Monotherapy trials: endpoints

Abstract

Prof Brodie stressed the importance of assessing the effectiveness of a new drug in addition to its efficacy. ‘Effectiveness’ is defined as the global outcome, combining both tolerability and efficacy. Global outcome measures in monotherapy trials, such as retention time, are of great importance because they are clinically meaningful. There may, however, be some problems with these global outcome measures. Retention time or time to treatment failure is influenced by both efficacy and tolerability. In comparing two treatments, it may emerge that drug A is better tolerated than drug B but is less efficacious. Therefore, as many patients may remain on drug A as on drug B. The consequence may be that the two treatments would appear to be equivalent using a global measure of outcome when, in fact, they have very different patterns of tolerability and efficacy which may be highly relevant to their use in clinical practice. It tends to be the case that drugs which are potent in terms of efficacy are less well tolerated than those of more modest efficacy, and global measures alone may lose these differences. This has been the experience of Dr Tony Marson in my Department, who has been undertaking a meta-analysis of comparative trials of antiepileptic drugs. A further global outcome measure, quality of life, might be seen as attractive in this area. However, it can be argued that if the clinical outcomes of a trial are those of genuine importance, these will, by definition, be immediately reflected by an impact on health-related quality of life. It is important to recognise that the outcome chosen for a clinical trial will be determined by whether that trial is explanatory in nature and be used for regulatory purposes, or whether it is essentially pragmatic to inform everyday clinical practice. Sometimes, these different objectives are confused. However, although global measures are important in pragmatic trials, it is important to recognise their limitations, and ensure that other secondary endpoints in a trial will assess the individual profiles of efficacy and tolerability of the drugs being investigated.