Vulnerability is one of the least examined concepts in research ethics. Vulnerability was linked in the Belmont Report to questions of justice in the selection of subjects. Regulations and policy documents regarding the ethical conduct of research have focused on vulnerability in terms of limitations of the capacity to provide informed consent. Other interpretations of vulnerability have emphasized unequal power relationships between politically and economically disadvantaged groups and investigators or sponsors. So many groups are now considered to be vulnerable in the context of research, particularly international research, that the concept has lost force. In addition, classifying groups as vulnerable not only stereotypes them, but also may not reliably protect many individuals from harm. Certain individuals require ongoing protections of the kind already established in law and regulation, but attention must also be focused on characteristics of the research protocol and environment that present ethical challenges.

The oversight of research involving human participants is widely believed to be inadequate. The U.S. Congress, national commissions, the Department of Health and Human Services, the Institute of Medicine, numerous professional societies, and others are proposing remedies based on the assumption that the main problems are researchers' conflict of interest, lack of institutional review board (IRB) resources, and the volume and complexity of clinical research. Developing appropriate reform proposals requires carefully delineating the problems of the current system to know what reforms are needed. To stimulate a more informed and meaningful debate, we delineate 15 current problems into 3 broad categories. First, structural problems encompass 8 specific problems related to the way the research oversight system is organized. Second, procedural problems constitute 5 specific problems related to the operations of IRB review. Finally, performance assessment problems include 2 problems related to absence of systematic assessment of the outcomes of the oversight system. We critically assess proposed reforms, such as accreditation and central IRBs, according to how well they address these 15 problems. None of the reforms addresses all 15 problems. Indeed, most focus on the procedural problems, failing to address either the structure or the performance assessment problems. Finally, on the basis of the delineation of problems, we outline components of a more effective reform proposal, including bringing all research under federal oversight, a permanent advisory committee to address recurrent ethical issues in clinical research, mandatory single-time review for multicenter research protocols, additional financial support for IRB functions, and a standardized system for collecting and disseminating data on both adverse events and the performance assessment of IRBs.