Effect and efficacy--on the function of models in controlled phase III trials and the need for prospective...

While the "effect" of a drug can be observed or deduced from observational data, the concept of "therapeutic efficacy" represents mainly a theoretical construction of a high degree of abstraction which is inconceivable without reciprocal combination with other theoretical constructs. The "therapeutic efficacy" of drugs can be investigated only via clinical-pharmacological or clinical "models". Several examples are given and discussed against the background of the actual considerations for shortening phase III studies and extending pharmacoepidemiological phase IV studies for scientific, practical and economic reasons. Of special relevance is the question whether study data of phase III allow an extrapolation to the wider patient population which it is intended to treat. Thus, it is well known that the criteria for representativeness in the investigated population are rarely achieved in phase III studies. Furthermore, observations have shown that various intervening moderator variables, such as the investigated subgroup or the trial setting (e.g. Inpatient or respectively out-patient treatment), might influence therapeutic efficacy and the possibility of generalizing the results. This again raises the crucial question of clinical relevance of significant effects. Possible ways of overcoming this unsatisfactory situation are suggested.