Phase 0 clinical trials in cancer drug development: from FDA guidance to clinical practice.
The Food and Drug Administration (FDA) recently introduced the Exploratory Investigational New Drug Guidance to expedite the clinical evaluation of new therapeutic and imaging agents. Early clinical studies performed under the auspices of this guidance, so-called "Phase 0" trials, have been initiated at the National Cancer Institute to integrate qualified pharmacodynamic biomarker assays into first-in-human cancer clinical trials of molecularly targeted agents. The goal of this integration is to perform molecular proof-of-concept investigations at the earliest stage of cancer drug development. Phase 0 trials do not offer any possibility of patient benefit; instead, intensive, real-time pharmacodynamic and pharmacokinetic analyses of patient tumor samples and/or surrogate tissues are performed to inform subsequent trials. Phase 0 studies do not replace formal Phase I drug safety testing and require a substantial investment of resources in assay development early on; however, they offer the promise of more rational selection of agents for further, large-scale development as well as the molecular identification of potential therapeutic failures early in the development process.
Kinders
Robert
R
Laboratory of Human Toxicology and Pharmacology, Applied/Developmental Research Support Directorate, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland 21702, USA.
Parchment
Ralph E
RE
Ji
Jay
J
Kummar
Shivaani
S
Murgo
Anthony J
AJ
Gutierrez
Martin
M
Collins
Jerry
J
Rubinstein
Larry
L
Pickeral
Oxana
O
Steinberg
Seth M
SM
Yang
Sherry
S
Hollingshead
Melinda
M
Chen
Alice
A
Helman
Lee
L
Wiltrout
Robert
R
Simpson
Mel
M
Tomaszewski
Joseph E
JE
Doroshow
James H
JH
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002986:Clinical Trials as Topic / Q000941:ethics / Q000379:methods*; D015195:Drug Design; D015507:Drugs, Investigational / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D014481:United States; D014486:United States Food and Drug Administration
D000970:Antineoplastic Agents; D015507:Drugs, Investigational