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Applied Clinical Trials
Addressing the health needs of host nations while guarding against subject exploitation and other pitfalls.
In the past 10 years, there has been a sharp increase in research conducted with human subjects. Research with human subjects, including clinical trials, has become more prevalent globally (i.e., outside the United States) and especially in developing countries.1,2 The increase in clinical trials in developing countries is fueled by the recent push for global commerce. Trends include the pharmaceutical industry's interest in new drugs; new emerging markets; emerging infrastructure from investigators in developing countries in the newly found, home-grown pharmaceutical services corporations; inability to conduct such research in developed countries; and the less costly and less restrictive regulatory environments found in developing countries. There are also trials sponsored by the National Institute of Health (NIH) and the World Health Organization (WHO) for largely humanitarian reasons. Private foundations, such as the Bill and Melinda Gates Foundation and the Wellcome Trust, also sponsor research in the developing world.
The studies contemplated in developing countries fall into three categories: development of new drugs, development of drugs targeted specifically to developing countries; and expansion of existing drugs for other therapeutic uses. These conditions have resulted in rapid growth of research with human subjects without a similar and adequate growth in infrastructure to protect subjects. Therefore, in addition to the concerns in the past 10 years that have plagued U.S. research with human subjects,1,3,4 a host of new and unique concerns emerged because of the risk of exploitation of poor countries by the wealthiest nations.5 This is, in part, because a large portion of the population in these developing countries lack infrastructure for basic health care. This results in lack of access to basic health care needs. Thus, citizens are vulnerable to coercion for enrolling in clinical trials.
The objective of this paper is to address some of the fundamental moral issues faced by industry and organizations conducting research with human subjects, including clinical trials, in developing countries. Suggestions based in large part on the work of others1,2,5,6 will be offered as to the fundamental principles that one must follow to conduct research with human subjects in developing countries. This paper will address the three most important issues when conducting research with human subjects in developing countries: relatedness of the study to the health needs of the host country; the use of placebo; and the availability of the studied drug to the local population after the trial.
The ethics of conduct of research with human subjects evolved in the past century in response to reports by respected groups about abuses, scandals, and atrocities.
The most important event in this area is the Nazi experimentation with human beings. The first report is the result of the tribunals in Nuremberg of the Nazi physicians by the U.S.-appointed court. The court issued 10 principles, now known as the Nuremberg code (1947).7 The first and most enduring principle is the absolute requirement for informed consent.
Within the United States, the public exposure of the 40-year Tuskegee syphilis study of 400 African-Americans without their true consent has had a profound impact on U.S. bioethics.1 A U.S. national commission deliberated for five years on these troubling issues, resulting in the Belmont Report (1979).8 The Belmont report enunciated three principles of American bioethics: respect for persons; beneficence; and justice.
Following these events and others, we have now accepted in the United States the existence of several tiers of protections for human subjects. From national oversight (by the federal government), institutional review boards (IRBs) or ethics committees (ECs) as the gatekeepers, and the principle of informed consent, subjects are safer. These protections and principles have influenced other countries as well. However, there may be important differences in the application of each of these tiers of oversight.
In the past five years, there have been numerous discussions, reports, articles, and committees dealing with issues of clinical trials in the developing world. Two reports from the United States stand out in this regard. One report was from the U.S. Office of Inspector General (OIG)2 on the globalization of clinical trials. The OIG report dealt primarily with the findings of deficits at the regulatory level and proposed recommendations.
Among the deficits found, the OIG report cited a growing number of studies being conducted outside the United States with oversight by the Food and Drug Administration (FDA). Moreover, there is a noticeable expansion of clinical trials in foreign countries by various sponsors. Furthermore, they found that the FDA was lacking assurance of adequate compliance in foreign countries. In addition, key entities involved in global research with human subjects raised concerns as to the adequacy of oversight by U.S. agencies. The OIG then recommended that the regulatory agencies, such as the FDA or the Office for Human Research Protections (OHRP), help foreign ethics boards (ECs or IRBs) build capacity; encourage sponsors to obtain attestation from foreign investigators (i.e., to adhere to ethical principles); encourage greater sponsor monitoring; develop a database to track growth; and encourage accreditation of IRBs and ECs. These are all sound regulatory solutions to compliance issues. However, the report does not deal with the fundamental ethical issues of conducting research in developing countries.
