Guinea Pigs in South Asia

South Asia does not have clear guidelines for medical research. Multinational firms eager to push their products take advantage of a 'drug-naive' population.

How long have you been on the medication? What are your symptoms?" These and a dozen more personal questions were the price I was paying for checking my blood levels of a prescription drug at the pharmacology department of a government hospital. I should have gone to one of the city's fancy diagnostic centres, where time is money, and only essential questions are asked. But my doctor had insisted that I get the test done at this department, and who was I to challenge her?

Why was such a detailed case history being filed I wondered, as I stared at the paint peeling off the walls while waiting for various ledgers to be thumbed through and long forms filled out. Why did the government doctor insist on going through all my medical papers and taking notes from them? She certainly had more questions than my own doctor had asked. And why did my doctor insist that I come to this centre for the test? "She wanted to save you money," said my interrogator. Kind thought that, but I was already out a couple of thousand rupees in this personal medical saga, and a few hundred more were hardly likely to make a difference.

Then the government doctor made an off-hand remark: "We're doing research on your problem, building up a picture of the Indian situation…"

When I returned to pick up the test results, I asked if my medical records were going to be

used for any research. "We conduct various studies here, write papers; they might refer to such records…" Do they get permission from the people whose records they use? "The notion of informed consent in India is very recent, and anyway, these are retrospective studies using medical records…"

"In that case, please note on my record that I do not give consent for it to be used for research purposes," I said abruptly, irritated as much by the doctor's evasiveness as her intentions. I stormed out of the office, my anger at the forces determining my own health and treatment, now directed at this cavalier attitude towards getting personal information for a research study.

That was the first time I got a tiny taste of what it felt like to be a 'research subject'—an object of unwarranted attention. The 'researchers' cared about only one thing: how the details of my health translated into a research paper for them.

Dangerous tests

While this experience disturbed me, the government doctors were only milking me for my fascinating medical history. They weren't depriving me of treatment, or using me as a guinea pig for new drugs. And this irritating experience was really nothing compared to what I discovered in the months that I spent investigating the sad state of research ethics in India.

I'd read of poor North Indian women with pre-cancerous lesions of the cervix, who were observed but not given treatment—this as a part of documenting the natural history of cervical cancer. (Researchers at the Indian Council of Medical Re-search, under whose aegis the study was conducted, argued that at the time of the study, the guidelines didn't require informed consent.)

In the country's commercial capital, Bombay, people with severe angina were paying private doctors thousands of rupees for transmyocardial revascularisation, a procedure of unproven benefit. The company manufacturing the equipment provided it free of cost to the doctors, in order to collect data on the treatment and promote the equipment at the same time. (Later, a review in The Lancet concluded that the procedure might reduce symptoms "at the cost of notable opera-five mortality". Also, it made no difference to other measures of cardiac health such as exercise capacity, survival or cardiac function.)

In Karnataka and West Bengal, American doctors on a mission to control the population of the poor, were providing allopathic and traditional practitioners with pellets of Quinacrine, a potentially carcinogenic anti-malarial drug, to insert into the uteri of women desperate for an end to child-bearing. The drug causes inflammation and damage in the fallopian tubes—effectively a chemical sterilisation. Quinacrine sterilisation was promoted despite warnings from the WHO asking for toxicology tests. The doctors reported on these sterilisations as research.

This procedure was being carried out on thousands of women in India, Bangladesh, Vietnam and other poor countries. A writ petition in the Indian Supreme Court by activist organisations forced the Drug Controller of India to undertake to ban this unapproved practice, though the court did not insist on following up on the thousands of women who had al-ready undergone the procedure, to see if they had developed complications. And reports indicate that the practice has continued despite the ban.

My own outrage does not begin to match that of Sharad Onta from the Resource Centre for Primary Health Care in Kathmandu, Nepal, who launched an agitation against clinical trials for a Hepatitis E virus vaccine. The trials were co-funded by Smith Kline Beecham and the US government's Walter Reed Army Institute of Medical Research, and conducted at its Nepal field station, WARUN. This particular viral infection affecting the liver can kill one in three affected pregnant women. It is spread through contaminated water, and is probably responsible for up to 90 percent of jaundice cases in Kathmandu where one in two people show signs of previous infection (one in 50 get the clinical disease), and Hepatitis E epidemics occur annually.

