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International Pharmaceutical Industry

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The implementation of new cardiac drug safety requirements by Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) could help to establish whether and in what way ethnicity impacts drug-induced proarrhythmic liability, according to a study1 published in International Pharmaceutical Industry.

The paper by Dr Rick Turner, University of Florida College of Pharmacy, draws from the Drug Information Association’s first Cardiac Safety Workshop, held last year in Tokyo and attended by several regulators from the PMDA along with representatives from Japanese pharmaceutical companies.  Visiting experts included regulators from Health Canada, the European Medicines Agency (EMA), and the US Food and Drug Administration (FDA).

Dr Turner’s report examines whether there is a significant ethnic component to proarrhythmia likelihood with certain drugs.  It questions whether Japanese regulators can be assured that foreign data will be applicable to the Japanese population, or whether the data must be collected from Japanese study participants.

Guideline E142 from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), adopted several years ago by regulatory agencies in Canada, Europe, and the US, was fully implemented by the PMDA in November 2010. From that date, all New Drug Application (NDA) submissions lacking Japanese Thorough QT/QTc (TQT) data are required to present the proper reasons why it was impossible to conduct a Japanese TQT study.

The ICH E14 TQT study represents an initial step in a two-fold strategy to identify potentially excessive risk of drug-induced proarrhythmia, with specific reference made to the polymorphic ventricular tachycardia Torsades de Pointes

The suitability of foreign data will now be assessed on a case-by-case basis, Dr Turner says.  “It is possible that foreign TQT data, or, if no foreign TQT data are available, foreign concentration-QT data, may be informative if a sponsor is able to demonstrate to a scientifically satisfactory degree that such foreign data can provide compelling evidence concerning Japanese risk”.

Factors that make a medicine ethnically sensitive or insensitive will emerge as effects in different regions are compared, the report states: “To assess a medicine’s sensitivity to ethnic factors it is important that there be knowledge of its pharmacokinetic and pharmacodynamic properties and the translation of those properties to clinical effectiveness and safety”.  However, current knowledge clearly shows that characteristics such as clearance by an enzyme showing genetic polymorphism and a steep dose-response curve will make ethnic differences more likely, Turner says.


1 Turner R.  Japanese Cardiac  Safety Requirements – The Rising of a New Regulatory Landscape.  Int Pharm Ind 2010;Summer:64-7.

2 ICH Guideline E14. The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. May 2005. (Available from

Published on: August 2, 2011

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