Humans are often intentionally exposed to various agents to evaluate possible health effects. Most intentional exposures occur during the development of potential new medicines and are used to characterize their efficacy and safety. The clinical-trial process is subject to numerous regulations, guidance, monitoring, and reporting obligations that attach primary importance to patient well-being. Specifically, the trials are conducted under multiple federal regulations (21 CFR 21, 50, 54, 312 ), good-clinical-practice guidelines, and technical requirements established by the International Conference on Harmonization (EMEA 2002). Such guidelines and regulatory requirements determine regulatory oversight processes, trial conduct, ethical review, informed consent, monitoring of drug supplies, adverse-event monitoring, and data integrity and quality assurance.
Preclinical safety testing of investigational new drugs must satisfy the appropriate regulatory bodies that the first clinical trials in humans will pose minimal risk for subjects. The exhaustive nature of the preclinical assessment, which includes high-dose acute and multidose chronic studies in animals, means that only a few potential new drugs will be deemed sufficiently safe for administration to human volunteers. The trial process itself is separated into distinct phases, and the study protocol for each phase is subject to review by an institutional review board or ethics committee. The phases of clinical trials are as follows:
Phase 1. This stage, typically performed in fewer than 100 healthy volunteers, is designed to establish dose-range tolerance. It may include a carefully controlled and monitored dose-escalation protocol. For some disease indications, such as cancer and HIV, the Food and Drug Administration supports an accelerated process in which efficacy and tolerance are assessed simultaneously in patients with the disease in question.
Phase 2. For most indications, this stage is designed to refine dose ranges, establishing efficacy and safety in typically 100-500 selected patients who represent the target population. Drug tolerance is monitored. Parallel safety studies in animals are also run to characterize potential adverse effects that may be a consequence of high-dose or long-term exposure and to characterize specific end points, such as reproductive and developmental effects.