Ethical issues in the development of new agents.

In the early drug development process for cancer therapy, several ethical dilemmas result from the use of cancer patients with advanced disease as the subjects of research in clinical trials studying agents of unknown toxicity and/or efficacy. Although several accepted ethical principles guide the behavior of involved physicians and investigators, many of these principles are allowed to be violated in order to achieve the overall goal of clinical research in improving medical care for future patients. Informed consent has been a process viewed by many as a mechanism which protects potentially vulnerable patients from harm in the clinical trial process. However, the ability of the traditionally regulated process of obtaining informed consent for clinical research may be inadequate to ensure appropriate understanding of the purposes and the goals of early clinical trial research by potentially vulnerable advanced cancer patients. This creates further dilemmas with regard to physician-investigator and patient-subject communications. In the setting of phase I trials, where the specific goal of the research is to obtain toxicity information regarding a new potential anticancer agent, many heightened ethical conflicts are present. The fact that patients do not participate in these studies as a result of altruism, and that their main goals of participation are intensely therapeutic, create issues that may be in direct conflict with the research purpose of phase I trials. As well, the presence of therapeutic intentions on the part of involved physician-investigators creates challenging issues when one realizes the very low likelihood of benefit for individual patients participating in these studies. Within the phase II setting, the statistical constraints placed on new drug trials and, again, the low likelihood of benefit for participating-subjects, also creates challenging dilemmas. These statistical requirements may be in direct conflict with involved clinicians' attitudes and beliefs regarding potential efficacy of an agent in this setting. As well, these issues become problematic when thinking about the desired structure and outcome for informed consent in phase II anticancer trials. The ability to conduct clinical research on advanced cancer patients using agents of unknown efficacy and toxicity is a daunting privilege granted to physicians and accompanying institutions. The weight of this privilege should not be underestimated, and involved physician-investigators should be aware of the significant ethical challenges involved in appropriately and successfully conducting this form of research.