- FROM BIOETHICS BRIEFINGS
Research in Resource-Poor Countries
Framing the Issue
In the 1990s, the term “the 10/90 gap” was used to refer to the gross inequity that only about 10% of global spending on health research was directed at alleviating the disease burdens of low- and middle-income countries, where roughly 90% of the world’s “preventable mortality” occurred. As diseases such as cancer, diabetes, and HIV/AIDS rise in global incidence, investment in research on these diseases are of increasing value to the developing world. Strategic partnerships between public, private, and nonprofit sectors have also formed to address health problems that afflict only or mainly low- and middle-income countries. Inspired by the World Health Organization 2020 roadmap to eradicate neglected tropical diseases, the 2012 London Declaration on Neglected Tropical Diseases seeks to advance research and development to find new treatments and interventions for neglected tropical diseases. Still, while the 10/90 gap has somewhat narrowed, it remains the case that current research and development efforts do not adequately target the health needs of all, particularly the world’s poorest populations.
International research holds the promise of promoting global health, which aims at improving health outcomes and equity for populations worldwide, and helps countries deal with the interconnected, cross-border threats of emerging and reemerging infectious diseases. Research funded by entities in wealthy countries and conducted in low- and middle-income countries is, however, beset by significant ethical issues because of the enormous disparity in health and health resources. The last decade has seen an increase in pharmaceutical and biotechnology companies outsourcing research to low- and middle-income countries, and while they may be moved by scientific reasons (such as the high prevalence of disease in these countries), they often do so for expediency’s sake: low financial and regulatory burdens, and the ability to recruit a large number of subjects quickly. Potential study participants there face heightened risks of exploitation due to weak socioeconomic conditions, limited health care access, and little experience and understanding of research. New or improved drugs and other products become available in wealthy nations through research–a good thing–but they may not reach the countries where research was conducted because of weak purchasing power. Thus research participants and communities in low- and middle-income countries could end up bearing the lion’s share of the risks and burdens of research without receiving a fair share of benefits.
As health care research and development increasingly crosses international borders, whether for scientific, philanthropic, or commercial reasons, there are several ethical considerations for researchers and policymakers:
- What are the ethical obligations of wealthy countries engaged in funding or conducting research in resource poor countries?
- What values should guide this research?
- How should ethics reviews be handled, and by whom, in light of intercountry differences in medical and research practices and law?
- Are changes needed in the process of obtaining informed consent from research participants, given cultural variations in understanding the principle of respect for persons?
- What safeguards are needed to protect research participants in low- and middle-income countries from possible harms and exploitation?
Challenges to Ethical Review
To safeguard research participants abroad from harm or exploitation, several international guidelines recommend that externally sponsored research be reviewed by ethics committees or institutional review boards (IRBs) from both sponsor and host countries. However, a resource-poor country may lack the human resources or an adequate research ethics governance structure to conduct effective ethics review. Another problem is that the independence of a resource-poor country’s IRB may be compromised by the prospect of collaboration with powerful sponsors from wealthy countries. In light of these deficiencies in ethical oversight, when U.S. government funds are used for a trial conducted abroad, researchers must comply with U.S. human subjects protections, and the approving IRB (which may be foreign) must obtain a Federalwide Assurance, an agreement to comply with the ethical standards set by the U.S. Office for Human Research Protections. . Non-federal sponsored foreign clinical trials do not have such requirements, but the U.S. Food and Drug Administration will only accept foreign trials’ results as evidence in approval applications if the sponsors adhere to the FDA’s good clinical practice guidelines to adequately protect human research volunteers, and allow the FDA to inspect the study site.
A standard requirement of ethics review is to ensure the informed consent of research participants. However, applying the requirements of valid informed consent may not only be difficult but even inappropriate in countries where familial and physician-patient relationships are more hierarchical than they are in the U.S. Hastings Center fellow Ruth Macklin, a bioethicist at Albert Einstein College of Medicine in New York, says that while procedural mechanisms should be allowed to differ between and within countries, ethical standards that pertain to universal human rights and welfare should be consistent. Using less formalized consent forms and seeking permission from community leaders or spouses may be accepted as cultural adaptations of the mechanism of consent. As emphasized by the International Research Panel of the Presidential Commission for the Study of Bioethical Issues, however, ensuring informed consent of each prospective research participant should remain the universal standard.
Standards of Care: Whose Standards?
Ethical guidelines for clinical research stipulate that patients participating in medical studies should have access to proven treatments, if available, for their condition. Such guidelines were put into place after the Tuskegee syphilis studies in which poor black men with syphilis in Alabama were studied for decades without getting antibiotics. But when research is conducted in low- and middle-income countries, what should be the standard of care: that of the host country or that of the sponsoring country, which is likely to be higher?
