Multinational Research and Capacity Building
Department of Bioethics, NIH
Background: Multinational research is essential to understanding and ultimately controlling diseases of global importance, but is beset with many inherent and complex ethical issues. There are four major issues:
- Informed consent
- Standard of care
- Ancillary care
- Post trial benefits
An overarching ethical concern is that of possible exploitation of vulnerable individuals or populations. Much multinational research is sponsored by developed-world entities (both public and private) and conducted in the developing world, which serves to heighten concerns about exploitation. Exploitation, usually understood as an unfair distribution of benefits, is more challenging in the context of multinational research conducted in developing countries because of background disparities in health, health resources, and power between developed and developing countries. The Department's initiatives aim to better understand the ethical complexities of multinational research, covering all of these four topics and situating this research within a larger examination of issues of exploitation and globalization.
Beginning in the fall of 2001, the Department focused a substantial portion of its research on conceptual and empirical issues related to the ethics of multinational clinical research. Many of these projects were collaborations with researchers from developing countries, including many NIAID supported researchers. Between 2002 and 2006, over 50 research papers have been published in peer reviewed journals including Science, The Lancet, BMJ, American Journal of Public Health, and the leading bioethics journals. Some of these articles represent the only scholarly work on a topic, others are already well-cited “classics” in the literature. These projects included:
- Empirical studies on the quality of informed consent in countries such as Uganda and Thailand.
- Empirical studies on attitudes towards consent to collection of tissue samples for research.
- Empirical studies of developing country research participants' perceptions of personal and community risks and benefits of biomedical research.
- Motivation of research participants to remain in the trial.
- Analysis of the “standard of care” controversy.
- Proposal of a new model for understanding researchers’ “ancillary care responsibilities” in the context of multinational research.
- Proposal of a new model of benefit arrangements for multinational collaborative research.
- Conceptual analysis of exploitation in the context of multinational collaborative research.
- Globalization and health policy, such as options for physician migration for developing countries.
In the following we will discuss empirical and conceptual research separately.
|Section:||Ethics of Human Subjects Research|
|Principal Investigators:||Christine Grady, R.N., Ph.D.
Reidar Lie, M.D., Ph.D.
David Wendler, Ph.D.
Background: Critical to an appropriate analysis of the ethical issues associated with multinational research are the perspectives of participants in such research. Because of poverty, limited education, limited access to health care and limited familiarity with research, potential research participants in developing countries are sometimes thought to be unable to provide informed consent. These handicaps either make it difficult to understand the nature of the research being proposed or compel them to enroll regardless of the details, or both. Nonetheless, limited empirical data describe the quality of informed consent in developing countries.
Another concern is that of exploitation. Research that benefits people in the developed world while exposing people in developing countries to risks and burdens is considered a quintessential example of exploitation. There is a spectrum of multinational clinical research, from research that can bring significant benefit to developing country research participants and economies to research that actually can make communities or individuals worse off. Understanding the spectrum of research, possible kinds of benefits and harms, and the perceptions of those involved in research as to what is fair and what is exploitation could help to minimize exploitative research. Yet, there are limited empirical data describing the views of developing country participants’ or researchers on these issues.
Finally, clinical researchers and IRBs around the world interpret national and international guidelines, decide whether certain trials adhere to ethical standards, and what information to provide during the process of informed consent. Again, there has not been any comprehensive assessment of the views of clinical researchers or IRBs throughout the world about controversies in multi-national research.
Departmental Research Initiatives: The Department has taken on several empirical research initiatives to complement our conceptual and policy work related to the ethics of multinational research. The primary aim of this empirical work is to explain how those involved in research think about clinical research, the quality of their consent and understanding, their expectations, and their views about research risks and benefits, stored tissue research, and international guidelines and controversies.
ESPRIT (Evaluation of Subcutaneous Proleukin® in a Randomized International Trial)
In one major initiative, in collaboration with the ESPRIT Executive committee and Coordinating Center, the Department developed a study of clinical researchers, IRB members, and research participants about their experiences with ESPRIT and their general attitudes about the ethics of multinational research. ESPRIT is an NIH sponsored open-label, randomized trial of subcutaneous recombinant interleukin-2 (IL-2) designed to assess whether IL-2 decreases the rate of disease progression and improves survival in anti-retroviral treated HIV patients who are 18 years or older with a CD4 + cell count of >= 300/ mm. ESPRIT enrolled approximately 4,000 participants in 22 countries, mostly European countries, but also Thailand, Argentina, and Brazil. For the ethics study, we developed complementary survey instruments for principal investigators, IRB chairs, and research participants about various aspects of multi-national research, including informed consent and the interpretation of ethical guidelines. From December 2000 to July 2003, we surveyed three multinational cohorts associated with ESPRIT: 1) chairs of institutional review board (IRB) or research ethics committee (REC) who reviewed the ESPRIT protocol (n=65, representing 18 countries); 2) clinical investigators who had enrolled at least 5 ESPRIT participants (n=117 representing 23 countries); and 3) ESPRIT research participants (n=500, representing 11 countries).
