PLANNING CONTROLLED CLINICAL-TRIALS

Objective. To address principles in the design and conduct of clinical trials on prostate cancer (PC) with special reference to localized di sease. Methods. In advance of and during the World Health Organization (WHO) conference on Prostate Cancer in Stockholm in September 1996, 6 members of a working group evaluated and reached consensus on key poi nts for the planning and conduction of controlled clinical trials in P C. The key points discussed were 1) hypothesis formulation, 2) general methodological principles, 3) special problems of PC trials, 4) alter natives to randomization, and 5) trial organization. Results. The hypo thesis must be clearly formulated and also clinically relevant enough to justify the expenses (in a broad sense) of a randomized clinical tr ial. Patient selection, definition of endpoints, and sample size calcu lations must be carefully considered and correspond to the aims of the study. Stratification on important prognostic factors should be conte mplated. Maintaining the accrual rate and ensuring compliance are crit ical for a quality study. Survival is the main endpoint and intention to treat analysis is the standard methodology. Secondary endpoints leg , quality of life and costs) are important for the evaluation of many treatment modalities. The use of surrogate endpoints for survival, suc h as prostate-specific antigen (PSA) elevation, may be misleading. Sur rogate endpoints require further validation. Special features, such as long natural history in localized disease and difficulties in assessi ng objective responses in advanced disease, need consideration in PC t rials. The controlled randomized trial is the gold standard methodolog y. Nonrandomized trials are often hampered by severe methodological pr oblems, such as selection bias and biased ascertainment of endpoints d ue to the doctor's or patient's preferences. For the organization of a successful trial, a well-constructed study protocol is essential. Goo d clinical practice as defined within the European Community helps def ine and solve practical problems. Conclusions. The past 30 years of po orly designed clinical research on PC has left us without reliable ans wers in key clinical issues regarding, for example, the efficacy of pr imary treatment of localized PC. It is a stimulating and important cha llenge to the urological scientific community to conduct well-organize d controlled clinical trials. (C) 1997 by Elsevier Science Inc.