In the global context of unethical practices in research involving human participants, the demand for strict monitoring and laws governing such work becomes more relevant everywhere.
THE most significant outcome of the Johns Hopkins-Regional Cancer Centre drug trial controversy could be an increase in public awareness in India about clinical trials and the effect of unseen, market-driven forces that threaten the safety of the patients involved and taunt the objectivity of investigators and the scientific integrity of drug trials.
Larrea tridentataUnlike in India, awareness about the extent to which academic research has become interlinked with the pharmaceutical and biotechnology industries and other commercial interests and the benefits and risks involved in such alliances is well-established in developed countries like the United States.
Daniel J. Kevles, Professor of History at Yale University (whose research interests include the interplay of science and society, history of modern biology and scientific fraud and misconduct) explained in an e-mail message to Frontline: "Since the 1970s in the U.S., the growth of biomedical research in academia has outpaced the growth of federal funding for its activities. University administrators have increasingly felt the need to turn to private, including industrial biotechnology, sources for support. For this reason, among others, they have fostered close relationships between biomedical firms and the laboratories on their campuses."
The most striking example for well-known academic-research institutions in the U.S. having such links with industry is perhaps the Johns Hopkins University (JHU) itself. Spurred by the fear of being left behind in the race for research funds and top-notch faculty and students, the institution, once dedicated to pure research, is now in the forefront of universities trying to forge partnerships with business.
After the cancellation of federal funds following the death of a "healthy volunteer" participating in an asthma study at the JHU on June 2, the university has remained in media focus with regard to the growing involvement of clinical investigators and research institutions with business. According to a report in The Baltimore Sun, the university had filed more patent applications in 1999 than all but two other major research centres in the U.S. Moreover, in recent years the JHU had helped launch 18 companies, and the volume of corporate-sponsored research at its medical school had nearly quadrupled in the last 10 years, the report said.
The point in The Baltimore Sun article is in its title - "The changing creed of Hopkins Science". It spoke of how the university's culture was being transformed as it embraced business opportunities, allowed its scientists to be consultants and paid scientific advisers to corporations and to own patents for discoveries developed in its laboratories using corporate funds. Significantly, it focusses on the risks that this new creed brings in its wake, "for the integrity of research, for the safety of patients participating in experiments and for the university's most valuable asset - its reputation".
The report quotes JHU officials as saying that the university's defence against bias in corporate-sponsored research is "disclosure" - the rule that volunteers in drug studies be told when the JHU has a financial interest. There is no bar on scientists conducting research when, for example, they have more than a certain amount invested in the company sponsoring the work, a situation that could bring forth many an ethical dilemma. "Instead, Hopkins officials say they 'manage' financial conflicts of interest by taking steps to discourage abuses - requiring scientists to place stock in escrow and to disclose to patients and publications their financial ties in drug trials," The Baltimore Sun report said. However, such a disclosure was conspicuous by its absence in the trial conducted on patients at the RCC by the JHU Biology Professor, Dr. Ru Chih C. Huang.
The JHU provides but one example of the conflicts of interest that face academic institutions in the developed world. Almost all the major universities today face the problem of having to rise above such conflicts of interest and yet are unable to resist the need to relax rules and to lend its name for almost purely commercial ventures. Recently, when the main academic "rival" of the JHU, Harvard University, thought aloud about relaxing its strict conflict-of-interest rules, there was a hue and cry in the U.S. It prompted The New England Journal of Medicine, widely regarded as one of medicine's most distinguished and influential journals, to write one of its best-known editorials - "Is Academic Medicine for Sale?" - urging Harvard to encourage other universities to adopt stronger conflict-of-interest guidelines instead of trying to soften its own rules.
All over the world one can find instances of commercial ties and financial requirements leading to unethical practices in research involving human participants, mainly to satisfy the market's need for speedy, cost-effective development of drugs and medical devices. This has also increased the demand for strict monitoring and laws regarding human research, especially in developed nations like the U.S.
On April 18, a U.S. presidential commission, the National Bioethics Advisory Commission, constituted to suggest ways to improve ethical conduct of international clinical trials, recommended a series of steps "to reduce the potential for exploitation of research participants in developing countries, ensuring that studies are responsive to the health needs of the country, and ensuring that post-trial access to successful research products are improved".
According to a press statement issued by the commission soon after its report was presented to President George Bush, its chairman (and president of Princeton University) Harold T. Shapiro said that the potential for exploitation of participants from developing countries by researchers and sponsors from prosperous countries "is cause for a concerted effort to ensure that protections are in place for all persons participating in international research".
Significant in the context of the JHU-RCC drug trial controversy is the recommendation of the commission that efforts to enhance research collaboration must account for the capacity of the ethics review committee in developing countries to review research, and the need for U.S. researchers and sponsors to ensure that their research projects are conducted "according to ethical standards applied in the U.S".
