Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey

Objective: To assess current practice in the pharmaceutical industry for as sessing the potential for QT interval prolongation by non-cardiovascular me dicinal products. Methods: The survey was based on responses from the Toxic ology and (Safety) Pharmacology laboratories (a total of 74 laboratories) o f 54 companies based in Europe, Japan/Asia and the USA, received between Ja nuary and March 1999. Results: All 54 companies conducted preclinical in vi vo electrocardiography (EGG) evaluation of new active substances (NASs). Th irty of these companies also conducted in vitro cardiac electrophysiology s tudies on their compounds. The majority of in vivo work was done in conscio us beagle dogs. There was no consistency within the industry in defining th e magnitude of change in QT interval that is considered biologically import ant. Most companies considered a change greater than 10% to be important, a lthough the design of the studies suggested that group sizes used may not g ive sufficient statistical power to detect this size of change. Bazett's fo rmula was used by 41% of laboratories to correct QT for changes in heart ra te, despite the fact that this formula is generally deemed to be unsuitable for use in dogs. For studies in anaesthetised dogs, the majority of labora tories used barbiturate anaesthesia, but researchers should be aware of the effects of this and some other anaesthetic agents on QT interval. As for i n vitro cardiac electrophysiology, there was wide diversity in the testing methodologies, particularly with regard to the test species and tissue type . As with QT prolongation, there was no consensus on the degree of action p otential prolongation to cause concern. For both in vitro and in vivo testi ng, the majority of companies tested a minimum of three dose (or concentrat ion) levels in order to ascertain any dose-response relationship. Conclusio ns: The survey provides a snapshot of the practice in the industry prior to any internationally-agreed consensus on the most effective and efficient a pproaches to minimising the risk of QT prolongation by new drugs in man. It must be stated that for any given methodology, the 'majority view' in the industry is not necessarily best practice. (C) 2001 Published by Elsevier S cience BN.