TISHLER AND BARTHOLOMAE RECRUITMENT OF NORMAL HEALTHY VOLUNTEERS DRUG DEVELOPMENT DRUG DEVELOPMENT The Recruitment of Normal Healthy Volunteers: A Review of The Literature on the Use of Financial Incentives Carl L. Tishler, PhD, ABPP, and Suzanne Bartholomae, PhD F rom the development of the Nuremberg Code to the publication of the Belmont Report, the ethical principles and guidelines for protecting human sub- jects in research have been a concern among the scien- tific community, including policy makers, institutional review boards (IRBs), and investigators. 1,2 The impor- tance of safeguarding human research subjects has be- come evident. Unresolved issues of ethical, method- ological, and legal concern in the use of normal healthy volunteers (NHVs) persist, and dilemmas surrounding human subjects research have rarely been addressed in a systematic manner. 3-5 Over the past several decades, increased public and professional attention has been drawn to the use of NHVs in research. 6-8 The 1999 death of an 18-year-old volunteer enrolled in a gene therapy clinical trial and the more recent death of a laboratory employee volun- teering for a challenge study in asthma research have provoked public scrutiny of the ethical issues in bio- medical and behavioral research. 9-11 Recent regulatory initiatives issued by the federal Department of Health and Human Services (DHHS) authorize the Food and Drug Administration (FDA) to penalize (1) clinical in- vestigators who violate research protocols in amounts up to $250,000 and (2) research institutions up to $1 million. 12 Attention has also grown with the increased need for NHVs for research and the increased use of NHVs as subjects. 13-15 Little attention has been given to the differ- ences among healthy volunteers as a group, 16 and the topic of using volunteers in clinical trials has been un- derstudied in the national and international arenas. 17 Among the complex issues surrounding the use of NHVs are recruitment, informed consent, risk-benefit calculation, dependency, volunteers from outside or inside an institution, self-experimentation, division of ethical responsibility, legal liability for injury, register- ing of volunteers in research projects, and payment. 6,18 Early examination of NHVs focused on the subjects’ motivation for volunteering, and more recently the fo- cus has been on the prevalence of psychopathologic disorders. 19 This review article considers a number of issues that arise from the use of normal healthy volun- teers. In particular, the article focuses on one over- J Clin Pharmacol 2002;42:365-375 365 Unresolved issues of ethical, methodological, and legal con- cerns in the use of normal healthy volunteers persist. Finan- cial incentives in their recruitment offer a unique ethical di- lemma because of questions surrounding payment. A review of literature was conducted to obtain research systematically examining volunteer motivation and the role of financial in- centives. The primary selection criterion was motivation and payment to volunteers; seven studies met the criterion for re- view. Studies that have systematically investigated volunteer motivation have found financial rewards to be an important motivator among normal healthy volunteers in their decision to participate in clinical trials. Also evident is that differences based on demographic characteristics exist in the motivation and rates of volunteerism. Ethical issues surrounding the use of normal healthy volunteers are discussed, with attention to the issue of financial incentives (e.g., economically vulnera- ble volunteers, undue inducements). Regulations, guidelines, and recommendations are discussed with regard to volun- teers and financial incentives. Journal of Clinical Pharmacology, 2002;42:365-375 ©2002 the American College of Clinical Pharmacology From The Ohio State University, Columbus, Ohio. This research was par- tially supported by the Grant/Riverside Methodist Hospitals Foundation, Columbus, Ohio. Submitted for publication October 1, 2001; revised ver- sion accepted December 21, 2001. Address for reprints: Carl L. Tishler, PhD, ABPP, Adjunct Associate Professor of Psychology, The Ohio State Uni- versity, 1776 East Broad Street, Columbus, OH 43203.