Year: 2021
Type: article
Abstract: Since the withdrawal of nearly a dozen marketed medicines 3 decades ago due to torsades de pointes-mediated sudden cardiac death, few safety issues have received so much interest and investment in drug discovery, development and regulatory science as drug-induced QT prolongation (Figure 1). The discovery that all these compounds caused QT prolongation through inhibition of the cardiac hERG channel resulted in the implementation of preclinical and clinical best practices and protocols, as, for example, described in the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and E141 and the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative.2, 3 These efforts and investments have clearly paid off, and the early de-risking of QT prolongation liability is arguably one of the greatest achievements of the Drug Safety Science discipline; no new drug has been withdrawn from the market due to QT-prolongation liability for over a decade. Despite these successes, however, Vargas and colleagues4 representing some 20 major pharmaceutical companies argue in this issue of Clinical Pharmacology & Therapeutics (CPT) that the current paradigm is not efficient and that non-clinical risk assessments still minimally influence clinical proarrhythmic risk strategies in drug development and approval. For example, they cite the more than US $1 billion spent on more than 450 obligatory thorough QT studies.4 In a response in this same issue of CPT, Strauss and coworkers5 from the US Food and Drug Administration (FDA) draw attention to a very recent update to the ICH E14/S7B original guidelines1 and related draft guidance from regulators.6 They conclude that the time for a fully integrated nonclinical-clinical risk assessment for corrected QT prolongation and torsades de pointes risk is indeed here, but that replacement of clinical trials still requires demonstration of successful implementation of the new ICH E14/S7B Draft Guidelines and recommendations from the ICH E14/S7B working group.5 The FDA authors state that “the integrated nonclinical-clinical assessment here can also serve as a model for other safety areas in drug development and regulatory evaluation,”5 which is obviously an area CPT will continue to follow with great interest. No funding was received for this work. The author declared no competing interests for this work.
DOI: 10.1002/cpt.2136
Author: Piet H. van der Graaf
Institution: Leiden University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3122597440