Thai research participants were interviewed in-person and an analysis of the perceived quality of their informed consent indicated that they overwhelmingly felt that the informed consent process was helpful, and they had a good understanding of most aspects of the ESPRIT trial, except randomization (Pace et al., IRB 2005). The views and practices of PI respondents regarding the process of informed consent were analyzed; overall respondents viewed the informed consent process positively, dedicated a substantial amount of time to the process, and thought it was effective. Many PIs (65 percent) described potential subjects who they thought should not be enrolled and often cited possible non-compliance as the reason. (Sabik et al., IRB 2005). A third analysis compared the responses from all three cohorts regarding their views on post-trial access of IL-2 and their interpretation of international ethics guidelines. Findings showed that most research participants believe IL-2 proven effective in research should be made available to everyone in the world who needs it, and half said for free — although there were significant geographic differences. IRB/REC chairs and researchers were less expansive regarding both who and how a drug should be guaranteed. They indicated that the CIOMS “reasonable availability” required a drug be available at a price the average person can afford and applied to people in the country where the study was conducted, and that host country governments have primary responsibility for making it available. (Pace et al., AIDS in press).
After completing the initial ethics survey, ESPRIT participants randomized to IL-2 or no additional therapy, are asked to return for regular clinic visits over 5 years. The department developed a follow-up survey for participants who had been in ESPRIT for at least 6 months. This survey provides us with a unique opportunity to address what motivates participants to stay in a clinical trial over time, especially when not randomized to the experimental intervention, how their expectations change and how they comply with protocol requirements, issues for which there is essentially no literature. More than 500 research participants from Argentina, Thailand, and Brazil have participated in the ethics follow up survey. These data are currently being analyzed and manuscripts describing their motivations for staying in the study, the extent to which they adhered to study requirements, and the self-reported impact of participation on their lives are in progress.
Little is known about the quality of developing country research participant consent, yet even less is known about the understanding and voluntariness of parents enrolling their children in clinical trials. Through collaboration with the East Africa Network for Monitoring Antimalarial Treatment, the department conducted a study to evaluate the quality of understanding and voluntariness of parents enrolling their children in a randomized study of malaria treatment at four sites in Uganda. The consent of these parents (n=347, predominantly mothers) was of mixed quality. They had a good understanding of the study purpose and requirements, but a poorer understanding of randomization and study risks. Many felt they could not have refused participation because their child was sick, and either did not know or did not believe their child would receive treatment outside of the study. Importantly, in a country where the common wisdom is that women do not make enrollment decisions alone, 94 percent said they made the enrollment decision themselves, and less than 15 percent felt any pressure from anyone else.
The survey instrument utilized in the Uganda malaria study was developed as a template for adaptation to other studies in developing countries. Initially, the instrument was designed to be utilized for an assessment of a study of measles vaccines among HIV infected women in Malawi. Subsequently, in addition to the Uganda malaria study, the instrument was adapted for use in HIV treatment study in Thailand, and a helminth treatment study among HIV infected individuals in Zambia.
Rakai Risks and Benefits
In collaboration with the Rakai Health Services Program (RHSP) in Rakai District Uganda, the department developed a study to determine what residents there — both research participants and non-participants — perceive to be the benefits and risks of having research activities in their community. Complementary surveys were developed for research participants in three different RHSP studies, for individuals identified as community leaders, those who declined participation in continuing RHSP studies, and individuals in neighboring communities unaffiliated with RHSP. A total of 915 individuals participated in the survey. The vast majority view research as beneficial both to them as individuals and to their communities, although some, mostly minor, risks were identified (Thiessen et al. in preparation). In response to questions regarding individual compensation and post-trial community benefit from a hypothetical HIV vaccine study, the majority thought that researchers should provide benefits. However, relatively few identified their preferred individual benefit as money or the preferred community benefit as the vaccine if proven effective. Instead, respondents suggested provision of health care services of various kinds, treatment for people with HIV infection, and other benefits. (Grady et al, under review).
Rakai Project data from a randomized, community based trial of intensive STD control, the STD Control for AIDS Prevention Trial, were analyzed to assess the question of whether people feel compelled to participate in research. The analysis examined how many times people refuse to participate when offered the chance to enroll (7.1 percent of eligible participants did not consent), how frequently they withdraw after enrollment (11.0 percent of participating respondents subsequently withdrew), and how frequently they refuse to participate in certain aspects of the research (~25 percent refused to provide blood samples, 12 percent refused to provide urine samples and 10 percent of eligible women refused to provide vaginal swabs). Such refusal suggests that pressure either from the research team, poverty, or lack of access to health care services does not always compel people to agree to participate or stay in a study.
