Pre-Approval Clinical Safety Dataset

PRE-APPROVAL CLINICAL SAFETY DATASET

The extent of the dataset required in terms of ECG monitoring in subsequent clinical studies will depend on a variety of factors, particularly the results from S7B-compliant preclinical studies and the ‘thorough QT/QTc study’ (Shah, 2005b).

The ICH E1A guideline (‘The Extent of Popula-tion Exposure to Assess Clinical Safety for Medicines Intended for Long-term Treatment of Non-life Threat-ening Conditions’) (Anon, 1995) is helpful when considering the clinical safety dataset necessary for regulatory submissions when exploring the potential of an NCE indicated for a long-term treatment of non-life threatening conditions, and for hazards associated with other drugs of the same chemical, pharmacologi-cal and/or therapeutic classes. For the most usual case, that is frequent and early onset (these are generally concentration-related) events, this guideline (adopted in 1995) provides for 1500 patients to be studied over 3 months. It is estimated that this database will char-acterize an adverse event with a cumulative 3-month incidence of about 1% or more. Whereas prolongation of the QT interval may be observed in some patients in the dataset, it is most unlikely that any episodes of torsade de pointes (induced by a non-antiarrhythmic drug) will be identified, since the latter is often tran-sient, requires an ECG machine for diagnosis and usually has a frequency in the order of 1 in 10 000 or much less.