Drug-Induced QT Interval Prolongation and Pharmacovigilance Planning (ICH E2E)

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Chapter: Pharmacovigilance: Withdrawal of Terodiline: A Tale of Two Toxicities

Withdrawal of Terodiline: A Tale of Two Toxicities : Drug-Induced QT Interval Prolongation and Pharmacovigilance Planning (ICH E2E)


The ICH E2E guideline on Pharmacovigilance Planning came into operation in the EU in June 2005, and is intended to assist in planning pharmacovigi-lance activities, especially in preparation for the early post-marketing period of a new drug (Anon, 2004). The guideline includes a section on Safety Specifica-tion that should be submitted at the time of marketing authorization application

In the context of drug-induced proarrhythmias, the guideline recommends that the preclinical elements that should be considered for inclusion in the Safety Specification of a new drug are its potential to prolong the QT interval and for drug interactions.

The Safety Specification also requires a discussion on populations that have not been studied or have only been studied to a limited degree in the pre-approval phase. The implications of this with respect to predict-ing the safety of the product in the marketplace should be explicitly discussed. Among the populations to be considered are the elderly, those with relevant co-morbidity (such as hepatic or renal disorders), patients with disease severity different from that stud-ied in clinical trials, those who carry known genetic mutations of relevant drug-metabolizing enzymes and/or pharmacological targets, and patients of differ-ent racial and/or ethnic origins.

In addition to providing a detailed account of impor-tant information that is missing from the regula-tory submission, the Safety Specification requires a summary of the important risks identified to be asso-ciated with a drug, any important potential risks and outstanding safety questions which warrant further investigations during the post-approval period to refine an understanding of its risk–benefit profile. With regard to potential risks that require further evaluation, the evidence that led to the conclusion that there were (or might exist) these potential risks should be presented. It is anticipated that for any important potential risk, there will be a further (post-approval) evaluation of the drug to characterize the association.

The ICH E2E also emphasizes that the Safety Specification should identify risks believed to be common to the pharmacological class of the new drug concerned.

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