Stored Sample Survey
Controversy exists regarding the ethics of research on stored biological samples. Much debate has ensued in the United States over this issue. Less is known about the attitudes of those involved in research internationally. The department had the opportunity to survey the attitudes of Ugandan parents enrolling their children in a randomized trial of malaria treatment about research with stored samples. The majority of respondents were willing to contribute coded samples for future research on any condition, and willing to share their samples with researchers from the UK or the US. (Wendler et al., IRB. 2005). Currently, the department is conducting a large international survey of researchers who work with stored samples to understand their attitudes regarding appropriate consent for using samples in research and issues that arise in collaborative research when human samples are collected in one country and analyzed in another. Up to 1,500 researchers in India, Germany, Egypt, Japan, and China are being surveyed. Data collection will be complete by 2007.
Impact of Research: The Department’s research represents a substantial contribution to the empirical literature on the key ethical issues associated with conduct of research both from the perspective of participants and researchers. The findings challenge the assumption made by many that poor resources are inherently exploitative and lead to defects in the informed consent process. The surveys on attitudes to ethical issues related to stored tissue samples represent the only systematic data from developing countries.
Future Research Initiatives: There are several empirical research initiatives in progress, and several planned for the near future. The ESPRIT follow-up data is a unique opportunity to understand how research participants experience research over time, their expectations, motivations for continuing and changing views. These rich data are being analyzed and manuscripts written. Based on these findings, the department may undertake additional studies to understand the experience of research participants over time.
The department is committed to a study of the comparison of shorter consent forms with traditional consent forms with respect to participant understanding and satisfaction. We are collaborating with a research group in Japan that will utilize two forms for a large cohort study of risk factors and the genetic basis for disease development. The two groups have been given a questionnaire that tests for understanding and satisfaction, and we will compare enrollment and retention in the two groups. The hypothesis is that enrollment, retention and satisfaction will be higher in the group with the shorter form, and understanding will be the same or better. Data collection has been completed for this study.
We are also collaborating with a research group in Durban, South Africa, where we will compare two ways of providing information and counseling about HIV prior to decisions about testing. The hypothesis is that shorter information sessions will increase uptake and will not affect understanding adversely.
|Section:||Human Subjects Research|
|Principal Investigators:||Ezekiel Emanuel, M.D., Ph.D.
Christine Grady, R.N., Ph.D.
Reidar Lie, M.D., Ph.D.
Henry Richardson, Ph.D., J.D., M.P.P (Visiting Scholar)
Alan Wertheimer, Ph.D.
Background: Since the controversy erupted over the perinatal HIV transmission studies conducted in the 1990s in African and Asian countries, the ethics of research in resource poor settings has received widespread attention in the bioethics literature. Many commentators and international guidelines have argued that 1) trial participants in resource poor settings are more vulnerable to exploitation compared with trial participants in richer countries; 2) trial designs that are unethical in resource rich settings are also unethical in resource poor settings; 3) researchers have obligations to ensure access to care for the health problems of research participants that are not being dealt with by the host country health care system; 4) trials in resource poor settings have to study products aimed at host country markets; and 5) prior agreements ensuring reasonable availability of such products have to be in place before research is approved. Only if certain additional conditions for research in resource poor settings are fulfilled, will one avoid exploitation of vulnerable subjects in such settings. Critics, however, have pointed out that these well-intentioned conditions with the laudable aim of ensuring access to beneficial care will have the paradoxical effect of preventing useful research that can lead to health care interventions that will eliminate access barriers in resource poor settings.
Departmental Research Initiatives: The Department has initiated a multi-pronged research program examining the current controversies associated with multinational research. This program complements the empirical component, and ranges from philosophical examination of the concept of exploitation to specific recommendations regarding the conduct of clinical research in resource poor settings.
Exploitation in Multinational Research: Some commentators have argued that the principle — “minimize exploitation” — is a or even the rationale for many of the oft mentioned principles of ethical clinical research. The four canonical principles of bioethics — non-maleficence, beneficence, respect for autonomy, and justice — do not specifically invoke the language of exploitation, nor do some of the standard principles of research ethics: social value, scientific validity, fair subject selection, favorable risk-benefit ratio, respect for human subjects. Still, it can be argued that many or all of these principles are instantiations of a more general principle: minimize exploitation.
The language of exploitation came to the fore in the context of criticisms of research on vulnerable populations and, in particular, research in underdeveloped societies. This concern may have reached its apogee in response to the use of placebo controlled trials of the efficacy of a short course treatment of anti-retrovirals in reducing maternal-fetal transmission of HIV when it was known that a long-course treatment was effective. Those studies promoted an outbreak of ethical outrage, even though no research subjects were worse off than they would have been if the studies had not been conducted.
Despite the intensity of the outrage, the argument that such research should be prohibited on grounds of exploitation needs careful examination. Moreover, the discussion of exploitation in actual clinical research raises other serious questions:
- If research should be permitted, what do researchers owe research subjects if they are to avoid exploitation?
- Must researchers provide ancillary care to subjects if they are found to have other diseases?
- Must researchers provide post-trial care for the disease being studied to research participants?
- What do researchers owe to the host country? Do they have obligations to provide the interventions being studied if the studies prove successful?