The research collaborations are also to comply with some basic requirements for the protection of human research participants, such as prior review by ethics review committees, minimisation of risk and having a reasonable risk-benefit ratio, voluntary informed consent by each participant and an equitable distribution of the burdens and benefits of the research.
Prof. Kevles agreed that this was indeed a new area of conflict of interest - of comparative requirements of ethical research conducted in developed and developing countries. "Human trials tend to be more strictly regulated, and thus more costly, in the U.S. than in developing countries. It is therefore tempting to conduct trials in the Third World," he said.
"THE Hopkins-RCC drug trial controversy is a wake-up call for India," said Dr. K. Mohandas, Director of the Sree Chitra Tirunal Institute for Medical Sciences and Technology. "India is an amalgam. We have the best of institutions and the worst. We have no uniformity of standards in our institutions and the regulatory mechanisms are not often very effective. But because of that we cannot keep away from doing clinical trials, because then we shall not be able to develop our own research and shall be completely sidelined by the rest of the world," he said.
Dr. C.R. Soman, chairman of the activist organisation Health Action by People, said that if the 'Ethical Guidelines for Biomedical Research on Human Subjects' formulated by the Indian Council of Medical Research's (ICMR) Central Ethics Committee on Human Research (CECHR) was accepted and adopted at least by the medical colleges in the country, India could be said to be truly ready for clinical trials. The ethics committee is headed by Justice M. N. Venkatachaliah, former Chief Justice of India.
Dr. Soman said that along with the concerns raised about clinical research involving scientists from reputed academic institutions which have commercial ties, multinational pharmaceutical companies are flooding the Indian market with a spate of "new molecules", "a whole range of chemicals". "But the majority in the medical profession is supremely ignorant of this, and drug manufacturers get away with everything. The majority of the doctors are unaware of even the different phases of drug development, or the principles behind the requirement for informed consent," he said.
Dr. Soman said the situation was compounded by the emergence of contract research organisations, "sort of event managers", who took up contracts to organise clinical trials and provide related services from the pre-clinical stage to the marketing of the drug for the pharmaceutical companies. He said: "All they require of the general Indian physician is to dot the 'i's and cross the 't's, and the majority of doctors mechanically do it with no intellectual input from their part."
However, Dr. Soman said, this did not mean that all companies were engaged in such operations. He said that out of self-interest many of them might be meticulous in following ethical norms while conducting clinical trials or introducing drugs into the market. "But there are a lot of imposters."
Dr. Mohandas said: "We really don't know what exactly is happening in the country. We don't know whether testing of drugs or clinical Phase I and II research (to gather data on the safety and efficacy of a drug respectively) is taking place on a large scale even in institutions or clinics not equipped to conduct such experiments. In the absence of a mechanism for monitoring and supervising clinical trials, we do not know the magnitude of the problem. There was this instance when a banned drug, which was used for the treatment of malaria, was tried out as a method of sterilisation in women, and there was a major public campaign by some doctors and activists. It definitely is there, but how big is the problem, we don't know."
However, cardiologist Dr. G. Vijayaraghavan, formerly of Kuwait University, cautioned that it should not be argued that clinical trials conducted on human beings should be stopped forthwith. "What we need to consider is the reason why, despite the widespread conduct of clinical trials all over the developed world, there is not much room left for complaints there," he said. "The answer lies in building up and strengthening institutional checks and balances. Unlike the happenings at the RCC, there are any number of examples of faults and ethical pitfalls in clinical trials being detected effectively by institutional review boards or other monitoring agencies sufficiently early and of even drugs or trials being withdrawn without affecting the faith that a patient has in his physicians," Dr. Vijayaraghavan said.
He added: "Monitoring has to be strengthened at the institutional level based on the well-laid-out principles enunciated in the Helsinki Declaration, the guidelines issued jointly by the Council for International Organisation of Medical Sciences and the World Health Organisation, the ICMR guidelines and so on. Each institution has to establish clear principles to evaluate research on human subjects and specific measures to protect human subjects from possible harm."
Already, according to Dr. Mohandas, there are moves in the right direction. The ICMR is planning to set up training centres in several parts of the country to provide support to institutions and professionals on the ethical issues involved in human research. International workshops are also being organised at the Sree Chitra Tirunal Institute and three universities - in South Africa, Mexico and in the U.S. at Harvard - on ethical guidelines in health research with special reference to international research. The seminar held in Sree Chitra had participants from 15 countries, the majority of them from the Third World. Dr. Vijayaraghavan said: "As long as institutions learn to insist and ensure meticulously that ethical safety guidelines are followed, developing countries like India need not be afraid of international collaborations in human research, pharmaceutical companies or contract research organisations."
