Keith Epstein

Living Proof

In U.S-run study, Ugandans expected treatment. They got dummy pills.

THE PLAIN DEALER
Monday, November 9, 1998

By BILL SLOAT and KEITH EPSTEIN

KAMPALA, UGANDA

Her husband lay dying, his spirit draining away into the earth as silimu consumed his body.

Joyce Namugenyi knew she would never see him again on this side of life.

The only enduring thing he would leave behind was a latent virus set free in her bloodstream – a death sentence passed through a loving act.

“Slim disease,” or silimu as the Africans call HIV, was everywhere around her.

Coffins were being built and sold along roadsides from open-air stalls resembling produce stands. Logs trucked in from equatorial forests were hurriedly hewn, planed and hammered into rough plank boxes.

The bereaved would arrive at the stalls, haggle over price, strike a bargain, then lash the new boxes across the backs of bicycles for the sad trip home.

And now silimu had hold of her own body.

Without much other hope of relief, and without really understanding her role in what was about to happen, Namugenyi in 1994 volunteered for a medical experiment sponsored by the U.S. government, and conducted in Africa by Case Western Reserve University.

For at least 19 months, tuberculosis was allowed to grow, unchecked by an effective drug, as American researchers charted the natural progress of the disease in a control group of about 500 Ugandans. All had human immunodeficiency virus, which causes AIDS. Most were young women of childbearing age, or soldiers recruited from the Ugandan army.

Tuberculosis, the world’s most deadly infectious organism, is particularly dangerous for HIV patients because each disease speeds the other. TB now accounts for approximately one-third of AIDS deaths worldwide.

Instead of being treated with isoniazid, an inexpensive drug shown to prevent dormant TB from becoming active, the Ugandans got nothing but vitamin C.

Researchers for CWRU and the Centers for Disease Control and Prevention, which paid for the experiment, said most Ugandans wouldn’t receive isoniazid anyway. The drug was unavailable for TB prevention in Uganda, and Ugandan officials were skeptical that TB prevention was cost-effective.

A six-month supply of pills costs $1.86, about the same as a pack of cigarettes.
Isoniazid was already being used with other drugs in Uganda to treat people dying from active tuberculosis. But the country was so poor it was barely able to help about 40 percent of those, the people in greatest need of care.

The Kampala clinical trial, according to the plan for the study, was less to test isoniazid and more to evaluate preventive therapy.

Altogether, the study involved 2,018 Ugandans with HIV and latent tuberculosis who were randomly assigned to different groups.

Most got isoniazid, alone or in combination with other drugs, in pills they were supposed to take over three to six months. Others received the vitamin C placebos – pills that did nothing.

The use of such an untreated control group is at the heart of a debate extending from Uganda to the CDC’s Atlanta headquarters to medical centers around the world. Experiments funded with U.S. dollars are supposed to adhere to U.S. ethical standards, and those regulations prohibit withholding a proven drug from people in need.

The CWRU and CDC researchers say the control group was requested by Ugandan officials and was a necessary part of convincing those officials.

Dr. Christopher Whalen, a CWRU epidemiologist who oversaw the experiment, said researchers decided to give the control group a placebo because their Ugandan research partners wanted a comparison. “There was a discussion about whether the placebo group was warranted and whether it should be used,” he said. “The Ugandans felt that it was important that it be included and maintained to find out whether [TB prevention] would work in their setting.”

Whalen said it was important to respect the decision of his Ugandan colleagues. “To do otherwise,” he said, “you might find yourself accused of exploiting a community.”

Whalen said there was also a scientific reason for the control group: to attempt to gather solid evidence that preventive therapy would confer lasting benefits in a country awash with TB.

No one in the control group was to be given anti-tuberculosis medications until being diagnosed with full-blown disease. However, when the experiment demonstrated isoniazid’s ability to suppress TB, the researchers felt morally obligated to track down members of the control group, and gave them the drug.

Dr. Neal Halsey, a Johns Hopkins University scientist who studies TB and AIDS in developing countries for the U.S. government, has seen it all before – the use of science not just to make discoveries, but to persuade.

