[Note: Although there are obviously other identifiable ethical issues in the articles below, the main focus is on the use of placebos (i.e., like "sugar pills" with no medication in them) in clinical trials in Third World countries. Many people may not be so interested or see much relevance in "research ethics", but those very issues rapidly evolve into "medical ethics" issues in "standard medical practice". The classic example currently is that research involving "stem cells" from cloned or from sexually produced human embryos will (presumably) then be used as "therapies" to treat sick patients in clinical trials -- and eventually become part and parcel of standard medical care. Clinical trials are research! Not until a drug or procedure is approved by the FDA (ahem) will they be considered "standard medical treatment". One hotly debated "ethical" issue still unresolved in research ethics is the use of placebos in clinical trials (i.e., with human patients) -- especially when used in Third World countries where citizens are incapable of giving true "informed consent" because they are often uneducated and vulnerable. While the "purpose" of using placebos is "intellectually" understandable from the perspective of statistical analyses of "data", their use is often still unethical, because by definition some sick patients are not receiving any treatment -- and hence their disease could get worse or they could die; or a well patient could get seriously sick or die. Some research using human patients just shouldn't be done -- regardless of any "risk/benefit" ratio. Amazingly, even though the use of placebos is still highly debatable even among researchers, it continues to be used anyway. In "bioethics" --the ethics used by NIH and its IRBs, etc., (below) -- the use of placebos is "ethical" because, in their utilitarian view of ethics, the benefits "outweigh" the risks. Or to put it another way, there is no research that is absolutely right or wrong. It all depends on whether or not the "benefits" outweigh the "risks" -- even if innocent human beings are made much sicker, or even die. Or put another way, the life and health of human patients in clinical trials are not absolutes for these researchers! -- DNI]
[emphases added]
Cambodia's Premier Halts Planned Trials of AIDS Drug Associated Press
August 11, 2004 11:12 a.m.
PHNOM PENH, Cambodia -- Cambodia's premier ordered a halt to plans for human trials of an anti-AIDS drug in his country that would have recruited hundreds of sex workers to determine if the medicine could prevent new HIV infections.
Health Minister Nuth Sokhom said he had been instructed by Prime Minister Hun Sen to stop the project to test the drug Tenofovir, also known as Viread DF, made by biotechnology company Gilead Sciences Inc., based in Foster City, Calif. He said the prime minister "is worried about the effect on the Cambodian people and on the human values and rights," and "is not allowing [the drug] to be tested on humans at all."
Cambodia, whose Health Ministry had approved the project last year, currently has the highest HIV infection rate in Southeast Asia, blamed largely on its flourishing sex trade.
The prime minister repeated his objection to any experiment of the anti-AIDS drug on his country's citizens, first voiced in a speech last week, and said it "should be tested on animals" instead, Nuth Sokhom told the Associated Press.
Viread is already used to treat people infected with HIV, the virus that causes AIDS. The new test in Cambodia was aimed at determining if the drug can prevent infection in those who don't already have the disease.
Partially funded by the Bill and Melinda Gates Foundation, the proposed trial would have recruited almost 1,000 sex workers, who are at high risk for becoming infected with HIV. The trial was to have given one group Viread and another a placebo over a period of a year to see if those taking the drug had a statistically lower incidence of HIV infection.
The trial was to be conducted by researchers from the University of California San Francisco, with additional funding from the U.S. National Institutes of Health and the University of New South Wales.
Members of a local sex workers' rights group, Women Network for Unity, have refused to participate in the planned study, citing a lack of insurance against potential side effects.
Activists at last month's International AIDS conference in Bangkok, Thailand, also protested the test, saying the prospective participants were being exploited. The protesters, led by the AIDS activist group Act Up, accused the researchers of purposely providing insufficient prevention education to the volunteers because infection data are needed to analyze Viread's potential to protect against the virus. The protesters also demanded that the company take care of the lifetime medical needs of any volunteers who contract AIDS during the experiment.
Cambodia's current HIV infection rate is 2.6% among those aged 15 to 49 years old, the highest in Southeast Asia.
© 2004 Associated Press
Key AIDS Study In Cambodia Now in Jeopardy
By MARILYN CHASE and GAUTAM NAIK
Staff Reporters of THE WALL STREET JOURNAL
August 12, 2004; Page B1
A key human trial of a potentially pioneering drug for preventing HIV is in jeopardy in Cambodia after prostitutes targeted for the study there protested its proposed terms and government officials raised concerns.
Although the government initially supported the trials, Cambodian Health Minister Nuth Sokjom said he has been instructed by Prime Minister Hun Sen to stop the project, according to the Associated Press, because the prime minister is "worried about the effect on the Cambodian people and on the human values and rights."
The drug Viread, made by Gilead Sciences Inc., Foster City, Calif., is being tested in several places world-wide in the first human trials for a pill that prevents the transmission of HIV, the virus that causes AIDS.
"It's a big disappointment that a well-thought out study that's been worked on by excellent groups -- Cambodian, Australian and American -- seems to be in limbo," says Howard Jaffe, senior medical adviser for Gilead. Others involved in the project said they were surprised by the news and are assessing their next step.
The decision highlights the problems researchers and pharmaceuticals companies face in creating drugs for high-risk diseases, especially in the developing world. Such new drugs represent perhaps the single greatest near-term hope for the prevention of AIDS as vaccines remain at least a decade away, researchers say.