However, Onta argued that for the people of Kathmandu, it made better sense to tackle the Hepatitis E problem by cleaning up the water supply. But that wouldn't suit the researchers. Testing the vaccine depends on the community being provided a poor water supply, so that many research participants are exposed to the virus. To make sure the vaccine works, you need a good number of your research participants to get infected. The more common the disease, the smaller the sample size needed, and the faster the trial can be completed.

Onta also argued that it was highly unlikely that any such vaccine would become available and accessible to the people of Nepal, let alone to others in the developing countries. (The real market would be military personnel and Western travellers to the developing countries.) According to The Lancet, where this controversy was reported, the trial was suspended by the deputy mayor because procedures for informing the local government had allegedly been ignored. Also, though Rob Scott, head of the WARUN field station, insisted that volunteers had given their informed consent to participate in the research, the deputy mayor insisted that "they had not told the people clearly what they were doing… Nepal should not be made a laboratory for the interests of the American army." WARUN officials maintain that the controversy was politically motivated, and that stopping the trial would deprive people in developing countries of the benefits of life-saving research.

Informed consent

This last controversy is the classic debate on the ethics of collaborative research between developed and developing countries. It has come back into the public eye for two reasons. First, pressures on drug companies to produce new drugs and fast, is sending them in droves to developing countries where trials can be done cheap. An article in The Economist (29 January 2000) declares that India has 'not-so-healthy' people in "industrial quantities, and contract-research organisations (CROs) which undertake clinical trials and other services for pharmaceutical companies, are beginning to notice".

The magazine mentions three CROs in India: Quintiles Transnational, a North Carolina-based company with an Indian joint venture whose customers are mainly American and European pharmaceutical firms, recently started clinical trials in India; the Bombay-based pharmaceutical company Nicholas Piramal expects to have revenues of INR 100-120 million within three years; and Max India signed a deal with an affiliate of Harvard Medical School to conduct clinical trials in India.

The article notes that the United States, Ja-pan and the European Union agreed some years ago on common standards for running clinical trials. This means the US would accept data (to-wards drug approval) from anywhere in the world as long as those standards were met. Trials in India would cost less than a third of what they would in the West. Access to large numbers of people suffering from diseases like cancer, heart disease and AIDS drastically cuts the time needed to bring new drugs to the market. The existence of a 'drug-naïve' population, particularly to AIDS drugs, further simplifies and shortens the research process.

The technological revolution in India is also proving that the country has the resources to conduct trials that meet Western standards. It is another matter that ethics is more difficult to monitor, and may fall by the wayside. Or that the benefits of such research are unlikely to be-come accessible to the people on whom such drugs are tested. In fact, almost the entire Sub-continent is available for drug research, according to an Internet listing of various companies in the area which conduct this work for a fee.

People have argued that such research does not bother to get true informed consent, and exploits patients' medical illiteracy. Informed con-sent is not a one-time event but a process which must ensure that potential participants are given all necessary information and its implications, understand this information, and are in a position to make a voluntary decision on participation. The fact is that the consent process is influenced by many factors, including potential participants' economic circumstances, their health, their access to health services, and by, whether the researcher really tries to communicate all the necessary information. A signed consent form is no guarantee of informed consent.

Unfortunately, some researchers take the position of the South African branch of a well-known CRO when it was ordered to stop all drug trials after reports of deaths. The company's representative insisted that the company had ensured that the participants had given their voluntary informed consent. How did that take place? "We checked all the forms to see if they were signed."

Research abuse

With the population hysteria, much of medical research in poor countries seems to concern contraceptives. Women's organisations such as the Saheli Women's Collective in Delhi and the Forum for Women's Health in Bombay, have held that contraceptive research is fundamentally different from other research: contraceptives are used by healthy women, and not for the prevention or treatment of any disease. Over the years, various activist publications have carried detailed articles challenging the many research projects on provider-controlled, long-acting hormonal contraceptives such as implants, injectables and, now, anti-fertility vaccines. For example, in the March 1985 issue of the Socialist Health Review, researcher Ramla Bauxamana dates India's role as a testing ground for contraceptives back to the 1960s, initiated by various international organisations. She estimates that by 1985, at least 50,000 women had taken part in research on various intra-uterine devices and hormonal contraceptives, through contraceptive testing units in Delhi and 14 other cities. Another article in the same issue argues that contraceptive research has tended to focus on provider-controlled methods, and was being conducted without evidence of informed consent or long-term follow-up—a theme repeated in publication after publication over the years.