“You often end up having to do studies that may not be absolutely scientifically necessary but are needed to convince people it’s the right thing to do,” Halsey said. “It’s human nature. It’s the way the world is.”

Dr. Fred Gordin, a Veterans Affairs researcher in Washington who headed another, international study of TB prevention, said there was an explanation for what happened in Africa: Ugandans ordinarily wouldn’t receive TB prevention drugs, and so were no worse off with vitamin C.

“Of course,” he added, “here in the U.S. that would be unethical.”

Not only were lesser standards of care applied in Uganda, but elsewhere around the globe as well, a top CDC official told the National Bioethics Advisory Commission last summer.

“In many of the studies that we conduct,” said Marjorie A. Speers, the CDC’s deputy associate director for science, “it is often an intervention that is below what is the standard in this country.”
The goal, Speers said, is to come up with life-saving solutions poor countries can afford and to

“ultimately benefit the host country for that research to have taken place.”

Since the clinical trial concluded, no nationwide drug-based TB prevention program has been started in Uganda.

Nor has there been money budgeted to start one.

Ugandan government officials said their country still cannot afford preventive therapy with isoniazid for the masses of Ugandans with HIV, raising questions among some about using foreigners to test medicine unlikely to benefit them or their communities.

“To do research without a commitment that if the drugs are found to be effective they will be dispensed and made useful – that drugs will be supplied and distributed – that’s unethical,” said Dr. William Freeman, president of the Applied Research Ethics National Association, whose members oversee human experiments.

CWRU’s Whalen said that even without immediate practical results, the Kampala experiment might eventually save lives.

“There are thousands of people dying of tuberculosis, more than any other infectious disease,” said Whalen. “We went into the study with the hope it would be beneficial. We wanted to make a difference – and did – by identifying why prevention of tuberculosis in people with HIV is crucial.”
“If we can establish use of a low-cost form of prevention like [isoniazid],” he added, “we’ll have made a real difference in the impoverished world.”

Alabama study sparked rules

On the consent form, patients were told that among the four “treatments” they could receive was “treatment with a placebo drug.” But they did not seem to comprehend there was a chance they would get a dummy pill.

Some patients said they thought “placebo” was the name of an actual medication that would help them.
“What I knew,” said Namugenyi, “is these drugs were to prevent me from getting TB.”

Fully informing patients and offering them an existing treatment has been required for two decades by ethics rules governing U.S.-sponsored medical experiments, whether at home or abroad, said Thomas Puglisi, director of human subjects protection at the U.S. Office of Protection from Research Risks.

The U.S. regulations emerged following disclosures in 1972 of a notorious government-sponsored syphilis study of 412 poor, black sharecroppers in Tuskegee, Ala. The men were allowed to sicken for years without being informed about the latent disease, or offered treatment with penicillin, an antibiotic known to be highly effective. The government simply wanted to observe the men to document what happened and learn more about syphilis. Health officials justified their actions by saying most of the men wouldn’t have received the known medication anyway.

Fred D. Gray, a noted civil rights lawyer who successfully sued the government on behalf of the Tuskegee survivors and families, said the Uganda study “may or may not be like the Tuskegee syphilis study. But it should raise to the level of someone taking a hard look at it.”

There seemed to be similarities, he said, but cautioned that controversial studies are equated with Tuskegee too often.

“I will say this: Our researchers should use the same standards in foreign countries that we use here,” said Gray, who is a member of CWRU’s governing board of trustees. “You’re dealing with human lives. A human life in a foreign country is as valuable to them as our lives are in this country.”

A human rights treaty signed by the United States in 1975 contains a similar message. Patients in a control group “should be assured of the best proven diagnostic and therapeutic method,” states the Declaration of Helsinki.

Lacking a proven alternative, patients can be given a placebo, as will happen in tests of a potential AIDS vaccine in the developing world, said Dr. Jose Esparza, a Geneva-based virologist who leads a United

Nations team developing the vaccine.

Asked about the Uganda TB study, he said if there was a drug such as isoniazid “proven to be effective in conditions that could be related to where you are doing the trial, my perception is you have to provide that” to members of a control group.

