Year: 2006
Type: dissertation
Abstract: Phase III clinical trials to assess the clinical benefit of\nnew treatment options often require large patient numbers and long follow-up, in\nparticular in diseases with a long natural history, such as prostate cancer. In\nthis thesis, we argue that in order to improve the efficiency of phase III\nprostate cancer clinical trials, a thorough understanding of prognostic factors\nof outcome is needed, as well as an exploration of potential predictive factors\nthat might affect treatment benefit and cause heterogeneity of results. In\naddition, the development of surrogate endpoints of the long term clinical\noutcome is needed in order to speed up the drug development process by reducing\nthe observation time required to assess the final endpoint. We assess the\nprostate specific antigen (PSA) as a potential surrogate endpoint.\n\nIn assessing predictive factors of treatment benefit by retrospective analysis\nof existing clinical data, we recommend the greatest care for the confounding\neffect between prognostic factors and predictive factors, because factors that\nare predictive of the treatment effect will influence the prognostic analysis in\npooled treatment arms analysis We also recommend that treatment effects in\nsubgroups of patients be considered only if there is evidence of heterogeneity\nof results from a single statistical test for interaction, so as to avoid\nmultiple testing problems that increase the chance of finding spurious\nstatistical findings. \n\nThe evidence that PSA progression is a surrogate endpoint for overall survival\nin endocrinally treated metastatic prostate cancer is moderate: we show that non\nnull treatment effects on survival would potentially be identifiable only in\nvery large new trials showing a very large effect on the PSA endpoint. The size\nof a study based on PSA should target a very precise estimation of the treatment\neffect onto the PSA endpoint rather than be based on statistical power. A study\nshould not be stopped whenever statistically significant PSA results become\navailable, we rather recommend that the follow-up should be continued to later\ndocument long term safety of the treatments and their impact on survival. With\nthe proviso that longer term analysis of the trial be planned, effects on PSA\nendpoints might serve as a basis for accelerated drug approval, together with\nother trial data documenting safety and other patient benefits. We also suggest\nthat a PSA endpoint could be used to sto!\n p the trial early on for futility in case no apparent effect on the PSA\nendpoint is shown and if there is strong evidence that the treatment effect is\nat least in part expressed through PSA changes. We recommend a thorough\nunderstanding of the treatment biological mechanisms of action and of the marker\nbefore defining a marker-based endpoint and using it in clinical trials.
Author: L.A.J. Collette
Language: English
Subfield: Statistics and Probability
Field: Mathematics
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W1494759145