{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:39:01Z","timestamp":1792093141926,"version":"4.4.0"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T00:00:00Z","timestamp":1714608000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:p>Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14\/S7B Q&amp;A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and\/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.<\/jats:p>","DOI":"10.1002\/cpt.3284","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T05:03:40Z","timestamp":1714712620000},"page":"42-51","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability"],"prefix":"10.1002","volume":"116","author":[{"given":"Robert M.","family":"Lester","sequence":"first","affiliation":[{"name":"Celerion  Tempe Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Engel","sequence":"additional","affiliation":[{"name":"Celerion  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6296-2123","authenticated-orcid":false,"given":"Aernout D.","family":"van Haarst","sequence":"additional","affiliation":[{"name":"Celerion  Belfast UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5666-942X","authenticated-orcid":false,"given":"Sabina","family":"Paglialunga","sequence":"additional","affiliation":[{"name":"Celerion  Tempe Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,2]]},"reference":[{"key":"e_1_2_13_1_1","first-page":"263","article-title":"Ventricular tachycardia with 2 variable opposing foci","volume":"59","author":"Dessertenne F.","year":"1966","journal-title":"Arch. 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International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use Updated June 15. <https:\/\/www.fda.gov\/media\/142501\/download> (2020). Accessed February 29 2024."},{"key":"e_1_2_13_15_1","unstructured":"ICH.2022. ICH E14\/S7B implementation working group clinical and nonclinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential questions and answers. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Updated February 21 2022. <https:\/\/database.ich.org\/sites\/default\/files\/E14\u2010S7B_QAs_Step4_2022_0221.pdf> Accessed January 25 2024."},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1003"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2137"},{"key":"e_1_2_13_18_1","unstructured":"FDA.Safety Testing of Drug Metabolites Guidance for Industry. 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