The CDC has since 1990 emphasized isoniazid’s routine use in the United States, especially for those with HIV who test positive for tuberculosis, including the foreign-born, and poor blacks lacking access to good medical care.

Not following the guidelines in the United States could be grounds for malpractice. “You would be open to charges that you would not be making a therapy available that has been shown to be effective,” said former Health and Human Services Secretary Dr. Louis Sullivan, who is now the president of Morehouse School of Medicine in Atlanta.

Since 1990, Third-World clinicial trials financed by the United States have confirmed the CDC’s advice to American physicians. In 1993, for example, a U.S.-funded trial in Haiti, a Caribbean country populated with descendants of African slaves, demonstrated the pills provided “significant protection.”
But “countries want to be shown it works in their country,” said Dr. Richard J. O’Brien, director of the CDC’s Division of Tuberculosis Elimination.

Dr. Francis Adatu Engwau, manager of Uganda’s National TB and Leprosy Programme, said he was among those who demanded more proof.

“Just because it would work in Haiti,” Adatu said, “it may not work in Uganda.”

Adatu felt that way despite co-authoring a World Health Organization study using isoniazid in Uganda during 1991 and 1992 that had concluded TB “might have been prevented in up to 62 percent of treated clients.”

Patients were told then “if we give you isoniazid, it will lessen your chances of breaking down,” Adatu said. “At that time, there was no placebo.”

In Kampala, the CDC found a ready-made human laboratory to make its pitch for preventive therapy. TB remains the leading cause of death among the 2 million Ugandans who are HIV-positive. Some 1.4 million people are believed to be carrying the pathogen, which spreads so easily it is known as “AIDS with wings.”

By the time the Kampala experiment was dissolved, there were 47 diagnosed cases of full-blown tuberculosis – a disproportionate number of which were in the group given vitamin C. There were 21 cases in the 464-member placebo control group. There were 26 cases among the 1,444 patients who received anti-tuberculosis pills.
There were deaths in all groups, though causes could not be determined because of the lack of reliable records in Uganda.

Confusion over placebo

When Joyce Namugenyi signed up for the experiment in 1994, she was infected with TB but not yet ill. She was subjected to a battery of tests. She had X-rays taken. Researchers collected sputum and blood samples.

They gave her a number – a code number.

From then on, she would be identified as test subject 42091.

Her documents show she was given some pills. But which ones? She has no clue.

She said she agreed to take the pills because she was told they might save her life, and because she was offered special medical care not available to most Ugandans.

In fact, most people who signed up had such expectations. Some 74 percent volunteered in hopes of prolonging their lives, resolving symptoms, avoiding full-blown tuberculosis or because they had sick relatives, according to CWRU’s data.

Like the other Ugandans, Namugenyi was required to sign the consent form before being given pills. She said she didn’t read it. A counselor, Kate Kataliwa, explained what was written on the piece of paper.

“We will give you tablets that will prevent tuberculosis,” Namugenyi recalls being told.
Then her picture was taken and stapled to the form.

Without the pills, Kataliwa “assured me I might get TB in the future.”

Almost four years after she volunteered, Namugenyi said she still did not understand what placebo means.

“They never explained,” she said.

Kataliwa was unwilling to discuss Namugenyi’s participation in the experiment, explaining she had been sworn to confidentiality about who took part. But she insisted she did her best to explain what a placebo was. She recalls telling patients “some of you will be getting a drug that is nothing.”
Another client of Kataliwa’s, Fatima Naduwula – test subject 40972 – also didn’t understand.

“They gave me medicine for six months, pills,” she said. “They did not tell me the name of the pills.” She doesn’t remember being told there was a chance she might get a placebo, whatever that was. She just thought she was going to be protected from getting akafuba, a Ugandan word for TB.

So did Efurance Ndibarekera – No. 38139 – and Dominic Lusiba, among a number of participants found and interviewed in Uganda by The Plain Dealer. None of them is clear about whether they got isoniazid or a placebo.

They said they were unaware that they had been in an experiment.

