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Phase 1 Clinical Trials

Lead Author(s): Bernard Lo, M.D.

Selection of Participants in Phase 1 Clinical Trials

In Phase 1 clinical trials, a common ethical and design question is who should be the participants in first-in-human trials – Healthy volunteers? Persons with advanced disease?

In cancer clinical trials, participants in Phase 1 studies are typically persons with advanced disease that is refractory to standard treatments. There are several reasons for this choice. New cytotoxic cancer agents are expected to have considerable toxicity. Also the therapeutic dose usually is close to the toxic dose. Thus it is difficult to justify giving such compounds to healthy volunteers, who would have no prospect of benefit. However, cancer patients who refractory advanced disease have a limited prognosis. Hence if they suffered serious toxicity, they would not lose many quality-adjusted life-years. Furthermore, there is some (albeit small) possibility that patients with advanced cancer might have some benefit in Phase 1 trials. Thus the risk-benefit balance for patients with advanced disease is more favorable than with healthy volunteers.

For other clinical conditions, in contrast, it often makes sense to enroll healthy volunteers in Phase 1 trials. For instance, in a Phase 1 trial of an agent to prevent progression of Chagas’ disease, it would be reasonable to test dosing and safety in healthy volunteers provided that several conditions were met. First, preclinical studies suggest the agent will have a large therapeutic ratio and mild toxicity, so that serious adverse events in humans are not expected at the doses administered. Second, the drug would not be primarily be used in persons with advance disease (at least in Phase II-III trials). The pharmacokinetics and pharmacodynamics of the drug in sick patients may be highly variable because of effects of the disease or other treatments. Thus investigators and sponsors might prefer healthy volunteers for Phase I studies because the data will be more reproducible and precise. Furthermore, healthy volunteers may be less susceptible to adverse events than sick patients.


For additional reading, see Lo, B. Resolving Ethical Dilemmas in Clinical Research. In press, 2009. Chapter 26 is on translational and first-in-humans research.

Topic revision: r4 - 05 Apr 2010 - 13:59:03 - MaryBanach
CTSpedia.Phase1ClinicalTrial moved from CTSpedia.SelectionOfParticipantsInPhase1ClinicalTrials on 22 Dec 2008 - 22:39 by CTSpediaAdmin
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