The most recent controversies have been on the safety and efficacy of anti-fertility vaccines, and their ethical testing. In Saheli's 1998 publication, Target Practice: Anti-Fertility Vaccines and Women's Health, the writers argue that current research violates international guidelines on the scientific basis for human trials, on research with unpredictable hazards, risk-benefit assessment, informed consent, the use of lactating women as research subjects, and protection of participants who suffer injury.

The toothless watchdog in the many cases of unethical research brought to the media's attention, has been the Indian Council of Medical Research (ICMR). Though in 1980, the ICMR's policy statement on medical research called for setting up ethics review boards at all research institutions, and insisted that it would not fund research which had not undergone ethical review, this national body has been unable to play a major role in the monitoring of its own research, not to speak of other organisations. Senior officials have admitted that many of the ICMR's own institutions do not have functioning ethics committees. Even where committees exist, they are driven by internal politics and the pressure for funds. They are worried that if the ethics committee rejects the project, the project—and the associated funds—will go to another institution. Not a small matter in these days of cutbacks.

Equally important, the ICMR has no say in research it does not fund. So unethical research is exposed by activist organisations and the press, but goes unpunished in the absence of a strong regulatory system. Nor can victims of research abuse count on the legal system to help them. In the US, errant researchers can be sued. In countries like India, even the rich don't believe the legal system works; the poor will rarely consider approaching it for justice.

Violations

The search for an AIDS vaccine is a good ex-ample of the potential for unethical research and how desperate people volunteer to become guinea pigs. In May 1999, IS Gilada, the founder-director of an NGO working with HIV patients, was arrested for helping a US company test a vaccine on 10 HIV positive people. The vaccine, administered in 1994, reportedly was based on a strain of bovine immunodeficiency virus. Investigating officer Dhanraj Vanjari charged that "Experiments were con-ducted under the guise of treatment… The doc-tors may have obtained consent, but the patients were under the impression that they were receiving treatment, not an untested, unapproved vaccine." The authorities responded four years after the trials, when one of the HIV-positive people filed a criminal complaint; he was under the impression that the vaccine was a cure for AIDS. The petitioner died and the case was pursued by his relatives. More recently, the National AIDS Control Organisation announced that India would participate in properly regulated trials for AIDS vaccines, for which cohorts from 'high risk' groups were being identified—STD clinic clients, commercial sex workers and injecting drug users.

A senior HIV researcher once remarked on the irony of AIDS vaccine research. The experimental group is given the vaccine, the control group a placebo. Both groups are supposed to be counselled in safe practices, and then observed to see how many become infected with HIV. In order to prove the vaccine's efficacy, the control group must get a relatively high rate of infection. In other words, the researcher needs participants to undertake unsafe behaviours and for some of them to develop a fatal condition so that the vaccine is proved effective. In a 1994 presentation to the American Association for the Advancement of Science, Riedar Lie, professor of philosophy at the university of Bergen who worked in Sri Lanka, noted that vaccine trials were being initiated in developing countries without any guarantee that they will be available there once it is proved effective—a stated ethical requirement.

Research on AIDS drugs has begun in earnest in India. According to The Indian Express, various trials looking at the feasibility of drugs to reduce vertical transmission, as well as prophylactic treatments for health workers ex-posed to HIV in their work, are taking place in 11 centres across the country. In Sangli, a local NGO successfully challenged the trial design looking at HIV transmission through breast-feeding in a local hospital. The Indian Express article points out that both doctors and patients are looking at collaborative research on AIDS drugs as an opportunity for these drugs: "But what will happen when the trial is over?"

AIDS research was responsible for triggering off a heated international controversy on the ethics of research in developing countries. It also led to a movement—opposed by one section of the research community—to revise international ethics guidelines to permit variable standards of care in developing countries. In 1997, an article and an editorial in the New England Journal of Medicine attacked ongoing clinical trials involving more than 15,000 pregnant, HIV-positive women in Asia and Africa, which wanted to see if a short course of the drug AZT reduced the chances of the women passing the virus to their children (a longer course of AZT, the 076 regimen, was accepted as standard treatment in the US). The problem was that the women in the control group were given a placebo or sugar pill instead of the established treatment. Such research would have failed ethical review in the US. It also violates current international guidelines requiring that Western researchers in developing countries provide study participants clinical care that meets the standards of care in their home country.

