Phase 0 clinical trials: conceptions and misconceptions

Abstract

Phase 0 clinical trials, developed in response to the United States Food and Drug Administration (FDA)'s recent exploratory Investigational New Drug (IND) guidance, are intended to expedite the clinical evaluation of new molecular entities. The exploratory IND supports the performance of first-in-human testing of new investigational agents at subtherapeutic doses based on reduced manufacturing and toxicologic requirements, allowing the demonstration of drug-target effects and assessment of pharmacokinetic-pharmacodynamic relationships in humans earlier in clinical development. The objectives of a phase 0 cancer clinical trial are to establish at the very earliest opportunity-before large numbers of patients have been accrued and exposed to potential drug-associated toxicity-whether an agent is modulating its target in a tumor, and consequently whether further clinical development is warranted. We review here the fundamental requirements of clinical studies conducted under an exploratory IND and address some common misconceptions regarding oncologic phase 0 trials.

FIGURE 1.

Shortening clinical development timelines with an exploratory Investigational New Drug (IND) guidance. Conducting a phase 0 trial under an exploratory IND can reduce the clinical development time for new agents and inform further clinical decision making. A, Phase I trials under a traditional IND require substantial preclinical toxicology studies and full-scale good manufacturing practice production of the investigational agent before clinical administration. Pharmacodynamic (PD) studies are generally not performed until phase II trials are initiated. B, Phase 0 imaging/biodistribution trials introduce sub-pharmacologic doses of the new agent to patients or healthy volunteers. Results from these trials may be sufficient to establish proof of principle, and no further dose escalation phase I studies may be needed. These imaging studies can be used as correlative studies in subsequent phase II/III trials of therapeutic agents. C, Phase 0 trials with a PD end point must have a validated PD assay before clinical trial accrual. The decision to proceed for further clinical development and conduct accelerated phase I/phase I combination, or phase I/II trials can be made based on whether the PD objective was met in the phase 0 trial.