Questions about standards of care were brought into sharp focus during the 1990s when clinical trials were conducted in parts of Africa and Southeast Asia to see if a short course of the drug zidovudine (AZT) could prevent mother-to-child transmission of HIV. The trials, funded by the U.S. government, compared the short course of AST to a placebo, but critics argued that the trials should have compared it to a long-course regimen, which was the standard of care in the U.S. The critics cited the Declaration of Helsinki, which stipulated at that time that in “every medical study, every patient–including those of a control group, if any–should be assured of the best proven diagnostic and therapeutic method” (italics ours).
Since that controversy first emerged, the Declaration of Helsinki has been revised several times. It currently permits departure from a default universal standard of care on compelling scientific grounds or when subjecting the patients or research volunteers to suboptimal care would not result in additional risk of serious harm. This language has been criticized for being ambiguous, possibly still disallowing valuable research into suboptimal but very economical care that could provide substantial benefits in resource-poor countries. In 2008, the FDA stopped requiring drug company trials conducted abroad to follow the Declaration of Helsinki. Thus, while there has been a shift towards allowing deviation from the best standard of care in international research, there is a lack of international consensus on the subject.
Another ethical concern is the extent to which treatment and care not directly related to the research design—and not usually available in the host community or country—should be provided for research participants. With preventive HIV vaccine research, some argue that sponsors and researchers have an obligation to provide care and treatment, including antiretroviral therapy, to those who become infected with HIV as a result of their behavior (and not the vaccine) during the course of the trial. Others say that the huge cost and logistical burden this would impose on sponsors and researchers would threaten the future of vaccine trials.
In 2005, the governments of Cambodia and Cameroon suspended ongoing placebo-controlled trials of the drug tenofovir to prevent HIV infection in sex workers when both governments could not reach an agreement with the sponsors and investigators on the level of treatment and care for those who become HIV-positive during the trials. “Ethical Considerations in Biomedical HIV Prevention Trials,” a guidance document from the Commission of the European Communities Joint United Nations Programme on HIV/AIDS, last revised in 2012 in collaboration with the World Health Organization, states that there is now consensus that sponsors have the responsibility to ensure access to internationally optimal care and treatment regimens, including antiretroviral therapy, to those who become infected during HIV prevention trials. This argument has been expanded by some commentators into a more general obligation to provide ancillary care to research subjects, although this has not been adopted by any regulatory body.
INTERNATIONAL GUIDELINES FOR ETHICAL RESEARCH
- World Medical Association, Declaration of Helsinki, Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects
- Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization, International Ethical Guidelines for Biomedical Research involving Human Subjects
- European Group on Ethics in Science and New Technologies to the European Commission, Ethical Aspects of Clinical Research in Developing Countries
- Joint United Nations Programme on HIV/AIDS (UNAIDS), Ethical Considerations in Biomedical HIV Prevention Trials
- National Bioethics Advisory Commission, Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries
- Nuffield Council on Bioethics, The Ethics of Research Related to Healthcare in Developing Countries
- Presidential Commission for the Study of Bioethical Issues, Research Across Borders: Proceedings of the International Research Panel of the Presidential Commission for the Study of Bioethical Issues
In the midst of an infectious disease outbreak in low- and middle-income countries, there may be desperation for a cure or vaccine. In cases where the standard of care is inadequate for treatment and prevention, there will be an urgent need for speedy research and development of effective interventions. Given the urgency for research, is it acceptable to alter standard scientific methodologies and subject protections?
The Ebola epidemic in 2014-2015 raised this question. The outbreak infected at least 28,000 individuals, killing over 11,000, primarily in Guinea, Liberia, and Sierra Leone. At its height, there were great fears that the epidemic could spread globally. Ebola is a deadly disease, killing about 40% of people who contracted it, and during the outbreak there was no proven vaccine. To ensure both quick development of and equitable access to experimental vaccines, some argued for eschewing the “gold standard” of randomized placebo-controlled trials, in favor of approaches that increase the chances of subjects receiving an experimental vaccine. Others objected to these approaches on at least two grounds. One, compromising scientific integrity is unethical because it jeopardizes the personal and social benefits that justify exposing subjects to risky experiments. And two, the emphasis on desperate research for a vaccine obscures more important efforts to improve basic care management (including hydration) that have a more certain effect on mortality and morbidity.