Because these questions are of paramount ethical and practical importance, the Department devoted one semester of its Joint Seminar in Bioethics (with Georgetown University, Johns Hopkins University, and the Center for Philosophy and Public Policy at the University of Maryland) to an examination of exploitation in clinical research. Several nationally recognized moral philosophers were asked to speak to the seminar, including Alan Wertheimer, Richard Arneson, and Thomas Pogge.
Drawing on this seminar, Ezekiel Emanuel and Jennifer Hawkins decided to edit a book on Exploitation in International Research. The book is organized around two highly controversial actual cases: the testing of the hepatitis A vaccine in Thailand and the proposed testing of surfaxin in several South American countries including Boliva. In the book, Wertheimer, Pogge and Arneson, along with participants in the seminar series from Georgetown, Hopkins and the NIH — Jennifer Hawkins, Ezekiel Emanuel, Margaret Little, Alisa Carse, and Andrew Siegel — have contributed chapters that discuss exploitation and ways to prevent it in the context of these two cases. The book will be published in 2007 by Princeton University Press.
Alan Wertheimer had previously published the major scholarly analysis of exploitation: Exploitation (Princeton University Press, 1996). He was invited to come to the Department initially as a visiting scholar in the 2005-06 academic year, and then has continued as a staff scientist to explore exploitation and its relationship to the ethics of clinical research. In his book, Wertheimer argued that it was of capital importance to distinguish between exploitation that is harmful and non-consensual and exploitation that is mutually advantageous and consensual. In addition, he argued that it is difficult to determine when a transaction or relationship is exploitative. Most importantly, even if a transaction is exploitative, it does not follow that it should not be allowed. Although it is clear that we should not allow harmful and non-consensual exploitation, it is arguable that we should allow exploitative transactions if the exploited party benefits from the transaction and consents to it. The question as to whether and when clinical research in developing societies is exploitative and whether it should be prohibited if it is exploitative is an issue with profound and far-reaching implications. It is an issue on which more heat has been cast than light, and the Department is seeking to reverse that trend.
During this time, Wertheimer has written the entry on Exploitation for the Oxford Textbook on the Ethics of Clinical Research which will be published by Oxford University Press in 2007.
We have also begun to place the examination of these specific issues into a larger theoretical framework of an appropriate understanding of exploitation and international obligations in general (Emanuel et al., 2006; Flory, Kitcher, 2004; Gbadegesin, Wendler, 2006).
Trial Design Issues: The discussion about the ethics of the HIV perinatal transmission studies started the debate in the bioethics literature on appropriate designs for studies in resource poor settings. A number of bioethicists were quick to condemn the studies as obviously unethical. The basis for the argument was that these studies would not have been approved in richer countries. They violated the universality of ethics, allowing studies to proceed in poor settings that would not be approved in the countries of the sponsor. Commissions established to develop guidelines, however, ultimately allowed differences in designs, under certain stringent conditions. In a series of articles we have proposed three conditions for when the choice of trial design in resource poor settings may differ from that chosen in a resource rich setting. The design must be scientifically necessary in order to obtain results that are useful for the host country, and trial participants are not denied access to care they would receive outside the trial (Killen et al., 2002; Lie et al., 2004; and Wendler et al., 2004). We have also argued that these conditions are in accordance with major international guidelines, except the Declaration of Helsinki.
Recently, a clinical trial demonstrated that circumcision had a dramatic preventive effect on HIV infection. This immediately raises the issue of whether circumcision should be provided to participants in any future HIV vaccine trial, similar to condoms or counseling. It even raises the question whether there is an obligation to provide circumcision in the control group of such trials. We have recently published an article examining this issue, where we argue that circumcision is sufficiently different from other types of interventions typically provided to participants in vaccine trials to not make it obvious that it should be treated analogously (Lie et al., 2006).
Ancillary Care: Researchers sometimes identify conditions in their subjects that need interventions. In a malaria trial, for example, subjects may be identified as HIV positive in need of treatment. At other times, subjects are tested for certain conditions because it is necessary to exclude them, or because there will be an analysis of the stratified results. In HIV vaccine trials, HIV positive individuals are excluded. In a malaria vaccine trial, one may want to study the effect of HIV on the degree of protection. The moral issue is what obligations, if any, this places on researchers to ensure care for the conditions identified. One could argue that there are no moral obligations to provide ancillary care not necessary for the design of the study: researchers have an obligation to research, not to clinical care. On the other hand, the researchers are often physicians, and have the knowledge and skills necessary to provide treatments that are often not available to their study participants. Does this not place some obligation on them to provide such treatment?
The issue of researchers’ ancillary care obligations had not been examined systematically in the literature until 2004, when Belsky and Richardson proposed a framework for when researchers are obligated to provide ancillary care to trial participants (Belsky, Richardson, 2004; Richardson, Belsky, 2004). It is based on the notion of entrustment and describes an obligation to provide care if certain conditions are fulfilled.