In contrast, the National Bioethics Advisory Commission1 addressed the ethical as well as regulatory issues. NBAC proposed 28 recommendations. The commission emphasized the fundamentals of ethical research: prior review, minimization of risk, proper risk/benefit ratios, informed consent; equal regards; and justice. The report further stresses the importance of considering the cultural context of the local area. It warned against using blanket waivers of informed consent, although its permissibility could be considered under special circumstances. These recommendations are a landmark in the development of ethical standards of research in developing countries. However, the effectiveness of these recommendations will have to be judged over time. Nevertheless, initial indications from OHRP and FDA indicate a strong and positive movement in this direction.
Finally, the 2004 European Directive on Clinical Trials,9 even though it relates to European members states, will have a large and positive impact on research conducted in developing countries. This new directive comes closer to the FDA rules in dealing with clinical trials data in support of a drug license than has previously been recommended. For example, Phase I clinical trials now require prior approval of their equivalent to FDA regulations prior to initiation of the study.
The three Belmont Report principles—respect for persons, beneficence, and justice—are widely considered and, at least in principle, applicable globally. However, differing environments such as those in developing countries may result in important differences when these principles are applied within local contexts. It is important that the ethics of conducting trials in human subjects in research in the developed world is not forced to fit into developing countries without consideration of local values. In other words, we should avoid what is called "ethical or scientific imperialism."
However, some would consider this is a double standard approach to research, and they instead promote a single standard. Even though one can understand the single standard and universal approach, it should not be absolute (see Resnik
for complete discussion).
This discussion will begin with each of the issues stated earlier and list the potential problems when various principles are applied within the context of developing countries. In these regions, the lack of health care infrastructure casts a large shadow on these principles. According to Benatar5: "Avoidance of exploitation in clinical research is a major challenge in a globalizing world in which disparities in wealth, health, and disease have reached grotesque proportions."
Developing countries have very large and pervasive health care needs. This is in large part due to poverty, social ills, and lack of education, compounded in some cases by corrupt political regimes. These regimes squander the country's resources on the governing elites, bringing into stark focus the overriding need for political reforms. The need for reforms is intertwined with any of the collaborative research studies sponsored by a company from western nations. Researchers in developing countries are faced by the realities of influencing and advancing political reforms with western democracies through either research collaboration and exchange of knowledge and personnel, or forcing the issue of instituting reforms prior to initiating such collaboration. This author favors greater research collaboration as a means to influence the political system. The greater the number of the host country's citizens that are exposed to democratic ideas through contacts and personnel exchanges, the more they can influence policy.
In 1993, the Council for International Organizations of Medical Sciences (CIOMS) issued (and later revised in 2002) the International Ethical Guidelines.13 These guidelines also address how to conduct research with human subjects in developing countries. Similar to NBAC's recommendations, guideline 10 emphasizes that research be "responsive" to the health need of the local population. In other words, we should not be conducting research on diseases that are not indigenous to the host community. For example, one can justify research on malaria and HIV in most developing countries. But to conduct research on obesity and cosmetic surgery would not be justified.
London14 has recently criticized the past approaches of confining the discussion to provide fair benefits to subjects in developing countries. He claims that this "minimalist" approach to justice ignores the linkage between the health care needs of citizens in developing countries from the broad and more important social, economic, and political issues. He further claims that "minimalism" would promote negotiating their research collaboration without considering these broad issues. London advanced the notion that: "[R]esearch initiatives are permissible only if they expand the capacity of the host community's basic social structures to meet the community's health priorities."
London labeled his approach as the "human development" approach. However, in the same article he recognized the Herculean task he has shouldered upon the research community. London then calls on researchers to attempt to bridge the gap between health needs and social institutions to enhance the health care infrastructure. While I can understand attempts to build health care infrastructure in the host country, I reject the task of linking research to changing the political and social system. It is unrealistic and unworkable, and one may even say it is fanciful.
There is a general agreement that research in developing countries should address the health care needs of the host country.
However, there remain important issues of exploitation, risk/benefit ratio, and informed consent, even if the research study addresses the need of the host country.
