Abstract
Despite ongoing advances in drug discovery science, anticancer agent development remains a laborious, time‐consuming process. Discouragingly, the overall approval rate for new oncology drugs is approximately ∼ 5%, with estimated R & D costs ranging from $0.8–1.7 billion for each new agent. Lack of efficacy, suboptimal formulation, poor bioavailability and other factors contribute to the high pre‐registration attrition rate, suggesting an urgent need for process enhancements that can facilitate earlier differentiation between viable and non‐viable candidate compounds. In January 2006, the U.S. Food and Drug Administration (FDA) issued a guidance document on Exploratory IND Studies (a.k.a. phase 0 trials). In brief, phase 0 trials should (a) be conducted prior to traditional phase I, dose‐limiting toxicity trials; (b) involve limited human exposure (usually ≤ 30 subjects); (c) have no therapeutic or diagnostic intent; and (d) be of relatively short duration (typically ≤ 7 days). Realistic goals for phase 0 trials include:
replicate preclinical mechanism(s) of action in a human intervention trial;
characterize initial pharmacokinetic/pharmacodynamic profiles;
evaluate biodistribution patterns, based on imaging technologies.
Achieving one or more of these goals in phase 0 trials would permit better selection of active versus inactive compounds for further development. By design, phase 0 trials portend lower risks to human subject than traditional phase I trials. As such, fewer preclinical supporting data are required prior to conducting a phase 0 trial. The initial agent dose depends in part on the stated trial objectives, but should be no greater than 1/50th of the no‐observed‐adverse‐effect level (NOAEL) estimated from animal toxicology testing. Validated pharmacodynamic assays, ideally with low variability in the molecular target, are suitable for application to phase 0 trials if the investigational agent can reasonably be expected to demonstrate target modulation at a non‐toxic dose. Standard operating procedures for tissue collection and biospecimen handling should be defined in advance and revised as necessary based on results of the phase 0 trial. Chemoprevention agent development is uniquely challenged by the need to identify widely acceptable, minimally toxic compounds (even when chronically administered) that favorably affect carcinogenesis when measured against surrogate biomarkers, rather than direct cancer endpoints. Methods to identify bioavailable, pharmacodynamically active candidates earlier in the drug development cycle would offer clear advantages with respect to process efficiency, resource utilization and other parameters. Natural products (or derivatives thereof) represent an attractive source for chemoprevention agent discovery and, given their oftentimes demonstrated favorable safety profile at standard doses, provide an excellent opportunity to explore potential benefits gained through the phase 0 trial paradigm.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):ED04-02.
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