The model remains controversial, and other researchers in the department have developed a critique of the model proposed by Belsky and Richardson (Dickert et al., in press). This article criticizes the scope requirement of Richardson and Belsky, arguing that sometimes it may be more important to provide care for conditions that fall outside their scope requirement. Merrit and Grady (2006) have provided a different critique, arguing that favoring seroconverters in HIV vaccine trials for treatment access may distort legitimate priorities set by national health authorities.
Reasonable Availability versus Fair Benefits: Many commentators in the bioethics literature have assumed that for research in resource poor settings to be ethical, it must be responsive to the health needs of the country. It is not completely clear what responsiveness entails, but it does at least mean that research that we know will not lead to a product useful for the country should not be approved. We have argued that this represents a narrow view of the benefits of the research. Research can also benefit a country by providing health care, and by training researchers. We have therefore proposed a framework for evaluating the benefits of research that goes beyond focusing simply on the availability of the intervention being investigated (Emanuel et al., 2002; Emanuel et al., 2004; Grady 2005; Grady 2006). It may be justifiable, assuming an appropriate risk-benefit ratio for the individuals in the study, to approve a research project that will lead to vital capacity building for the host country but not necessarily to an intervention that is a public health priority.
Multinational Research and Health Policy: The discussion about the ethics of multinational research is affected by developments in the social context in which research occurs. One example is the increase in the outsourcing of clinical trials to countries such as India and China by industry because of the liberalization of trade in services and the cost savings of doing research in these countries. Another example is the need to be concerned about availability health care personnel if there is an increase in the availability of drugs due to programs such as PEPFAR. The challenge then is the increase in the migration of skilled health care workers to industrialized countries. In order to address these issues, we organized a major international conference on Globalization and Health in October 2003. The follow up of this conference has resulted in publications on issues related to GATS, patents, and participation in an EU funded project on Bioethics and Globalization (Barton 2004; Barton, Emanuel, 2005; Belsky et al., 2004; Permanand, Lie, 2005; Novotny et al., 2006). We conducted an empirical study of the policy issues related to medical migration (Astor et al., 2005; Astor, Lie, in press), asking policy makers about their views about the causes of and policy options for physician migration. One striking result is the almost universal agreement that the root cause is economic, and that there are few effective options that will reverse the trend, except dramatic increase in pay, working conditions and improvement of general health infrastructure in resource poor settings.
Impact of Research: The Department’s work on conditions for deviating from a universal standard for trial design has been more or less accepted as valid by most commentators. It is reflected in the overview published on the scidev.net web page as well as the fact that one of us has been commissioned to write the chapter on this topic in the current revision of Gillon’s standard textbook in bioethics. The Department’s publications on the issue of ancillary care have been recognized as setting the agenda for research in this area. The proposal for a fair benefits framework been controversial, but is recognized as the point of departure for discussions of this topic, as reflected in a recent major article by Alex London in the Hastings Center Report. Departmental members are recognized as being the leading experts in the field of ethics of multinational research, as reflected in participation in international advisory bodies to WHO, UNAIDS, and the European Commission, as well as invitation to speak on this topic at major international meetings.
Future Research Initiatives: Three areas will be the focus of research over the next few years. First, we will develop further the proposed ancillary care framework, both by raising difficulties, as we have done in an article accepted by the Lancet (Dickert et al.) and by responding to criticism.
Second, we will develop an appropriate understanding of exploitation in the context of multinational research. Alan Wertheimer will be continuing his work on exploitation and related issues. He is presently working on a book which seeks to expand on his completed work on exploitation in clinical research. One chapter is an in depth examination of what he calls the “interaction principle” (IP) This principle claims that one has special obligations or moral reasons to provide supra-minimal benefits to those with whom one engages in mutually beneficial and consensual transactions that one would not have if one had chosen not to interact with them, even if they are better off than if one had chosen not to interact with them. Although this principle is intuitively attractive, it is also deeply problematic: how can it be worse to interact with someone in a way that raises their well-being than not to interact with them at all? The claim that the placebo-controlled trials of anti-retrovirals were unethical rests on IP.
Third, we will place the discussion in the larger context of outsourcing of drug development, by initiating a comparative study of appropriate benefit arrangements focusing on four countries, Brazil, China, India, and South Africa. These are the four countries that have the capacity to develop their own pharmaceutical industries, and are also countries that are being used by Western pharmaceutical companies for clinical trials to develop their drugs. These two facts make them key countries for understanding the regulatory and ethical challenges of multinational research. Some of the central questions will be, what are appropriate regulatory structures, and how should one understand the requirement that research be responsive to the health needs of the population being tested?
Between March 2001 and May 2006, the Department has conducted 25 international ethics training workshops in 15 countries, averaging 5 per year. While the Department has been responsible for the academic content of all of these workshops, all have involved local or international co-organizers, as well as sponsors. NIAID has provided approximately $475,000, for an average of $20,000 per workshop. Additional funding has been provided by local co-organizers, and international entities such as WHO and EU.
