Pitfalls of Large Clinical Studies

Overview

In the last years, several new drugs were withdrawn from the market, or their approval was either postponed orrejected, mostly for safety reasons. Serious adverse events were found to be the sixth most important cause of deathin hospitalised patients in the USA. Mibefradil (Posicor) was withdrawn because of side effects caused by interactionswith many cardiovascular drugs, based on common biotransformation via cytochrome P450 isoenzymes. Moreover,the prolongation of the QT-interval and of QTc (LQTS) was found in two cases reported here and two syncopesappeared in patients on Posicor. This effect might have been overlooked, disregarded or underestimated in preclinicaltrials. The main disadvantage of big multicenter studies is the heterogeneity of populations compared, caused byethnic and other individual differences, the instability of some criteria used, and the manifold concomitantmedication. This disparity is a limiting factor of internal and external validity: only a small part of patients recruitedinto the study can be evaluated: 7% in SOLVD, 1% in SHEP and 19,4% in EPICAL study. Consequently, the resultsare not applicable to some special groups of patients and have only a limited predictive value for the managementof individual patients.

Key words:
clinical studies - heterogeneity of population, validity of results, drug interactions, QT-interval, LQTS.J.