Dealing with Global Safety Issues
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Drug-induced torsade de pointes (TdP) is a potentially fatal iatrogenic entity. Its reporting rate in association with non-cardiac drugs increased exponentially from the early 1990s and was associated with an increasing number of new non-cardiac drugs whose proarrhythmic liability was not appreciated pre-marketing. This epidemic provoked a comprehensive global response from drug regulators, drug developers and academia, which resulted in stabilization of the reporting rate of TdP. This commentary reviews the chronology and nature of, and the reasons for, this response, examines its adequacy, and proposes future strategies for dealing with such iatrogenic epidemics more effectively. It is concluded that the response was piecemeal and lacked direction. No one entity was responsible, with the result that important contributions from regulators, industry and academia lacked coordination. While the process of dealing with QT crisis seemed to have worked reasonably well in this instance, it does not seem wise to expect the next crisis in drug development to be managed as well. Future crises will need better management and the challenge is to implement a system set up to respond globally and efficiently to a perceived drug-related hazard. In this regard, we discuss the roles of new tools the legislation has provided to the regulators and the value of an integrated expert assessment of all pre-approval data that may signal a potential safety issue in the postmarketing period. We also discuss the roles of other bodies such as the WHO Collaborating Centre for International Drug Monitoring, CIOMS and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
KeywordsCisapride Terfenadine Palonosetron Ranolazine Sertindole
The authors have not received any financial support for writing this commentary. Norman Stockbridge and Christine Garnett have no other affiliations or interests except at the FDA. Christine Garnett’s current affiliation is Certara, Cary, NC, USA. Joel Morganroth is the Chief Cardiac Consultant of eResearch Technology Inc. (ERT), Philadelphia, PA, USA, which provides cardiac safety services to the drug development community. Rashmi Shah was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency, London, UK, and the ICH E14 Topic Leader, representing the EU. Both Joel Morganroth and Rashmi Shah now provide expert consultancy services on the development of new drugs to a number of pharmaceutical companies.
The views and opinions expressed in this review are those of the authors and do not necessarily represent the views or opinions of their affiliate organizations, any of the regulatory authorities or their advisory committees.
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