Over the past 5 years, approximately 1200 people have been trained in the workshops — a substantial contribution to capacity building. The target groups for the workshops have included biomedical researchers, research ethics committee members, Ministry of Health officials, and other policy makers in regions and countries where there is significant NIH funding for clinical research. NIAID funds have been used to pay for the cost of travel for participants to attend the training workshops.
The Department has already edited and published a well received book of key readings in research ethics, useful for individuals in developing countries (Emanuel EJ et al., eds. Ethical and Regulatory Aspects of Clinical Research: Readings and Commentary. (Baltimore: Johns Hopkins University Press, 2003).
Later this year (2006), a case book on multinational research edited by members of the Department will be published by Oxford University Press. The book contains 21 multinational research ethics cases, each with 2 commentaries. Many of the commentaries are authored by NIH funded researchers from developing countries.
In 2007, the first comprehensive textbook on the ethics of clinical research, edited by 5 members of the Department will be published by Oxford University Press. This book includes 72 chapters that address all the important topics in research ethics authored by the leading international authorities. It is meant to be the definitive textbook on this topic — the “Harrison’s” or “Cecil’s” of research ethics.
In addition to these 3 books, the Department has also prepared training material on research ethics in electronic formats, both CD and Web based. This material contains video-presentations from previous workshops, links to all major international guidelines and regulations, as well as background readings written by Department members. There are two versions of the training materials, one Introductory and one Advanced. The introductory module has been developed in both English and Spanish. A module addressing topics in clinical ethics that will be available in both English and Spanish is under development.
Long term collaborations
The Department has initiated long-term research and educational collaborations with key institutions in Europe, Asia, Latin America and Africa. One aim of these collaborations is to initiate major studies on key issues in multinational clinical research, including proposals for reforming ethics review, comparative studies of the effects of different methods of obtaining informed consent, analysis of benefit arrangements for research and attitudes and policy options for use of stored tissue samples. A second aim is to establish continuing programs in capacity development for research ethics. These institutions include:
- University of KwaZulu Natal, South Africa
- Rakai Project, Uganda
- University of Tokyo, Japan
- University of Sao Paulo, Brazil
- NAMRID, Peru
- Chulalongkorn University, Thailand
- Peking Union Medical College, China
- Science and Society Directorate, European Commission
- Indian Council of Medical Research, India
- Foundacion Centro de Estudios Infectologico, Argentina
Members of the Department have worked with and served on national and international bodies, such as the European Commission and the World Health Organization. These efforts typically focus on advice in policy development. A recent and on-going consultation focuses on the development of an international guidance document on treatment obligations to vaccine trial participants during and after a vaccine trial.
Support to NIH international activities
Members of the Department have provided expertise and assistance to the NIH regarding development of policy and other training programs. For instance, members of the Department were instrumental in advising NIH on developing its policy for coverage of anti-retroviral drugs in HIV/AIDS trials. Members of the Department have served on — and even chaired — the study sections reviewing the bioethics grants for Fogarty International Center. Members of the Department have also helped organize and speak at international conferences held under the auspices of NIAID and the Fogarty International Center. They have also worked with extramurally funded Fogarty bioethics grantees both at American universities and in developing countries.
The Bergen Ph.D. Program in Bioethics: The Department is collaborating with the Center for International Health at the University of Bergen, Norway, on a Ph.D. program in bioethics for students from developing countries. Students receive scholarships from the University of Bergen for the Ph.D. program, and fulfill the Bergen requirements, but have the option of spending time in the Department and be supervised by faculty from the Department. Currently, three Ph.D. students are in the program, from the Philippines, Thailand, and Sri Lanka. All three students are on leave from permanent positions at their home institutions.
International Capacity Building Workshops
Blantyre, Malawi, March 2001
Accra, Ghana, March 2002
Entebbe, Uganda, March 2002
Seoul, Korea, June 2002
Bangkok, Thailand, September 2002
Bamako, Mali, January 2003
Kampala, Uganda, March 2003
Iguazu, Argentina, June 2003
Bangkok, Thailand, September 2003
Chennai, India, January 2004
Cairo, Egypt, March 2004
Sao Paulo, Brazil, June 2004
Nagasaki, Japan, July 2004
Bangkok, Thailand, September 2004
Zanzibar, Tanzania, December 2004 (Advanced Workshop)
Cape Town, South Africa, January 2005
Durban, South Africa, January 2005
Lima, Peru, June, 2005
Nagasaki, Japan, July 2005
Bangkok, Thailand, September 2005
Jakarta, Indonesia, November 2005
Lima, Peru, March 2006
Lima, Peru, March 2006 (Clinical Ethics Workshop)
Cuzco, Peru, March 2006 (Clinical Ethics Workshop)
Iquitos, Peru, March 2006
New Delhi, India, June 2006
Nagasaki, Japan, July 2006
Jerusalem, Israel, December 2006 (planned)
Beijing, China, June 2007 (planned)
Bamako, Mali, December 2007 (planned)
Publications Related to Multinational Clinical Research:
Dickert N, DeRiemer KL, Duffy P, Garcia-Garcia L, Sina B, Tindana P, Lie RK. Ancillary care responsibilities in observational research: Two cases, two problems. Lancet. (In Press).
