Improving the Quality of Cancer Clinical Trials: Workshop Summary1

INTRODUCTION

The science underpinning cancer drug development has been changing rapidly in recent years because of a more mechanistic understanding of cancer. Today, hundreds of cancer therapeutics are in development, and many target specific molecules, genes, or pathways. To be most effective, preclinical studies indicate that many of these drug candidates need to be combined with other targeted agents, reflecting the complexity of multistep carcinogenesis.

Clinical trials must receive regulatory approval from the Food and Drug Administration (FDA) for these innovative drug candidates before bringing them into clinical use. Not only are these trials expensive and lengthy, but they are extremely prone to failure because prediction of efficacy and toxicity in humans from findings in animal models has often proved unreliable, as has early testing in humans. Only a small percentage of drug candidates ultimately become useful therapies. The novel and more mechanistically based cancer drugs may be even more inclined to fail traditional clinical trials, which are not tailored to the combination testing that may be required, or to the different standards or procedures needed when

1

The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop.



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Improving the Quality of Cancer Clinical Trials: Workshop Summary INTRODUCTION The science underpinning cancer drug development has been chang- ing rapidly in recent years because of a more mechanistic understanding of cancer. Today, hundreds of cancer therapeutics are in development, and many target specific molecules, genes, or pathways. To be most effective, preclinical studies indicate that many of these drug candidates need to be combined with other targeted agents, reflecting the complexity of multistep carcinogenesis. Clinical trials must receive regulatory approval from the Food and Drug Administration (FDA) for these innovative drug candidates before bringing them into clinical use. Not only are these trials expensive and lengthy, but they are extremely prone to failure because prediction of efficacy and toxicity in humans from findings in animal models has often proved unreliable, as has early testing in humans. Only a small percentage of drug candidates ultimately become useful therapies. The novel and more mechanistically based cancer drugs may be even more inclined to fail tradi- tional clinical trials, which are not tailored to the combination testing that may be required, or to the different standards or procedures needed when 1The planning committee’s role was limited to planning the workshop, and the work- shop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. 

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS agents are effective only in small subpopulations. For these and other rea- sons, scientists and clinicians seek a new paradigm that could improve the efficiency, cost-effectiveness, and overall success rate of cancer clinical trials, while maintaining the highest standards of quality. To explore innovative paradigms for cancer clinical trials and other ways to improve their quality, the National Cancer Policy Forum held a workshop, “Improving the Qual- ity of Cancer Clinical Trials,” in Washington, DC, on October 4 and 5, 2007. As Dr. John Mendelsohn explained, the main goals of the workshop were to examine new approaches to clinical trial design and execution that would (1) better inform decisions and plans of those responsible for devel- oping new cancer therapies, (2) more rapidly move new diagnostic tests and treatments toward regulatory approval and use in the clinic, and (3) be less costly than current trials. At the workshop, experts gave presentations in one of five sessions: • New clinical trial designs, including exploratory investigational new drug (IND) and Phase 0 trials, adaptive trials, trials that target mul- tiple pathways with multiple drugs, and preclinical model systems that better inform clinical studies • Molecular imaging, including molecular imaging strategies in drug development and how they can facilitate clinical trials • Screening for predictive markers • Collaborations among academia, the pharmaceutical or diagnostics industries, and government, including ways to reduce the costs and regulatory burdens of clinical trials and increase patient accruals • Regulatory issues, including the laws, regulations, and policies that help or hinder improvements in cancer clinical trials In addition, participants in five small-group discussions explored the fol- lowing topics: • Phase 0 trials • Adaptive trial design • Imaging • Use of proteomics/genomics to assign therapy in lung cancer • Use of genetics/genomics to assign therapy This document is a summary of the conference proceedings, which will serve as input to the deliberations of an Institute of Medicine committee