But testing the drug on humans who are at risk of catching -- but don't have -- HIV raises ethical questions: Is it ethical to use human guinea pigs and give them a placebo in a trial of a potentially lifesaving treatment where participants could contract HIV? Or to test such treatments among the poor and uneducated where gaining true consent may be difficult?
"Individual rights, balanced against the greater public good -- that's the tension of clinical trials and it always will be," says Helene Gayle, head of AIDS prevention at the Bill and Melinda Gates Foundation. The foundation is sponsoring similar studies in four African countries and is co-sponsoring the Cambodia trial.
Organizers of the Cambodian trial, which is sponsored by the U.S. National Institutes of Health, promised that the 960 participants, who have yet to be selected, would receive counseling about safe-sex practices, monthly testing, condoms, and $3 a day for transportation. If Viread proved effective as a preventative, participants would receive a free supply of Viread for two years. But any that contracted HIV may have to rely on Cambodia's low standard of healthcare and limited access to antiviral drugs.
A group of about 150 prostitutes protested the proposed terms. Half of the participants would be on placebos in the trial -- a fact that the group claimed is unethical even though prostitutes were chosen because of the high risk of infection they face in their work. The protest group also demanded more counseling, female as well as male condoms, and a lifetime's course of free follow-up care if they are infected with HIV or suffer adverse effects from the drug.
Human trials are particularly sensitive in developing nations, where trial participants may not fully understand the nature of consent, and may lack sufficient after-trial care and the money to afford the AIDS medicines they are testing. It is an issue that is likely to become increasingly contentious as developing nations become a favorite spot for Western pharmaceuticals companies to test drugs: The cost of clinical trials can be 60% lower there than in the U.S.
A Johns Hopkins University survey of health researchers published in February's issue of Journal of Medical Ethics found that one quarter of clinical trials conducted in developing nations don't undergo ethical review. Yet developing nations that allow trials benefit from the laboratories, equipment and training that typically accompany a trial; those that impose too stringent demands such as long-term drug supplies risk losing out. The Viread study sponsors say it passed ethical reviews by all countries involved.
"We should negotiate for a lifetime supply of drugs but then companies would not want to do studies in our country," says Kiat Ruxrungtham, an AIDS researcher with the Thailand Red Cross. "We have to balance it with reality."
Viread, which also is known as tenofovir, already has proven an effective and popular treatment for combating the effects of the HIV virus among those who have it. Sales of the drug in the second quarter rose 18% from a year earlier to $197 million. It costs about $3,900 a year in the U.S. In developing nations, Gilead sells it at a steep discount -- just under $300 a year in the world's poorest countries, including Cambodia.
When tested as a preventative in monkeys, Viread was 100% successful in blocking HIV transmission. Its effects were so long-lasting that doses could be stretched from once daily to several times a week. Still, Viread potentially can damage kidneys and bones. And while most AIDS patients use the treatment without major problems, the safety of frequent use by uninfected people remains unknown.
Earlier this year, teams of scientists charged with conducting human trials chose their first target populations of high-risk individuals: prostitutes in Cambodia, heterosexual adults in Africa, intravenous drug users in Thailand and gay men in Atlanta and San Francisco. So far, none of the groups participating in similar studies now getting underway have withdrawn their support.
The Cambodia trials may have been targeted because critics contend that marginalized populations such as prostitutes are vulnerable in these studies because they lack bargaining power to negotiate terms, and cash or insurance to obtain care if they get sick during the trial.
Sponsors, including NIH, the Gates foundation, and the U.S. Centers for Disease Control and Prevention, pledged a total of $12 million, a number expected to increase as new trial sites are added. The other trials are proceeding as planned but the results from Cambodia are considered key because Asia is likely next in line for the world-wide pandemic.
The Cambodian trial, known as the "Hope of Women Study," is being conducted by researchers from the University of California at San Francisco and the University of New South Wales in Australia. Project coordinator Saphonn Vonthanak says he and co-workers from the U.S. and Australia convened focus groups, interviewed sex workers, and sought guidance from community and external advisory boards to prepare an ethical trial.
Officials at the National Institute of Allergy and Infectious Diseases, a unit of the NIH, also recently visited the trial site and said they were satisfied that the study had passed all its ethical reviews and that it will receive wide support among the target group. But before the researchers could even start to recruit participants, a group of prostitutes began to protest, holding press conferences in Phnom Penh, Cambodia's capital, and at a major international conference on AIDS in Bangkok last month.
At the Bangkok conference, AIDS activist group Act Up Paris and a group of prostitutes called the Asian Pacific Network of Sex Workers brandished signs that read, "$3 can't buy sex workers' lives." They seized the stage at a scientific session and spilled fake blood on displays, including Gilead's.
Mary Fanning, associate director for clinical research at the National Institute of Allergy and Infectious Diseases, says offering volunteers 30 to 40 years of care, as the protest group demands, wouldn't pass an ethics test because it is an "undue inducement." Incentives "so enormous" could entice volunteers to enroll in a study regardless of the risks, she says, tainting the informed consent process.
Write to Marilyn Chase at marilyn.chase@wsj.com
and Gautam Naik at gautam.naik@wsj.com
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