The Miami Herald, Inc.; Monday, March 17, 1997
Katherine Ellison; Herald Staff Writer

Merck was testing an exciting new drug: the protease inhibitor indinavir.

Joining the trial raised Forster's hopes, but what happened next dashed them: From having no symptoms, he said, he got chronic diarrhea, his weight ultimately dropping from 184 to 144 pounds.

"I begged my doctor to change my medication," he said. But he was told the study's guidelines forbade it -- until, he said, in May of last year, he contracted esophageal thrush, or lesions inside his throat, and dehydration so severe that he was hospitalized.

Three leading groups of AIDS activists in Brazil, who object to the Merck trial on various grounds, have filed complaints with Brazilian state and federal supervisory agencies. In Miami on Monday, a special board of review of five Brazilian and U.S. medical experts will meet to consider if the study should proceed.

The controversy, meanwhile, is raising these questions: Do studies such as Merck Protocol 028 put clinical results ahead of volunteers' health? As fast-breaking medical discoveries overtake common notions of standards of care, how flexible must scientists be in protecting patients in their trials? And are AIDS patients in undeveloped nations, with less access than U.S. counterparts to advanced therapies, more desperate and thus more willing to stay in controversial trials?

Merck officials say they have acted responsibly, and that their study was approved by the ethical committees of all five Sao Paulo clinics participating, and reviewed by the U.S. Food and Drug Administration. Moreover, they stress, all volunteers were free to quit at any time.

But that hasn't quelled concern. Merck's experiment "wouldn't fly in this country," said Peter Hawley, medical director of the Whitman-Walker Clinic in Washington, D.C. "I don't think they could get it past U.S. ethical committees."

The terms of the Merck trial, at the start, were these: One-third of the volunteers would take indinavir alone, another third AZT, a first-generation AIDS drug, and the remainder a combination of the two. In the "double-blind" experiment, records were sealed: Neither patients nor doctors knew who was taking what. The records would only be opened, and a change in medication authorized, if a volunteer reached a "clinical endpoint," defined for the trial as a tumor or a serious AIDS-related illness.

Eduardo Motti, head of Merck's clinical research in Brazil, said the volunteers received better care than they would have outside the experiment. And indeed, Forster said he stayed in the group because he hoped to have access, at least eventually, to state-of-the-art treatment.

Free therapy promised

While Brazil's health system now theoretically guarantees AIDS patients free access to the best proven treatment -- a combination of three drugs -- in practice those drugs sometimes aren't available. In contrast, Merck has now promised Forster free combination therapy for as long as the drugs benefit him.

Still, the AIDS activists who criticize Merck point to a 1989 declaration of the World Medical Assembly saying that in any medical study, all patients, including those in control groups, must be provided with the best proven diagnostic and therapeutic treatments. They read that as meaning the best in the world -- not just in Brazil.

Next to the United States, Brazil has both the highest population and highest number of AIDS cases in the hemisphere. The World Health Organization in 1994 estimated that 550,000 Brazilians are HIV-positive.

Motti said Merck chose to do the study in Brazil for the relative ease in finding HIV-infected volunteers who were "treatment virgins" -- who had never received drugs to combat the virus. The trial began in April 1995, as a step toward winning full FDA approval to market indinavir, under the brand name Crixivan.

Nearly two years later, the Data Safety and Monitoring Board reviewing the Merck study has reported that under 2 percent, or fewer than 18, of the original volunteers have died -- a low mortality rate, according to the board. About 100 have, like Forster, reached "clinical endpoints," allowing their doctors to alter their treatment. And at least 108 have quit the study.

AIDS activists in Brazil have been trying to persuade other volunteers to quit, or at least get second opinions on their cases by doctors not being paid by Merck. Joined by some U.S. medical experts, the activists have three main complaints against Merck's study.

Lower standards

As new and improved treatments have become available, they say, volunteers have been kept on a lower standard of care than Merck could and should have provided. Specifically, Merck researchers have continued to treat patients with single drugs when most AIDS experts have reached a consensus that combinations are better.

Even though, as Motti acknowledged, Merck had "confirmed" knowledge in January of last year that AZT alone was less effective than in combination with at least one other drug, he said Merck did not add a second drug to the group taking AZT until May of 1996. (The activists say it was not added until August.)

And today, one-third of the volunteers continue to take indinavir alone, despite concern, on the basis of studies over the past 18 months, that patients taking single-drug therapy with a protease inhibitor may quickly become resistant and may experience less durable effects than those taking drugs in combination.

Brazil's public health system began to offer free combination therapy for certain AIDS patients last winter. But Motti said there is no clinical data showing indinavir alone is inferior to combination therapy.

AIDS experts and activists also question Merck's diagnostic methods. Even though Merck researchers have conducted state-of-the-art tests measuring how much AIDS virus is in patients' blood, the results haven't been shared with the patients or their doctors.

"In trials in this country, the viral loads are being reported; it has become a standard of care," said Hawley, at the Whitman-Walker clinic. "So it would no longer be considered ethical to do them and not report them."

An open letter last December, however, from the Data Safety and Monitoring Board reviewing the Merck study, said: "The relationship of viral load to clinical outcome is not well established."

Life-threatening crises

Finally, the AIDS activists in Brazil challenge Merck's "clinical endpoint" requirement, in which, they charge, doctors have witnessed volunteers reach life-threatening crises before altering their treatment.

Clinical endpoint studies are required by the FDA, but they have become controversial in the United States, where doctors are struggling to find alternatives. Moreover, at least in Forster's case, the judgment of what constituted such an endpoint may have been especially rigid.

Murray, at the FDA, said a loss of 10 percent of body weight -- which in Forster's case would have been 18 rather than 40 pounds -- constitutes "AIDS wasting," an "AIDS event" that has qualified as a clinical endpoint in all U.S. studies he could call to mind.

In any case, the critics say, Merck researchers were forced by the terms of the study to offer less than optimal care, since any doctor routinely treating an AIDS patient would not wait until that patient fell seriously ill before changing his or her therapy.

In their efforts to get Merck to change its practices, Brazil's AIDS activists in recent months have held press conferences in Brazil and sent e-mail abroad to potential sympathizers.

David Gilden, acting director of treatment education at the Gay Men's Health Crisis, said he was "infuriated" when he first read the e-mail last year. He later broached the subject at a meeting with fellow activists.

"They shrugged their shoulders," he said. "They said: `Oh, well. It's Brazil.' "

CAPTION: photo: Luiz Sergio Forster (a)

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