The potential for exploitation of the population in developing countries—by using them primarily for the benefit of developed countries—is of real concern to many. Such exploitation could occur when clinical trials are conducted in developing countries where the outcome will have little, if any, health value to the developed country. In developing countries, the issue of justice has an added dimension. For example, our concern in developed countries is that we distribute the risks to participants in clinical trials to the population at large who would benefit from the outcome. In developing countries, when a trial is conducted without taking into account the health care needs of the host developing country, the issue of distributing risks and benefits to the population is moot since the entire population would not benefit from the trial. Resnik
argues that this "minimally exploitative" method may be justified when there are other moral considerations such as autonomy of the subject and social benefits. I think one needs to be very careful in tilting the scale towards such exploitative research.
A report of a group from developed and developing countries18 objects to the "reasonably available" standard as too stringent and offers the term "fair benefit." They suggest that the "fair benefit" standard will take into consideration 14 factors such as: health improvement, collateral health services, benefit to participants and population during research, public health measures, employment and economic activity, availability of the intervention for the population, long-term collaboration, financial rewards, and transparency. Unfortunately, proposing a laundry list of benefits may pose a risk of adding small, indirect, and at times inconsequential benefits to overwhelm the magnitude of risks associated with the study. At this stage, where there is a lack of education and adequate infrastructure for health care and research, clearer and more straightforward language for compliance with ethical standards is required.6 If the "standard of care" or "the best current treatment" is available in developed countries, the use of placebo in developed countries is usually excluded. However, if the "standard of care" or "the best current treatment" is not available or not practical in the developing country, should we then insist on its use? Should we then deprive the subjects from the use of the best new experimental drug through the trial, or should we just forgo the entire trial? If the answer is to forgo the trial, then we are avoiding potential exploitation of subjects and promoting the concept that standards of care are universal.19 However, we must face the issue of harm and potential for avoidance of harm to the population of the developing country due to the potential benefits of developing a new drug. Therefore, the case for the use of placebo should be considered and not outright rejected. We should, however, assess the risks and benefits. If the difference is tolerable and the benefits outweigh the risks, then it should be permissible.
The lack of an adequate economic means is a strong motivation for people in developing countries to utilize clinical trials as a means of obtaining an income. This is understandable because motivation to enroll in clinical trials as a source of income, especially for healthy subjects, is even problematic in developed countries among the poor and uneducated population.20 Globally, the lack of economic means could result in exploiting the population of developing countries to the sole benefit of the developed countries. This will be then an injustice on a global scale that could have political ramifications beyond the realm of clinical trials. Moreover, this lack of economic means could result in skewing the risk/benefit ratio for the detriment of human subjects, since they lack the economic and educational means to advocate for their rights. Thus, one can conceive of clinical trials in developed countries in which the risk to subjects is higher than those tolerated in developed countries because of economic issues rather than for issues indigenous to local health needs.
The risk/benefit ratio may also differ in developing countries from developed countries. Insistence on absolutist standards could do harm to the people of developing countries by the lack of health care progress that results.
The problem of malaria in Africa is a good example. The issue of conducting clinical trials with "newer drugs" was the subject of intense discussions recently (see acknowledgment). Malaria is estimated to kill over one million people (mostly children) per year in Africa. In the United States, the death rate from malaria is nearly zero. Thus, one can conceive of clinical trials in Africa in which the risk to subjects of developing malaria or having certain adverse events during a trial could be tolerable (depending on local conditions) while such a risk would not be tolerated in the United States.
In a poor environment lacking in adequate health care, it is understandable how duress and coercion may play a role in participating in research with human subjects/clinical trials. The strong desire of desperate patients to receive health care would be a strong inducement or coercive incentive to enroll. This "inducement," however, should not be used to eliminate such research because, as Tangwa
stated, it "would amount to a prohibition of all medical research, which may not be ethical or even rational under the circumstances." Thus, protecting human subjects should be the primary aim,
and informed consent is a very important step in protecting human subjects when conducting the trial. Informed consent rests on the three components of sufficient knowledge, lack of duress and coercion, and comprehension. In conducting research with human subjects in developing countries, the potential subjects may lack education and general knowledge regarding research principles, techniques, and risks—the investigator may not have even provided this in the local language!
One can see that providing the typical information about the clinical trial that we normally provide in the developed countries would be insufficient in developing countries. Furthermore, comprehension of the protocol and making a reasoned judgment could be deficient. However, it should be noted that providing such information in the language and cultural idiom of the local population is one of the requirements of respect for persons, and it should not be surprising if subjects do not understand "Americanese." Thus, it is imperative that informed consent be administered appropriately culturally and methodologically.22 We need to be flexible in using a variety of methods such as verbal and witnessed, written, or recorded consents. Moreover, we should consider whether it is appropriate to use individual, family or communal consent.
