End points in cancer clinical trials and the drug approval process.

The sequencing of the human genome and the elucidation of many molecular pathways important in cancer cell proliferation, apoptosis, and metastasis have provided unprecedented opportunities for development of new agents to prevent and treat cancer. The types of molecules in development are increasingly varied and include small molecules, monoclonal antibodies, antisense oligonucleotides, and ribozymes. Thus, the variety of anticancer agents in clinical development is now greater than ever before, and the number of agents currently in clinical trial for various cancer indications is estimated to exceed 400. Many of these drugs would be expected to work in only narrowly defined patient populations that must be prospectively identified. Thus, the development of the therapeutic agent must often be linked to the development of a molecular diagnostic product. Drugs that produce primarily cytostatic effects might not be expected to produce regression of tumor masses; thus, evaluation of such agents would best be done in populations of patients with low tumor burdens but high risk of disease progression. As traditional clinical end points prove more difficult to apply in evaluation of molecularly targeted therapies, a great need exists to define and validate surrogate markers of effect and of benefit. New clinical trial designs and end points are necessary to permit more efficient evaluation of putative cancer treatments. This editorial will review commonly used clinical trial end points and describe their potential advantages and disadvantages to expedite the drug approval process required in the United States.