Many were illiterate and most hadn’t finished school.

The approved consent form states the study’s purpose as “TB prevention” and mentions “research” in fine print at the bottom of the second page.

“All material for recruitment [of patients] will describe the study as TB prevention,” according to the scientists’ plan for the study, known as a protocol.

That was Emmanuel Jjagwe-Kizza’s understanding.

Jjagwe-Kizza, 31 – test subject 38875 – is fluent in English and his tribal language, and has studied Latin. He holds a university degree in philosophy and is the author of a grammar school social studies textbook.

“I was told from the start this is TB prevention,” he said. “Why should I ask too many questions? TB prevention is TB prevention.”

Jjagwe-Kizza learned only this summer that “placebo” was a dummy pill.

“I had taken it to be a medical word that I was not required to know,” he said.

Patients weren’t necessarily misled, he added; they may have simply missed the point.

Janet McGrath, a CWRU anthropology professor who for two years has been preparing a group of Ugandans to take an experimental AIDS vaccine by explaining scientific terminology, said “placebo” is something that continues to baffle many of the people she has studied.
“I’m not sure it’s an inherently clear concept,” she said. “It’s specialized knowledge.”

But if placebo was misunderstood in Uganda, there was no such confusion in a similar U.S.-sponsored experiment at the time that also involved TB prevention pills – no confusion because there was no placebo.

Like the Ugandans, the patients – in Cleveland and 52 other locations across the United States, Mexico, Haiti and Brazil – were afflicted with HIV and tested positive for TB.

Unlike the Ugandans, all 1,583 patients were given anti-TB drugs, including the best proven therapy, isoniazid.

In that study, sponsored by the National Institutes of Health, researchers saw no scientific necessity for an untreated control group. They explicitly told their patients: “There is no placebo – fake pill – in this study,” according to records of the NIH’s Community Programs for Clinical Research on AIDS.

The study by the VA’s Gordin found that a two-month course of TB prevention drugs, rifampin and pyrazinamide, prevented TB as well as 12 months of isoniazid. Those findings now are leading to change. The CDC is preparing to advocate use of the new drugs as well.

Outside the United States, however, preventive therapy is still far from being accepted.

Gordin said as recently as this year that he had spoken with world health officials who remain skeptical.

“People in Africa, even with the data in front of them, feel it’s not worth it and won’t work,” he said.

That frustrates Whalen, the CWRU researcher who headed the Kampala study. “What I’m up against is there are people who have spent their entire lives developing a method for TB control that emphasizes treatment of active disease,” he said. “They argue that TB prevention is expensive and would take money away from their programs. These are mostly Europeans at the International Union Against Tuberculosis or the people at the World Health Organization. They’re not easily convinced.”
Adatu, Uganda’s top TB fighter, said that while preventive therapy would do some good, his country still can’t afford the pills without foreign assistance. Uganda spends less than $3 per person, per year, on all health services.

“There’s no way to implement it on a national scale,” he said. “The money is not available.”
Within the CDC, senior scientists believe the Uganda study was conducted appropriately but they are disappointed at the lack of results.

Said Dr. Kevin M. DeCock, director of the CDC’s AIDS division: “If good science doesn’t lead to public health action, one should start to question why on Earth we’re funding this research in developing countries in the first place. All this TB research is one such example. It’s terribly frustrating. It risks making you become very cynical.”

Wondered the CDC’s O’Brien: “Is it possible that a study that is `unethical’ in one socioeconomic and epidemiologic setting can be `ethical’ in a different setting? We all long for a simple world in which adherence to one golden rule can assure us all that our conduct consistently meets the highest ethical standards.’

But ethical challenges, he added, will confront researchers in developing nations “as long as the unethical reality of widespread, grinding poverty persists.”

An official thank you

As of this summer, Joyce Namugenyi had not yet contracted full-blown symptoms of TB.

In March 1996, she received an official form letter: “We thank CByou for your participation and cooperation in this study.

“The results of this study will go a long way in improving our understanding of the management and prevention of tuberculosis.

“You will not have another formal appointment for further visits.”

——

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