CLASS EFFECTS AND THE RATIONAL COMPARISON OF DRUGS David Woolner & Nick Holford, Department of Pharmacology & Clinical Pharmacology, University of Auckland Auckland, New Zealand INTRODUCTION No two molecules are exactly the same. Even minor differences in molecular structure can sometimes result in important differences in pharmacological activity. Paracetamol, phenacetin and acetanilide for example, differ by only single chemical groupings, but exhibit markedly different toxicity profiles [1]. Despite this, drugs have long been placed in groups. According to Katzung [2], it is unnecessary “To learn each pertinent fact about each of the many hundreds of drugs” as “almost all of the …drugs currently available can be arranged in about 70 groups”, and “many drugs within each group are very similar…”. Typically, groupings are built around some original or prototypical drug about which much is known, and other group members are then studied in terms of similarities and/or differences between these drugs and the original. Such groupings have formed the basis for teaching, studying and presenting pharmacology, and appear as chapter headings in most textbooks of the subject. As such, they are mainly an aid to understanding and learning rather than a means of predicting characteristics of drugs, and are largely uncontroversial. More recently, the pace of pharmaceutical development has increased. The number of drugs available, including so called “me too” drugs has risen dramatically. There has been increasing promotion of drugs by the pharmaceutical industry, and there has been increasing pressure from various groups to control drug usage and prices. Against this backdrop, drug groupings of various kinds have become increasingly important tools, not least for pharmaceutical companies, advocates of treatment guidelines, and pharmaceutical funding agencies [3]. Such groupings are nowadays typically referred to as drug classes. An approach of (more or less) controlled extrapolation of knowledge from one class member to another has become increasingly common, a concept of so called class effects. Despite widespread usage, definitions of the terms “drug class” and “class effect” are not easy to find. Most pharmacological texts are silent on the matter, despite using the terms more or less widely. There is no established regulatory definition of these terms. The FDA utilizes class labeling when “all products within a class are assumed to be closely related in chemical structure, pharmacology, therapeutic activity, and adverse reactions”, although the term class and the grounds for such assumption are undefined. Furberg has pointed out this lack of clarity and has referred to class effects as a term of convenience [4].