Ethical Review and the Globalization of Clinical Trials

On 2 October 2001 the Inspector General of the U.S. Department of Health and Human Services, Janet Rehnquist, released a report entitled The Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects.¹ This report marks a significant point in U.S. policy toward the protection of human subjects in foreign clinical trials, providing a needed impetus, along with clear direction, for a full U.S. framework that will ensure the highest level of protection for clinical trial participants abroad. Just as importantly, the report marks an historic benchmark in biomedical research.

Ten years ago it would have been awkward to speak of the globalization of clinical trials, let alone title a pivotal report with such an ominous (and promising) burden. But during the 1990s, industry-sponsored research moved rapidly beyond the familiar territory of the United States, the European Union, and Japan (the so-called ICH regions) into large parts of Central and Eastern Europe, South America, Asia, and Africa.²

While the primary purpose of this report is to assess the capacity of the Food and Drug Administration (FDA) for human subject protections in foreign clinical trials in which data is to be submitted for FDA approvalthus, nearly entirely industry-sponsored researchthe report also provides an overview of current oversight available in the United States regarding protections for research participants on foreign soil. Its recommendations are directed, not only to the FDA, but also towards integrated approaches that would apply across federal agencies and to federally funded and New Drug Application research conducted at non-U.S. sites. Specifically, it citesand encourages the expansion ofthe leadership role of the DHHS Office for Human Research Protections (OHRP).

A major finding in the report is that there is generally a lack of knowledge with regard to the performance of foreign institutional review boards (IRBs) (or, more generically, ethics committees). Not only do the FDA and other federal oversight agencies have an incomplete understanding of the operation and quality of ethical review in clinical trials outside the United States, there are well-founded reasons for concern with regard to the independence and quality of IRBs in many foreign institutions. Thus, the report rightly recommends that FDA, OHRP, the National Institutes of Health, and other regulatory bodies increase the information they have on foreign IRBs and contribute to capacity building for foreign IRBs, and that OHRP encourage a voluntary system of accreditation for foreign IRBs. The report also points toward the responsibility of sponsors of foreign clinical trials, stating, sponsors should take steps to educate the non-U.S. boards [IRBs] that they use.

The need to develop an integrated approach to information gathering, capacity building, and voluntary accreditation of foreign IRBs across federal agencies and in cooperation with sponsors and researchers could be a daunting task. If one examines ethical review systems and IRB authority, composition, and practices in the European Union alone15 largely well-developed research environments and pharmaceutical marketsthe findings are striking. No two countries have the same review structure, the same requirements for ethical review jurisdiction, or the same procedures for submitting and evaluating applications to IRBs. While since April 2001 these countries now share a European law³ that requires certain harmonization in the area of ethical review, human subjects legislation in the different EU member states is at various levels of development and inevitably reflects national practices and values in ethical review. Transpose this situation to the 191 member states of the World Health Organization (WHO)countries (and regions) with enormous political, social, and economic differencesand the requirements for achieving, understanding, and harmonizing ethical review practices in the globalized clinical trials marketplace are, at the very least, complex.⁴

Based on broad experience in promoting and carrying out research and training in countries with high disease burdens and weak health-care infrastructures, the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) launched a number of initiatives aimed at strengthening capacity for sound ethical and scientific research. In the area of ethical review, TDR/WHO has worked in collaboration with a number of leading organizations, including the OHRP, FDA, European Forum for Good Clinical Practice (EFGCP), and the International Federation of Pharmaceutical Manufacturers Associations (IFPMA).

A recent achievement of this partnership was the publication of the Operational Guidelines for Ethics Committees That Review Biomedical Research.⁵ These guidelines mark a significant contribution in the development of independence, competence, and quality in ethical review around the world. They provide a high standard of excellence, encouraging IRBs and ethical review systems to grow and improve with a significant amount of autonomy. These globally accepted guidelines establish guidance for IRBs concerning appropriate operating procedures. At the same time, TDR/WHO and its collaborators recognized that guidelines are only a first, necessary step. Much more needs to be undertaken in capacity building for ethical review that will lead to sustained development at local, national, and regional levels.⁶

International guidance and national legislation are essential to developing well-functioning ethical review systems. However, international guidelines and national law alone will not suffice. Without a systematic approach to information gathering and capacity building, standards alone will not achieve greater protections for research subjects through independent and competent ethical review in all countries. Given the enormous complexity of cultural variations, national laws, and local medical and research practices, local knowledge and local engagement are essential to develop ethical review. In addition, the principles of bioethics and the need for sustained development demand that responsibility be born at the local level, as close to the patient as possible.⁷