The use of placebo (i.e., control group) in developing countries remains ethically troubling to many.
NBAC proposes that the protocol should utilize the established effective treatment regardless of whether it is available in the host country. CIOMS's guideline no. 11, similar to NBAC's recommendation, recommends that in general, research participants should receive "an established effective intervention." It opens the door slightly for the use of placebo, however, if there is no effective treatment, being on placebo will only cause minor discomfort or the research outcome may be invalid without the control group having placebo, or the use of placebo would not add much additional risk to the subject. However, guideline 11 also suggests exceptions to the use of placebo.
The Declaration of Helsinki (par. 29)
recommends "the best current methods," but it does not exclude the use of placebo.
In the controversial area of continuation of treatment after the end of the trial, NBAC proposes that a "good faith effort" ought to be made for continuation. CIOMS
recommendations require that the research outcome (i.e., drug) be made "reasonably available" for the good of the local community (whereas NBAC's recommendation [no. 4.1] is stronger in that it requires "reasonable, good faith efforts" to make it available to all participants). It is hard to see how a pharmaceutical company could provide an open-ended commitment to provide the "successful" drug to all of the participants and/or the local community. One of the important factors for industry is the knowledge of the cost of a project. The open-ended commitment runs contrary to that practical principle. Possibly, a standard upper cost limit for what it would reasonable cost to make the drug available after the trial's end could be included in the proposed study protocol. The ethics committee reviewing the study protocol should consider this and other aspects of the study in its totality during its deliberation and approval.
Clearly there is a consensus that research with human subjects in developing countries ought to serve the health needs of the host country. The citizens of developing countries should not become the "guinea pigs" for the developed countries. Therefore, the first criteria for conducting research in developing countries should be that the research must serve their health needs. The persistence of the lack of health care infrastructure in some developing countries raises concerns as to the fundamental problems facing these nations, including poverty, economy, and the political system. Research collaboration could become a tool to expose the host country to democratic ideas through personnel exchanges and research collaborative contacts. These contacts could enhance future reforms.
On the issue of the use of placebo in the control group, it is advisable that the default position ought to be to use the current standard of care. However, under unique and compelling circumstances, the use of placebo should be contemplated. It is difficult, if not impossible, to use an absolutist rule in this area. Decisions should be made on a well-reasoned, case-by-case basis as long as we remain within ethical bounds of treating all human beings as morally equivalent. The investigators should justify the unique and compelling circumstances for the use of a placebo where there is the possibility of more than minor discomfort as the CIOMS recommends. In other words, we could use placebo if it is well justified.
The most difficult issue is what the study sponsor should offer in terms of providing the drug after the trials to the participants and/or local community conclude. How does one define the local community? How does one define the time period? Is it for one year or forever? Unless these questions are answered reasonably, the potential cost to the sponsor could be unlimited. All of the proposals made so far are complex and subject to varied interpretations. Therefore, it will be prudent to suggest that the decision ought to be made on a case-by-case basis. In each case, the sponsors should be required to adequately justify their decisions and should do so on the basis of dialogue with host investigators and their institutions24 prior to the beginning of the trial. Therefore, a good faith effort ought to be made to offer the drug to the participants after the trial if it is economically viable to the sponsor. A part of the consideration to be given when the drug is made available after the trial is whether it will discourage other sponsors from continuing their sponsorship of the trials in developing countries.
1. National Bioethics Advisory Commission (NBAC), vol. I, Report and Recommendations (2001), "Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries," Bethesda, Maryland, April 2001, ISBN 1-931022-13-5 (can be accessed at:
2. J. Rehnquist, Office of the Inspector General (OIG), DHHS, "The Globalization of Clinical Trials—A Growing Challenge in Protecting Human Subjects, September 2001, OEI–01–00190.
3. A.E. Shamoo, "Future Challenges to Human Subject Protection," The Scientist, 35–35 (June 26, 2000).
4. A.E. Shamoo, "Adverse Events Reporting—The Tip of an Iceberg," Accountability in Research, 8, 197–218 (2001).
5. S.R. Benatar, "Avoiding Exploitation in Clinical Research," Cambridge Quarterly of Healthcare Ethics, 9, 562–565 (2000).