In the end, at least one promising vaccine was successfully developed without being tested against placebo. Defenders of the compromise may point to the apparent effectiveness: during the study, none of the thousands who received the vaccine contracted Ebola. However, the test was performed just as the epidemic was ending and there were very few new Ebola cases in the target population. Without a placebo control, it was unclear whether the vaccine or a combination of epidemic downturn and treatment effects explained the lack of infection in the study population. This uncertainty may hamper investment in and stockpiling of the vaccine in anticipation of another outbreak.
Fairness and Benefit Distribution
It would be unethical for a country to bear the risks of hosting clinical trials without reaping some benefits. But what should these benefits be, and how should they be ensured?
The National Bioethics Advisory Commission and the Nuffield Council on Bioethics recommend that posttrial benefits, such as therapies developed as a result of the research, should be discussed and agreed upon by all relevant stakeholders from sponsor and host countries before the initiation of the research. This difficult negotiation involves the challenges of calculating the value of the research, deciding who will receive benefits, and addressing structural issues in the host country’s health system that may limit access to those benefits. Opinions differ on whether posttrial benefits and implementation plans should be guaranteed or merely defined.
What would constitute fair posttrial benefits is another highly contentious issue. The Council for International Organisations of Medical Sciences (CIOMS)–a group established by the WHO and the United Nations Educational, Scientific, and Cultural Organization (UNESCO)–stated in its 1993 guideline that “as a general rule, the sponsoring agency should agree in advance of the research that any product developed through such research will be made reasonably available to the inhabitants of the host community or country at the completion of successful testing.” It was sharply criticized by participants of the 2001 Conference on Ethical Aspects of Research in Low- and middle-income countries because focused on the type rather than the level of benefit, and applied only to successful Phase III clinical trials. The group suggested a framework of benefits that included health services beyond those essential to conducting the research, and sharing in financial rewards or intellectual property rights.
In response, CIOMS revised its guidelines in 2002 to include under its “reasonable availability” any knowledge generated from the research, in addition to any product developed. However, draft revisions to the CIOMS guidelines released in 2015 removes the language of “reasonable availability,” replacing it with a requirement to “make every effort to provide communities with any interventions or knowledge developed, in collaboration with local authorities.” The revisions also weaken the strict requirement for sponsors to provide posttrial benefits to subjects themselves, stating more tentatively that sponsors “may” have such an obligation.
Another concept widely endorsed as a requirement for fairness in international research is responsiveness to the health needs or priorities of resource-poor countries. Commentators have linked responsiveness to obligations of global justice such that sponsors and researchers from wealthy nations should conduct research in poorer ones only if the research questions could enhance the latter’s health systems to address their urgent health problems. It remains a matter of debate, however, why it is unethical to do research on a disease or condition that is not a health priority of a developing country but could potentially save or improve the lives of a good number of people living there and elsewhere.
Major sources of funding for research in low- and middle-income countries include:
- Bill & Melinda Gates Foundation
- Fogarty International Center (National Institutes of Health)
- Global Fund to Fight AIDS, Tuberculosis and Malaria
- International Finance Facility for Immunization
- President’s Emergency Plan for AIDS Relief (White House)
- Joint United Nations Programme on HIV/AIDS (UNAIDS)
- Wellcome Trust
- World Health Organization
Empowering Host Countries
In dealings between nations, there is often no shared international standard of justice. As a counterbalance to potentially exploitative research, partnership models have emerged. True partnerships require that the research capacity of developed and low- and middle-income countries be bridged. Writing in the Bulletin of the World Health Organization, Mary Ann Lansang and Rudolfo Dennis define capacity-building as “the ongoing process of empowering individuals, institutions, organizations and nations to define and prioritize problems systematically, develop and scientifically evaluate appropriate solutions, and share and apply the knowledge generated.” (See Resources.) During the last 10 years, several groups (see box, “Financial Support) have funded capacity-building initiatives, including:
- educational programs in the biomedical sciences,
- training programs and global forums for research ethics and ethics
- contribution to research and health care infrastructure, and
- creation of networks and alliances to deal with specific health care issues.
In the future, capacity building is likely to expand from late-phase clinical drug trials to emerging areas of biomedical research such as early-phase gene transfer trials and genomics research involving biobanks and sharing of data and samples of human biological material. The ability of researchers from low- and middle-income countries to analyze and publish data is essential to mutual respect, equity, and trust in collaboration. Success will depend on adequate funding, sustainability and strategic resource planning and allocation, and political will.
Voo Teck Chuan, PhD, is an assistant professor and G. Owen Schaefer, PhD, is a research fellow at the Centre for Biomedical Ethics at the National University of Singapore.