Emanuel E.J, Hawkins J (eds.) Exploitation in International Clinical Research (Princeton University Press, forthcoming).
Gbadegesin S, Wendler D. Protecting Communities in Biomedical Research from Exploitation. Bioethics. 2006. (In Press).
Lie RK. Standard of care owed to participants in trials: Different standards in different countries? In: Ashcroft R, Angus Dawson, Heather Draper and John McMillan, eds. Principles of Health Care Ethics, John Wiley, London, (In Press).
Wertheimer A. “Exploitation in Clinical Research” (Chapter in volume noted above).
Wertheimer A. “Exploitation in Clinical Research” (Entry in Emanuel E...Oxford Textbook of Research Ethics (forthcoming).
Merritt M, Grady C, “Reciprocity and Post-trial Access for Participants in Antiretroviral Therapy Trials” AIDS. 2006;20:1791-1794.
Pace C, Grady C, Wendler D, Bebchuk J, Tavel J, McNay L, Forster H, Killen J, Emanuel E. for the ESPRIT Group. Post Trial Access to Tested Interventions: The Views of IRB/REC Chairs, Investigators and Research Participants in a Multinational HIV/AIDS Study. AIDS Research and Human Retroviruses. 2006;22:837-841.
Lie RK, Grady C, Emanuel EJ. Circumcision and HIV prevention research. An ethical analysis Lancet. 2006;368:522-25.
Grady C. Ethics of International Research: What Does Responsiveness Mean? Virtual Mentor. April 2006;8:235-240. Available at: http://www.ama-assn.org/ama/pub/category/16102.html.
Novotny TE, Mordini E, Chadwick I, Pedersen JM, Fabbri F, Lie R, Thanachaiboot N, Mossialos E, Permanand G. Bioethical Implications of Globalization (BIG): an International Consortium Project of the European Commission. PLoS Medicine. 2006;3:e43.
Lavery J, Grady C, Wahl E, Emanuel EJ, editors. Case Book of International Clinical Research (New York: Oxford University Press, 2006).
Emanuel EJ, Crouch RA, Grady C, Lie R, Miller FG, Wendler D, editors The Oxford Textbook of Clinical Research Ethics. (New York: Oxford University Press, 2007).
Astor A, Akhtar T, Matallana MA, Muthuswamy V, Olowu FA, Tallo V, Lie RK. Physician Migration: Views from Professionals in Colombia, Nigeria, India, Pakistan and the Philippines. Social Science & Medicine. 2005;61:2492-2500.
Barton J, Emanuel EJ. The Patents-Based Pharmaceutical Development Process. JAMA. 2005;294(16):2075-2082.
Diallo D, Doumbo O, Plowe C, Wellems TE, Emanuel E, Hurst S. Community Permission for Medical Research in Developing Countries. Clinical Infectious Diseases. 2005;41:255-259.
Emanuel EJ, Currie XE, Herman A, on behalf of Project Phidisa. Undue Inducement in Clinical Research in Developing Countries: Is it a Worry? Lancet. 2005;366:336-340.
Grady C. The Challenge of Assuring Continued Post-trial Access to Beneficial Treatment. Yale Journal of Health Policy, Law, and Ethics. 2005;5(10):425-435.
Pace C, Talisuna A, Wendler D, Maiso F, Wabwire-Mangen F, Bakyaita N, Okiria E, Garrett-Mayer E, Emanuel E, Grady C. Quality of Parental Consent in a Ugandan Malaria Study. American Journal of Public Health. 2005;95(7):1184-1189.
Pace C, Emanuel E. The Ethics of Research in Developing Countries: Assessing Voluntariness. Lancet. 2005;365:11-12.
Pace C, Grady C, Chuenyam T, Duncombe C, Bebchuk J, Wendler D, Tavel J , McNay L, Phanuphak P, Forster H, and Emanuel E for the ESPRIT Group. The Quality of Informed Consent in a Clinical Research Study in Thailand. IRB: Ethics and Human Research. 2005;27(1):9-17.
Sabik L, Pace CA, Forster HP, Wendler D, Bebchuk JD, Tavel JA, McNay LA, Killen J, Emanuel EJ, Grady C. Informed Consent: Practices and Views of Investigators in a Multinational Clinical Trial. IRB. 2005;27(5):13-18.
Wendler D, Pace C, Talisuna A, Maiso F, Grady C, Emanuel E. Research on Stored Biological Samples: The Views of Ugandans. IRB. 2005;27(2):1-5.
Books and Book Chapters
Meulen RT, Biller-Andorno N, Lenk C, Lie R, editors. Evidence-based Practice in Medicine and Health Care. A Discussion of the Ethical Issues. (New York: Springer-Verlag Berlin Heidelberg, 2005).