6. P. Wilmshurst, "Scientific Imperialism: If They Won't Benefit from the Findings, Poor People in the Developing World Shouldn't be Used in Research,"' BMJ, 314, 840–841 (1997).
7. Nuremberg Code, 1947, (can be accessed at: http://ohsr.od.nih.gov.nuremberg.php3).
8. Belmont Report, 1979, (can be accessed at: http://ohrp.osophs.gov/humansubjects/guidance/belmont.htm
9. Medicines and Healthcare Products Regulatory Agency (MHRA) (2004), http://medicines.mhra.gov.uk/ourwork/licensingmeds/types/clintrialdir.htm (accessed on 7/27/04)
10. M. Angell, "Ethical Imperialism? Ethics in Collaborative Clinical Research," New Engl. J. Med., 319, 1081–1083 (1988).
11. N.A. Halsey, A. Sommer, D.A. Henderson, R.E. Black, "Ethics and International Research [Editorial]," BMJ, 315, 965–966 (1997).
12. D.B. Resnik, "The Ethics of HIV Research in Developing Nations," Bioethics, 12, 286–306 (1998).
13. Council for International Organization of Medical Sciences (CIOMS) (2002), "International Ethical Guidelines," http://www.cioms.ch/frame_guidelines_nov_2002.htm (accessed 7/28/04).
14. A.J. London, "Justice and the Human Development Approach to International Research," Hastings Center Report, 35, 24–37 (2005).
15. M. Angell, "The Ethics of Clinical Research in the Third World," New Engl. J. Med., 337, 847–849 (1997).
16. D.B. Resnik, "Developing Drugs for the Developing World: An Economic, Legal, Moral, and Political Dilemma," Developing World Bioethics, 1, 11–32 (2001).
17. D.B. Resnik, "Exploitation in Biomedical Research," Theoretical Medicine & Bioethics, 24, 233–259 (2003).
18. "Moral Standards for Research in Developing Countries—From 'Reasonable Availability' to 'Fair Benefits'" (MSRD), Hastings Center Report, 34 (3) 17–27 (2004).
19. S.R. Benatar, "Reflections and Recommendations on Research Ethics in Developing Countries," Social Science & Medicine, 54, 1131–1141 (2002).
20. A.E. Shamoo and D.B. Resnik, "Ethical and Safety Issues in Phase I Trials on Healthy Subjects," Submitted to Am. J. of Bioethics (2005).
21. G.B. Tangwa, "Between Universalism and Relativism: A Conceptual Exploration of Problems in Formulating and Applying International Biomedical Ethical Guidelines," J. Med. Ethics, 30, 63–67 (2004).
22. Z.A. Bhutta, "Beyond Informed Consent," Bulletin of the World Health Organization, 82 (10) 771–778 (October 2004).
23. Declaration of Helsinki, World Medical Association, http://www.wma.net/e/policy/17-c-e.html
24. A. Costello and A. Zumla, "Moving to Research Partnerships in Developing Countries," BMJ, 321, 827–829 (2000).
This paper benefited a great deal from the discussions and deliberations of the Special Issue Ethics Advisory Group for GlaxoSmithKline in 2003. The Advisory group consisted of: Adil E. Shamoo, PhD, Chairman; Mary Faith Marshall, PhD; James Campbell, MD; Arthur L. Caplan, PhD; Prof. Wen Kilama; Solly Benatar, MBChB, FRCP; Godfrey Tangwa, PhD; Angela Wasunna, LLB, LLM; and Sandy Macrae, MRCP, PhD,Vice President Clinical Development and Medical Affairs.
This paper was supported in-part by a grant from Fogarty International Center/NIH 1R25TW007090-01.
Adil E. Shamoo, while chairing the GSK advisory committee, was paid as a consultant. However, Dr. Shamoo wrote this article on his volition and was not paid by anyone.
Adil E. Shamoo, PhD, is a consultant to industry, and professor and former chairman at the University of Maryland, School of Medicine, 108 N. Greene St., Baltimore, MD 21201, (401) 706-3327, fax (401) 706-3189, email: email@example.com, http://www.umaryland.edu/bmb/faculty/shamoo.html