Clinical research in low-resource countries: historical perspectives, issues, and implications for research coordination capacity building.

The growth of research in low-resource countries presents both challenges and opportunities to the planning, implementation, end dissemination of research. Between 1990 and 1999 the number of countries serving as sites for clinical studies supported by the U.S. government increased from 28 to 79 countries. (1) Factors that have contributed to such expansion include: lower costs to sponsors, high incidence of diseases for which treatments are being tested, access to personnel who conduct the studies, and limited exposure of participants to other drugs that may interfere with testing of new drugs and medical treatments. (2) Specific ethical issues that confront researchers working in low-resource countries include the use of placebos and withholding effective treatments from patients randomized to the placebo or control group, definitions of efficacy, standards of care, and access to care within the context of global studies. (3-8) Other issues that must be addressed when planning and conducting research in low-resource countries include contextual realities, recruitment and retention of research participants, and human resources for health care and research. The success of clinical research conducted in international sites, and in particular in low-resource countries, requires appropriate infrastructure (including facilities, equipment, and personnel), an adequate pool of research participants, end qualified investigators. (1) The purpose of this paper is to examine in low-resource countries the historical evolution of clinical research, ethics and other issues in conducting clinical research, and implications for capacity building of research practitioners.

Key words: capacity building, low-resource country, research coordination, research ethics

Introduction

Over the past 20 years there has been a rapid expansion of clinical research in low-resource countries, although there continues to be an imbalance in the global investment of research dollars and the global disease burden. There are many ways to categorize countries in terms of availability of resources and level of development (economic resources, level of industrialization, education, and health status). For the purpose of this paper, in lieu of the term "developing" country, we utilize the term low-resource. A low-resource country refers to a country with limited economic resources, limited numbers of trained scientists, and limited experience in the conduct of biomedical research. (2)

The growth of research in low-resource countries presents both challenges and opportunities to the planning, implementation, and dissemination of research. The success of clinical research conducted in international sites, and particularly in low-resource countries, requires appropriate infrastructure (including facilities, equipment, and personnel), an adequate pool of research participants, and qualified investigators. (1) This article will examine the historical evolution of clinical research, ethics and other issues in conducting clinical research, and implications for capacity building of research practitioners in low-resource countries.

Historical evolution of clinical research in low-resource countries

Large epidemiologic and clinical research sites have existed in low-resource countries for decades. Between 1990 and 1999 the number of countries serving as sites for clinical studies supported by the U.S. government increased from 28 to 79 countries. (1) In 2000, the U.S. Office of Inspector General (OIG) began inquiries into industry-sponsored clinical trials conducted outside of the United States, especially in low-resource countries. The resulting report, The Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects, documented a dramatic increase in the number of foreign investigators listed in FDA Investigational New Drug (IND) applications from 41 in 1980 to 4,458 in 1999. (4) However, these data underestimated the trend because many foreign investigations were being conducted outside of the IND process. The report also suggested that the increase of pharmaceutical company-sponsored research in low-resource countries is due in part to the desire for rapid recruitment of large numbers of subjects who are naive to treatment in diseases under study. (4) Factors that have contributed to such expansion include lower costs to sponsors, high incidence of diseases for which treatments are being tested, access to personnel who conduct the studies, and limited exposure of participants to other drugs that may interfere with testing of new drugs and medical treatments. (2) In a recent published interview, Ira Spector, vice president of clinical development operations and vice chief of operations at Wyeth Research, stated that "our goal is to be approximately 30% U.S. and 70% non-U.S." He also stated that the United States and Western Europe have not been good places to enroll patients and that "quite simply, we're going where we can find patients." (6)

Because of the increasing amount of research being conducted in low-resource countries, the Office of Inspector General issued a number of recommendations covering topics such as Ethics Committee/ Institutional Review Board (EC/IRB) capacity building and accreditation, FDA inspections and tracking of foreign study activity, sponsor oversight, and protection of humans participating in studies. (4,9,10) Although these recommendations were moving in a positive direction, they also were criticized as being generally weak. (4)

Costello and Zumla suggested that the evolution of clinical research sites within low-resource countries is associated with three semi-colonial models: postal research, parachute research, and annexed research. (7) In postal research, local colleagues within low-resource countries mail or ship samples to researchers in the "North" (e.g., Western researchers). Parachute research is more involved, because researchers travel to low-resource countries for brief periods and then take back biological samples. Finally, annexed research, similar to field research, is a situation whereby research sites are established within a low-resource country and are staffed and sometimes led by locals, with funding and oversight by Western institutions.

Global economic disparities have had a marked influence on the development of research in low-resource countries. In 1990, the Commission on Health Research for Development estimated that only 10% of the world's research dollars were being invested in low-resource countries, which shouldered 90% of the world's disease burden. This led to the concept of the 10/90 gap. (11,12) The combined annual gross domestic product of the 95 poorest nations is less than the total annual gross sales of pharmaceutical industry. (13) In 1998, a non-governmental organization, the Global Forum for Health Research, was created to address the 10/90 gap and address three goals: (a) change the priorities governing how existing resources for health research are used; (b) encourage new resources that will be directed to research in the neglected areas; and (c) foster research in the neglected areas to reduce the burdens of disease and disability. (14) In reality the conduct of clinical studies has been an important resource for confronting health crises in low-resource countries. (2)

Ethical issues related to clinical research in low-resource countries

A study that had a significant impact on the development of ethical guidelines related to research in low-resource countries was a multisite study evaluating the effects of Zidovudine (AZT) therapy on mother-to-child transmission of human immunodeficiency virus (HIV) infection. (15) This trial involved a lengthy and complex therapy with AZT throughout pregnancy and for the infant during the first six weeks after birth. Procedures included in this study could not be implemented realistically in low-resource countries with limited access to health care resources. For example, in Malawi, the cost of the drug for one mother-child pair would have been 600 times the annual per capita allocation for health care. (3) In addition, the study involved random assignment of participants to either experimental or placebo control groups, even though other research had demonstrated that AZT could reduce the risk of mother-child HIV transmission. Several subsequent trials were conducted in Africa and Thailand using placebo-controls to test effective measures that block vertical transmission of HIV. By 1997, trials such as these were halted after the publication of a series of articles in the New England Journal of Medicine that raised ethical questions about the use of placebos …