Can clinical trials ever be truly ethical?

Unless the rights of those who participate in clinical trials and their ability to get the best treatment in case of injury or infection are guaranteed, the trials will not be fair even if they yield useful scientific results.

Kalpana Sharma

FOR THE benefit of the many, is it all right to endanger the health of a few? This question lies at the heart of bioethics. It was central to the discussions held over three days at the First National Bioethics Conference organised by the Indian Journal of Medical Ethics in Mumbai last week. The timing could not have been more appropriate coming as it did on the eve of World AIDS Day, December 1. For India is now poised to undertake several important clinical trials on the AIDS vaccine.

In a country where the poor and the most vulnerable have minimal access to health care, ensuring "informed consent" for clinical drug trials is an issue with many dimensions but above all ethical aspects. How do you check that the person who is being used as a guinea pig for a new drug actually knows what is happening? For decades, women's groups have been in the forefront exposing how poor women have been used for clinical trials of various contraceptives without them fully understanding the consequences.

The issue of ethics has taken on greater urgency in the face of the growing private sector interest in conducting clinical drug trials in India. According to T.V. Padma writing in Nature (July 28, 2005), while the average cost of a clinical trial in the U.S. is $180 million, in India it would cost $100 million. Not surprisingly, Contract Research Organisations (CRO) are setting up shop in India and recruiting people to conduct such trials. Indian companies stand to gain from their being held in India. According to one estimate, U.S. and European pharmaceutical companies could spend as much as $1.5 billion per year on clinical trials in India once the system is in place.

Although "bioethics" as an issue was first raised in the context of Nazi medical experiments in the concentration camps, there have been several more recent incidents of medical experimentation where the health of the participant was sacrificed for a so-called "larger cause." The most scandalous of these was the Tuskegee Syphilis Trial in which between 1932 and 1972, the U.S. Public Health Service experimented on 399 black men from Tuskegee, Alabama, one of the poorest areas of the United States. The men, all poor illiterate sharecroppers, were in late stages of syphilis. They were told nothing except that they were being treated for "bad blood," the term used locally for syphilis. Although in the course of these 40 years an effective treatment for syphilis had been discovered in the form of penicillin, these men were denied the treatment. They were turned away from public health facilities and their families had to surrender the body after death for an autopsy. This was described as "the longest non-therapeutic experiment on human beings in medical history".

The lid was finally blown off this experiment when one of the doctors involved in it went public and the details appeared in the media. As a result, the experiment had to be stopped. But by this time, immense damage had already been done. Many of the men died or passed on the syphilis to their partners and their children in utero.

The Nazi experiments and thereafter trials like the Tuskegee experiment have compelled the formulation of international and national ethical guidelines for clinical trials. Despite such guidelines, incidents of unethical trials, with elements of the scandalous Tuskegee experiment, continue to be reported, particularly in poor countries and amongst vulnerable populations.

In India, one of the most shocking recent examples is the illegal use of quinacrine, an anti-malarial drug, to sterilise women. This was done by private American researchers with the help of local doctors in West Bengal. By the time this story became known, more than 30,000 women in India, including almost 10,000 in West Bengal, had been sterilised through this brutal method that consisted of inserting the drug into the woman's uterus. This led to scarring of the fallopian tubes and in effect ensured that the woman could not conceive. The procedure was stopped only after health and women activists took the matter to the Supreme Court. As a result, sterilisations by using quinacrine have been banned in India. Yet, despite the ban, the drug is still available and continues to be prescribed illegally.

There has also been at least one instance in India where, as in Tuskegee, the progress of a disease in humans was studied without ensuring that the participants in the trial were treated. The Institute for Cytology and Preventive Oncology in New Delhi studied 1,158 women from 1976 to 1988 and monitored the progression of cervical dysplasia or precancerous lesions of the cervix. The object of the study was to see how many of these women, who had mild, moderate and severe dysplasias, would develop cancer if left untreated. The Indian Council for Medical Research (ICMR) sponsored the study.

By 1988, 71 women had developed malignancies, at least nine had invasive cancer and 62 developed localised cancer that was treated. Ten women could not be followed up. When the researchers were asked whether they had informed the women about what was being done, they said they had taken verbal consent as the women were illiterate. Only when the study became public in 1997 and the question was raised about the ethics of a study where you allow people to develop a disease even though a cure is available did the ICMR begin the process of formulating ethical guidelines for biomedical research on human beings. These were finalised in the year 2000.

As far as the AIDS vaccine is concerned, the trials are only at a very preliminary stage conducted by the National AIDS Research Institute in Pune. These began in February 2005 and are being implemented with great caution. Similar trials will also be conducted at a later stage in Chennai. These trials are essentially for a preventive vaccine. That itself has been the centre of considerable debate as there is a school of thought that suggests that work on a therapeutic vaccine should be the priority given the spread of the disease in India and the need to treat those already infected with HIV.

Informed consent

Whatever the nature of the vaccine, the issue of ethics and consent continue to be of primary importance. Health activists ask how real "informed consent" can be guaranteed in such clinical trials and whether the participants in the trials will be assured the best treatment in the event of any of them becoming infected with HIV, in the case of AIDS vaccine trials. The counter argument often put forward is that participants are promised the best "available" treatment in such an eventuality. But in a poor country, with an inadequate health infrastructure, what is available is neither "best" nor even adequate to deal with such diseases. Is it fair then to put people through such a trial if at the end of it they might end up worse off than if they had never agreed to participate in it?

Also, although the ICMR has issued guidelines and there are bioethics committees that are supposed to apply them before biomedical research involving human subjects, there are several loopholes. There is also an absence of a legal framework that prescribes punishment for those violating the guidelines. Furthermore, in India we do not have the kind of independent monitoring boards that exist in most industrialised countries that keep a watch on such trials. Such boards have the power to insist that drug trials be modified or even abandoned if they are perceived to be violating bioethics codes. In the absence of such a regulatory system, there is a real reason for concern about clinical drug trials. The Mumbai Bioethics conference took many of these concerns on board and identified HIV/AIDS as "an arena where massive bioethics, human rights and public health battles will be fought."

Few will argue for a ban on all human clinical trials as it is evident that they are essential to test the safety and efficacy of drugs and medical interventions. ICMR guidelines have also laid out the basic framework within which trials can be conducted. But unless the rights of the individuals who participate in the trials and their ability to get the best and most effective treatment in case of injury or infection are guaranteed, the trials will not be fair even if they yield useful scientific results. Ultimately, as Dr. T. Jacob John of the Christian Medical College, Vellore, said in his keynote address at the conference on "Bioethics and Public Health", "What is not in the best interests of the individual cannot be in the best interest of the community."

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