The studies' proponents argued that the longer course of AZT was too expensive and difficult to administer in the research environment. Alternative study designs would require a longer study, and this information was needed urgently to help thousands of women in developing countries. The participants, they said, had given their informed consent, and local ethics boards had approved of the studies. Finally, the argument was that the control group would not have had access to the drug anyway.

However, others pointed out that the re-searchers had got their information by knowingly putting participants at risk, which went against all ethical principles. And the benefits of this research would not go to the participants' community—where even the short-course AZT was unaffordable because pharmaceutical companies fought to keep the prices high—but to the developed world.

More recently, a study in Uganda looking at the role of sexually transmitted diseases and HIV viral load as risk factors for heterosexual transmission of HIV, omitted to provide STD treatment to one group in the study. Also, contrary to standard practice in the US, researchers did not ensure that HIV-positive people in-formed their partners of their status. Ninety partners became infected with HIV during the course of the study.

Such controversies have been directly be-hind the current move in the World Medical Association to revise the Declaration of Helsinki. The Helsinki Declaration is one of a set of international statements developed to ad-dress ethical issues raised by international re-search. Although not legally binding, such statements carry a lot of weight in the international community, and are taken seriously by regulatory bodies that formulate ethical guide-lines or regulations for biomedical research. If the Declaration is revised, researchers in developing countries will be required to provide participants the care depending on the standards in the country where the research is being done.

ICMR guidelines

Such controversies, and the growing potential for drug research in India may have also hastened the ICMR's own interest in developing ethical guidelines for research. Perhaps it also envisaged the need for guidelines and an ethics review structure in place if India were to become the research centre it aspired to be.

Drawn up in 1997, the proposed guidelines were the first effort to set down detailed guide-lines. The last document addressing this subject was a four-page policy statement issued in 1980, and acknowledged as inadequate by senior ICMR officials. Over the next year, the ICMR held a series of public discussions all over the country.

However, these guidelines attempted too much. For example, they included within their scope assisted reproductive technologies such as in-vitro fertilisation and related technologies used primarily—but not exclusively—for infertility, for which it set down standards of practice, not research. It also failed to articulate the different issues arising in research and medical practice, and this was particularly evident in the sections on transplants and assisted reproductive technologies. At the same time, the proposed guidelines did not adequately ad-dress genuine problems in research ethics, which Indians are bound to encounter with growing collaborative research. There has been no information on how they will be implemented; nor how they will govern institutions outside the ICMR's ambit. Still, the 1997 guidelines will represent a big step forward for research ethics, once they become public.

In July 2000, a report in The Times of India announced that after more than two years of deliberations, the ICMR's guidelines had been finalised and would be made public within a week. It's September and we're still waiting.

Meanwhile, the WHO has pointed out that 90 per cent of health research in the world ad-dresses the problems of the healthiest 10 per-cent of the population. We need research which addresses the needs of majority of our people. The question is: can this be done ethically and effectively?

Ethical island

If any country in the region is serious about medical ethics, it has got to be Sri Lanka. Professor Janaka de Silva, faculty in the department of medicine, University of Kelaniya and joint editor of the Ceylon Medical Journal, argues that ethics committees in Sri Lanka are hard to get past. "Medical ethics is a well-developed area in the country," he writes. "Most medical schools have ethics modules running through the five-year course." (Only a couple of medical schools in India have an extended programme on medical ethics in the syllabus.)

As for collaborative research in Sri Lanka, de Silva delineates the criteria: "There are three 'requirements' for international collaboration: the subject must be relevant to Sri Lanka, the material difficult to collect in the West, and it should be an area in which Sri Lanka does not possess the technical expertise, such as basic science research in tropical diseases." All universities and research institutes have ethics committees, and the Sri Lanka Medical Association provides ethical review of researchers without direct access to institutional ethics committees. Though research is not registered in a central system, it is registered with the various universities or grant providers, university research committees, the National Research Council, or the National Science Foundation. And research grants cannot be awarded unless ethical approval from the relevant ethics committee is submitted with the proposal. Most journals will not publish articles unless an ethics certificate is submitted with the paper.

