided one-size-fits-all approach to women's health, and wishful thinking, suggested Roberta Ness during a Science 2002 session on "The Shifting Sands of Scientific Consensus in Clinical Research."

"I really think that a lot of the reason [for overly optimistic claims for HRT] is that we wished for it so badly," said Ness, professor of epidemiology in the Graduate School of Public Health and associate professor of obstetrics, gynecology, and reproductive sciences and associate professor of medicine in the medical school.

"Everyone wanted so badly to have a magic pill that would do just what R.A. Wilson told us it would do."

Wilson wrote the influential 1972 book, "Feminine Forever," which predicted that the hormone estrogen would prove to be a virtual cure-all not only for menopausal symptoms (including hot flashes, vaginal dryness, mood swings and sleep disturbances) but also in preventing fractures and loss of bone density, memory loss, some cancers — and, most importantly, cardiovascular disease, by far the No. 1 killer of American women. (While breast cancer evokes more visceral fear, it accounts for only 4 percent of deaths among women in this country, Ness pointed out.) Following two decades of research on estrogen and the HRT mix of estrogen-plus-progestin, many doctors believed that a consensus had been reached by the 1990s: For most menopausal women, hormone replacement therapy improved quality of life and probably longevity as well.

A few "squeaky wheels" such as Pitt epidemiology professor Lewis Kuller questioned the consensus, noting that it was based on observational studies rather than large, randomized clinical trials. Scientists couldn't be sure, for example, whether HRT actually prevented cardiovascular disease or if women who sought the therapy tended to be healthier than average and therefore less likely to develop heart and blood vessel problems.

A growing body of evidence also indicated that HRT increased blood clotting and breast cancer in women at risk for it.

In 1994, the long-awaited big clinical trial — the Heart and Estrogen/progestin Replacement Study (HERS) conducted by the National Heart, Lung and Blood Institute — got underway. Nearly 2,800 women participated, including 200 in Pittsburgh.

Four years later, HERS researchers announced that, contrary to earlier belief, hormone replacement therapy did not protect women from heart disease. Ness said the impact among women's health researchers was comparable to the JFK assassination: "We all remember exactly where we were and what we were doing when we heard the news."

Researchers decided to continue monitoring HERS patients for several more years, to see whether hormone replacement therapy required more time to show benefits. But HERS II, as the extended study was called, confirmed the earlier results.

Ness recommended prescribing HRT for a few years to women suffering severe menopausal symptoms who are not at risk of breast cancer. Cholesterol-lowering drugs, weight loss and blood pressure control are more effective than HRT in reducing the risk of heart attacks and stroke, she said.

q For high-risk malignant melanoma patients, the only known effective therapy is with the drug interferon alpha-2b, a University of Pittsburgh Cancer Institute (UPCI) researcher told the "Shifting Sands" session audience.

Melanoma patients considered to be at high risk are those with primary tumors greater than 4 mm. deep or whose melanoma has spread to the lymph nodes, said John M. Kirkwood, Pitt professor and vice chairperson of research, Health Sciences, and director of the UPMC Melanoma Center.

Last spring, Kirkwood announced the results of a national study confirming that interferon alpha-2b dramatically increases relapse-free and overall survival rates in such patients.

A drawback is that interferon is toxic (Kirkwood called it "the distilled, bottled essence of the flu virus") and causes fevers, fatigue and vomiting in many patients. "We're getting better at administering it, though," he said. "In our most recent trial, 90 percent of patients got through a whole year of treatment without having to drop out."

Malignant melanoma is the deadliest form of skin cancer. Nearly 51,400 cases were diagnosed in the United States in 2001, resulting in 7,500 deaths. The five-year survival rate for malignant melanoma patients is only about 6 percent.

"The lifetime risk of [an American] developing melanoma had increased from 1-in-1,500 in 1935 to 1-in-75 by 2000," Kirkwood said.

He cited promising research, begun a decade ago, on the role of lymph nodes in malignant melanoma. "We now know that every square centimeter of your skin is, in effect, wired to a lymph node, which we can remove" to discourage the spread of tumors, Kirkwood said.

"One downside is that doctors often don't see patients until their melanomas have reached the advanced stage," he added.

q From 1932 until a journalist exposed it 40 years later, a U.S. government-funded research project systematically denied treatment to 391 mostly poor and illiterate African American men infected with syphilis, to see if the disease progressed differently among blacks than whites.

Men enrolled in the Tuskegee Syphilis Experiment were told they had "bad blood." Some 200 who tried to enlist in the U.S. armed forces during World War II were turned away — partly because, in accepting the men, the military would have treated them with life-saving penicillin, thus spoiling the experiment.

"Unless you are an overt sociopath, you are appalled by that experiment," said S. Clifford Schold Jr., Pitt assistant vice chancellor for clinical research, Health Sciences, and professor of neurology in the School of Medicine.

But you don't have to go back to the 1930s to find other irresponsible, even arguably criminal, U.S. government-funded research projects, Schold said.

"Department of Defense-supported radiation experiments following World War II exposed at least 20,000 soldiers and, in some cases, children to various doses of radiation to determine its side effects. There are well-documented cases of hepatitis virus being injected into institutionalized children, to study the natural history of the disease," he said.

Closer to home, the Salk polio vaccine first was tested on institutionalized children without their consent or that of their families, Schold noted. "Fortunately, it turned out well. The vaccine worked."

To discourage research abuses as well as fraud, the United States has developed an elaborate system of regulatory controls "to the point that it has been estimated that about $200 million is spent in this country on the [research] review process," Schold said. In parallel, the scientific community has refined the model of a randomized, blind clinical trial.

He cited five ingredients of a scientifically sound trial: asking research subjects the right questions, enrolling sufficient numbers of participants so that findings are statistically significant, analyzing results carefully and conservatively, disseminating results (whether they are positive or negative) and informing participants exactly what they're getting into.

Gaining informed consent "is never as easy as it sounds," Schold said. "There have been numerous studies showing that people have signed impeccable informed consent forms, and then when quizzed on what they just signed have virtually no concept about what was about to be done."

With the unraveling of the human genome, people will know what diseases and conditions they are at risk for, Schold added. "There's going to be a big shift toward prevention trials, so we all have a personal interest in properly conducted trials.

"The strongest advocate for quality clinical research," he told the audience, "is you."

— Bruce Steele

Filed under: Feature,Volume 35 Issue 3

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