6.7 Methodology of intervention trials in individuals

Abstract

An intervention trial, or a clinical trial, has been defined in various ways and may be of several kinds. The International Conference on Harmonisation defines a clinical trial as ‘any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product (s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy’ (International Conference on Harmonisation 1996). This definition has the advantage of applying to all phases of a clinical trial (I–IV), as traditionally defined (Friedman et al. 1998). The International Conference on Harmonisation definition has the disadvantage of not including trials of non-pharmacological or non-device interventions (for example, surgical procedures, diet, exercise). To encompass trials of all kinds of interventions, and given that even many trials of drugs, devices, and biologics do not neatly fit into the usual phases, it makes sense to think about early and late phase trials. Early phase trials generally address questions such as proper dose, physiologic response, tolerance, and toxicity in small number of subjects. The subjects are often healthy volunteers, but may also be people with disease who have not responded to other treatments. The early phase trials inform the design and conduct of subsequent late phase trials. This chapter will mainly address issues relating to late phase trials that use outcomes of clinical interest and are large enough to influence clinical practice. Such a clinical trial may be defined as ‘a prospective study comparing the effects and value of intervention(s) against a control in human beings’ (Friedman et al. 1998).Clinical trials are needed because only rarely is the precise pattern or outcome of a disease or condition known. It is not yet possible to identify all of the genetic and environmental factors that lead to disease progression, recovery, and relapse. Also rare is the treatment that is so overwhelmingly successful that even with a vague understanding of the course of the disease, it is possible to say, in the absence of a control group, that the treatment is obviously beneficial and has few major adverse effects. More often, the treatment, while useful, is less than perfect. Therefore, in order to determine the true balance of potential benefit and harm from a new treatment or intervention, it is necessary to compare people who have received the treatment with those who have not. Ideally, this comparison will be made in an unbiased manner so that, at the end, any difference seen between those treated and those not treated is most likely due to the treatment.This chapter can only cover some of the key issues in clinical trials. For more extensive discussions, the reader is referred to any of several textbooks (Friedman et al. 1998; Meinert & Tonascia 1986; Piantadosi 1997; Pocock 1983) as well as journals such as Clinical Trials and Statistics in Medicine.