Danis M. Evidence-Based Medicine and Managed Care, pp 163-172 in Evidence-Based Practice in Medicine and Health Care: A Discussion of the Ethical Issues, RT Meulen R, Biller-Andorno N, Lenk C, Lie R, editors. (New York: Springer-Verlag, 2005).
Lie, RK. Research Ethics and Evidence Based Medicine, pp 97-104 in Evidence-based Practice in Medicine and Health Care. A Discussion of the Ethical Issues (New York: Springer-Verlag, 2005) pp.97-104.
Permanand G, Lie RK. Globalization, Liberalization of Trade and Health, pp. 55-64 in Bioethical Implications of Globalization. E. Mordini, editor. (Rome: CIC Edizioni Internationali. 2005).
Barton J. Discussion Note on Patents in Pharmaceutical R&D by Carlos Correa. Bulletin of the World Health Organization. 2004;82:787-788.
Belsky L, Richardson H. Medical Researchers’ Ancillary Clinical-Care Responsibilities. BMJ. 2004;328:1494-1496.
Belsky L, Lie R, Emanuel E, Mattoo A, Sreenivasan G. The General Agreement on Trade in Services: Implications for Health Policy Makers. Health Affairs. 2004;23(1):137-145.
Emanuel E, Grady C, Wendler D, Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries. Moving Beyond Reasonable Availability to Fair Benefits for Research in Developing Countries. Hastings Center Report. 2004;34(3):17-27.
Emanuel E, Wendler D, Killen J, Grady C. What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research. Journal of Infectious Diseases. 2004;189:930-937.
Flory JH, Kitcher P. Global Health and the Scientific Research Agenda. Philosophy & Public Affairs. 2004;32(1):36-65.
Grady, C. Ethics of Vaccine Research. Nature Immunology. 2004;5(5):465-468.
Lie, RK. Health, Human Rights and Mobilization of Resources for Health. International Journal of Health and Human Rights. 2004;4(4)(online journal).
Lie R, Emanuel E, Grady C, Wendler D. The Standard of Care Debate: The Declaration of Helsinki versus the International Consensus Opinion. Journal of Medical Ethics. 2004;30:190-193.
Lie R. Research Ethics and Evidence Based Medicine. Journal of Medical Ethics. 2004;30:122-125.
Lie, RK. Ethical Issues in Bioterrorism Research. In: Proceedings of an international conference on ethical implications of research into the prevention of bioterrorism. European Commission, Brussels, 2004.
Richardson H, Belsky L. The Ancillary-Care Responsibilities of Medical Researchers: An Ethical Framework for Thinking about the Clinical Care that Researchers Owe Their Subjects. Hastings Center Report. 2004;34(1):25-33.
Wendler D, Emanuel E, Lie R. The Standard of Care Debate: Can Research in Developing Countries Be Both Ethical and Responsive to Those Countries’ Health Needs? American Journal of Public Health. 2004;94(6):923-928.
Gross M, Ravitsky V. Israel: Bioethics in a Jewish-Democratic State. Cambridge Quarterly of Healthcare Ethics. 2003;12(3):247-255.
Lavery JV, Upshur REG, Sharp RR, Hofman KJ. Ethical Issues in International Environmental Health Research. International Journal of Hygiene and Environmental Health. 2003;201:1-11.
Lie RK. The Absolute Ethical Requirement of Individual Informed Consent: A Commentary on Barrett and Parker. Monash Bioethics Review. 2003;22(3):18-22.
Pace C, Grady C, Emanuel E. What we don't know about informed consent. SciDevNet. 2003: August 28, http://www.scidev.net/dossiers/ethics/.
Books and Book Chapters
Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C, eds. Ethical and Regulatory Aspects of Clinical Research: Readings and Commentary (Baltimore: Johns Hopkins University Press, 2003).
Brock, D. Separate Spheres and Indirect Benefits in Making Choices in Health in WHO Guide to Cost-Effectiveness Analysis (Geneva: World Health Organization, 2003).
Brock, D. Chapter 3.2: Fairness and Health; Separability of Health and Well-Being; and Chapter 12.4: Empirical Ethics, Moral Philosophy, and the Democracy Problem, in Summary Measures of Population Health, Murray C, Salomon J, Mathers C. Lopez A, Lozano J, editors. (Geneva: World Health Organization, 2003).
Emanuel EJ, Grady C, Lie R, Wendler D, Participants in the 2001 Conference of Ethical Aspects of Research in Developing Countries. Fair Benefits for Research in Developing Countries. Science. 298:2133-2134.
Killen J, Grady C, Folkers G, Fauci A. Ethics of Clinical Research in the Developing World. Nature. 2002;2:210-215.
Robertson DW, Bedell R, Lavery JV, Upshur R. What Kind of Evidence Do We Need to Justify Humanitarian Medical Aid? Lancet. 2002;360:330-333.
Sreenivasan, G. International Justice and Health: A Proposal. Ethics & International Affairs. 2002;16(2):81-90.
Weatherall D, Brock D, Chee H-L, and Members of the WHO Advisory Committee on Health Research. Genomics and World Health (Geneva: World Health Organization, 2002).