This system works fairly well, according to the professor. "In fact some of the ethics committees and journals are considered too demanding and strict by many researchers in this country. Research in paediatrics is the toughest to get ethical clearance for. The Sri Lanka Medical Association has a standing committee for ethics which reports to the Council every month." Professor Priyani Soysa, chairman of National Health Research Committee, notes that the committee is preparing legislation on ethical review for all research in the country.

The system works better in Sri Lanka than in India probably because "it's a smaller country, easier to regulate, people are literate and becoming more demanding", writes de Silva, who argues that this has resulted in powerful and independent ethics committees with top rate researchers. Academic discussions on research often include references to ethical issues.

But what is to prevent individual researchers from coming in and conducting their own research, without institutional support? This might happen in survey research, de Silva concedes, "but interventional research such as drug trials, or anything requiring taking blood or tissue samples, may not be conducted without permission." A foreign doctor who wants to do that "would have to get registered locally with the Sri Lanka Medical Association". Presumably, then, the medical association's ethics committee would be kept informed.

No debate in Pakistan

Medical ethics, particularly research ethics, is not debated extensively in Pakistan, says Kausar S Khan of the Aga Khan university. But his university has been teaching bioethics to undergraduate students for at least a decade, and recently introduced it at the resident doctors' level. Though the university ethics review committee reviews all research within the institution, there is little information on trials in other centres. "Though bioethics has entered the discourse in the physicians' community in Pakistan, it is not as organised as it should be," says Dr Khan.

The Pakistan Medical Research Council (PMRC) has its own Ethical Review Committee that reviews any research project submitted involving human beings, for approval and funding. In 1992, when the PMRC conducted a national health survey in collaboration with the US National Centre for Health Statistics, and the Federal Bureau of Pakistan, there were no research ethics guidelines in the country. A paper published in the October 1992 issue of the Pakistan Journal of Medical Research describes the ethical issues addressed in the course of the survey, and its compliance with WHO guidelines. The standards set in the survey guided future epidemiological studies in the country. An institutional review board was established during the study design period.

Unsafe practices

Bangladesh has long been the site of extensive research in maternal and child health and in contraceptives, including the hormonal implant, Norplant, and injectable hormones such as Depo Provera. A medical researcher notes that there is strong opposition to the way both family planning and other re-search is carried out in the country but provides no further comments. In her article on the Global Reproductive Health Forum page, Farida Akhtar of UBIGIN, a Bangladesh-based NGO, declares: "Research and pre-market trials are carried out on the bodies of poor women in Bangladesh for new contraceptives. Women become subject of these trials without their knowledge or consent…More coercion is exercised as they do not want to give women any choice of opting out of the trial." However, the article provides insufficient details on the studies referred to.

In an undated article on the site www.quinacrine.com, professor Syeda Nurjahan Bhuiyan, a senior faculty member of the Chittagong Medical College, reports of having sterilised 710 women since 1989 with an antimalarial drug not approved for use as a chemical steriliser, through the medical college and two community clinics. Her comment on the women's profile is telling of how the practice is seen by the involved doctors: 65 percent of the women were between 31 and 40 years old; 78 percent had four or more children; 80 percent were either illiterate or had only a primary education, and 75 percent had a family income of less than 3000 taka a month. There is no mention of information to the women, let alone con-sent, nor of how many women were actually followed up on and for how long, but the doctor reports that "side effects were mild and transient", and that there were "no life threatening complications". Bhuiyan states that QS is safe and "acceptably effective".

One organisation that may be heading towards the right direction is the International Council for Diarrhoea Disease Research, Bangladesh (IDDR,B)—at least going by the fact that it mentions the functioning of its ethical review committee. This research body funded by various international organisations, carries details of its history, composition and ongoing work. It has an ethical review committee that meets regularly to examine and consider the ethical issues of research protocols involving human subjects, and has a subcommittee to monitor on-going research. The 15-member full committee comprises four from the Council, one each from the Programme Coordination Committee, Bangladesh Medical Research Council, WHO's Country Programme Office in Bangladesh, and eight from varying disciplines.

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