Clinical trials, immunosuppression and renal transplantation: new trends in design and analysis

Abstract.

Clinical trials provide a framework to search for more effective and less toxic immunosuppressive agents to control renal transplant rejection. Some methodological aspects are presented. Patient selection and the choice of study endpoints are discussed with emphasis on standardized definitions and classification of histopathology, and on qualification and quantification of chronic rejection. Choosing a Bayesian or a frequentist approach and the afferent hypotheses is discussed together with the interpretation of a P-value and a confidence interval. Strategies for limiting the number of patients, increasing power and feasibility are reviewed, including discussion of surrogate endpoints. New approaches to statistical analysis are then presented, including intention-to-treat versus per-protocol analysis, analysis of correlated data, dependent censoring, and meta-analysis applied to renal transplantation. Pharmacoeconomics are finally introduced as necessary for implementation of decision making regarding therapeutic strategies. Reporting research increases its standards, and the CONSORT (Consolidated Standards of Reporting Trials) and QOROM (Quality of Reporting of Meta-analyses) criteria are to be integrated in the process of clinical trial procedures. In conclusion, observational studies are presented as part of an evidence-based approach in the hierarchy of evidence, keeping in mind that high quality, randomized, controlled trials are still necessary to decrease uncertainty in the field of renal transplantation.