title: The statistics of phase 0 trials.
abstract: The PD-driven phase 0 trial is a new form, designed to be a first-in-man study, often of a new agent, conducted to assess drug effect on a molecular target, by means of a pharmacodynamic (PD) assay, in a very small number (10-15) of patients. Such a study is meant to be a proof of principle trial to determine whether the agent yields the PD effect predicted by pre-clinical studies. The dosage is meant to be pharmacologically active, but is neither toxic nor likely to yield clinical benefit. Such a trial may be used to serve as a very early test of an agent's biologic effect, allowing for early weeding out of ineffective agents, or as an early means of determining the most promising of competing analogue agents. This manuscript will present designs for such PD-driven studies that are statistically efficient and rigorous, focusing on non-comparative trials. The phase 0 trial promises to become an increasingly important tool for facilitating and speeding the development of new therapeutic agents, particularly in oncology.
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA. rubinsteinl@ctep.nci.nih.gov
authors.forename: Larry V
authors.initials: LV
authors.lastname: Rubinstein
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: Robert
authors.initials: R
authors.lastname: Kinders
authors.forename: Ralph E
authors.initials: RE
authors.lastname: Parchment
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D015507:Drugs, Investigational / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010599:Pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational