© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 19, 1555,
October 4, 2000
© 2000 Oxford University Press
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How Does a Drug Get to Phase III Trials?
NCI’s Drug Development Group (DDG; which replaced the Decision Network Committee in January 2000) handles most decisions on whether to continue moving investigational agents along the pipeline from preclinical testing to Investigational New Drug application filing to phase I trials. DDG is co-chaired by the associate directors of the Developmental Therapeutics Program and the Cancer Therapy Evaluation Program; the other members are NCI scientists who head branches and sections involved in drug development.
An application from the drug’s "originator" is reviewed by DDG staff and two external reviewers, and prioritized according to strength of the proposal’s credentials, novelty, costs and benefits, and need for NCI involvement. The group votes on each agent at four key "go–no go" decision points based on its performance from screening through toxicology to phase I trials.
Only rarely, in cases where toxicity occurs at doses too low to have useful effects, does a drug fail to advance from phase I to phase II. From 1980 to 2000, more than 300 agents entered oncology phase I trials under NCI IND, and "only a handful didn’t get any phase II trials," said Louise Grochow, M.D., chief of the Investigational Drug Branch, although the criteria used for making this decision are shifting as new classes of drugs emerge.
"With many of the novel agents that have no dose-limiting toxicities, we are evaluating other end points for phase I, such as the achievement of drug concentrations in humans that are comparable to—or an order of magnitude higher than—the level that produced useful effects in animals," she said, or biologic effects that indicate that the intended target is affected by the agent. Because phase I to phase II decisions have become more complex, NCI has a new grant program to develop tools to assess novel end points that will help in these decisions, she said.
An alternative route for drug development support is NCI’s new RAID program (Rapid Access to Intervention Development), which helps academic investigators take their own drugs to early clinical trials.
Richard Ungerleider, M.D., chief of the Clinical Investigations Branch, said the decision to move from phase II to phase III is based on whether the agent demonstrated the response rate of interest that was specified in the phase II protocol. "In a perfect world, all agents meeting the protocol-specified criteria would go on to be tested in a phase III trial," he said. "But since we live in an imperfect world, where not enough patients are enrolled on phase III trials and where resources are limited relative to the number of interesting new compounds, the decision to move forward is made collaboratively by the investigators, NCI, and the commercial partner, if any. Consideration is then given to toxicity profiles, novelty of the new agent, and competing agents of interest."
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