• 1. Regulatory management of drug-induced LQTS
• 2. ICH Guidelines ICH S7A and ICH S7B

1.1. Cisapride Story: Since its introduction into the US market in 1993, the oral gastrointestinal prokinetic agent cisapride was associated with 270 cardiac adverse effects (cardiac arrhythmias) and 70 fatal reactions (see also FDA Talk Paper). Therefore, the manufacturer of cisapride discontinued marketing on July 14, 2000. Similarly, a number of other drugs (e.g. terfenadine, grepafloxacin, astemizole) have been removed from the market because the potential risk of lethal ventricular arrhythmias was believed to outweigh the pharmacological benefits of these agents. Attempts to solve the problem included:

• Removal of drugs from the market by the FDA (e.g. cisapride, terfenadine etc.)
• Cardiac Arrhythmia Suppression Trial (CAST, 1991)
• Points to Consider Document (CPMP, 1997)
• Guidelines by the International Conference on Harmonization: ICHS7A and ICH S7B

1.2. Worldwide awareness of acquired LQTS risk: Consequently, in the past decade, the assessment of proarrhythmic toxicity of new drug applications has attracted significant attention from regulatory authorities and pharmaceutical industries. Following the release of the Points to Consider document on the assessment for the potential for QT prolongation by noncardiovascular medicinal products by the Committee for Proprietary Medicinal Products (CPMP) in 1997, a worldwide awareness of the potential danger of such agents has compelled pharmaceutical companies to review their policies regarding the establishment of cardiac safety of new drug candidates.

2.1. ICH Guidelines: In 2000, the ICH S7A guideline, and in 2005 also the ICH S7B guideline, have been issued by the International Conference on Harmonization (ICH). For the design of cardiac safety studies the following strategy is recommended in the ICH S7B guideline. Also it is has to be mentioned here that these kind of studies must be accomplished according to GLP Principles.

2.2. ICH S7B strategy: The chemical class of drug candidates determines the preclinical safety strategy. The golden standard for the in vitro IKr assay is the test for HERG interaction by means of patch-clamp studies. The in vivo telemetry assay allows the study of QT interval with integrated risk assessment. For in vitro cardiac APD studies multicellular preparation from animal heart is needed to study potential adverse effects of drug candidates on the whole concert of cardiac voltage-gated  ion channels.