The Safety Pharmacology Society is pleased to invite you to a webinar presentation on Thursday, May 16, 2019 at 11:00 EDT, 15:00 UTC (GMT) / 16:00 BST / 17:00 CEST.
Title: Drug-induced QTc prolongation and Torsades de Pointes (TdP): evolving ICH-S7B and E14 in light of emerging data
Presenters: Jean-Pierre Valentin, PhD, HDR, ERT, CBiol, FSBiol, FRCPath, DSP, UCB Biopharma SPRL and Derek Leishman, PhD, DSP, Eli-Lilly and Company
Abstract: The ICH S7B and E14 described the non-clinical and clinical risk assessment strategies respectively, to inform the potential risk for proarrhythmia of a drug and contribute to the design of clinical investigations. Since the implementation of these guidelines in 2015 there has been no drug withdrawn for an unacceptable risk of TdP and most drugs evaluated clinically nowadays are negatives owning largely to a “hERG centric” discovery screening strategies. Over the past several years, emergent data (e.g., CiPA, JiCSA) has increased our mechanistic understanding of drug-induced QTc prolongation and TdP. Consequently, guidance is needed regarding best practices for the design, conduct, analysis, interpretation, presentation and reporting of in silico, in vitro and in vivo non-clinical assays in order for these assays to influence non-clinical and clinical evaluation. Although ICH E14 identifies non-clinical data as a factor that can be used to reduce the need for a TQT study, there has been no consensus on how non-clinical data can be used to influence the design and/or interpretation of a clinical QT assessment. That said, there are several clinical scenarios that could benefit from high quality non-clinical data such as clinical QT assessments that are confounded by issues like heart rate changes, inability to test a sufficiently high multiple of the clinically relevant exposure to waive the positive control and when a TQT study is not feasible in healthy volunteers. On the other hand, ICH S7B recommends “Follow-up Studies” to inform the integrated risk assessment if a drug blocks the hERG current or prolongs the QT interval. These could include evaluating drug effects on additional ionic currents, and the use of in vitro and in vivo assays. Newer assays and technologies such as in silico ventricular models and human primary and induced pluripotent stem cell-derived cardiomyocytes, can provide insights into the relative proarrhythmic liability of drugs. Therefore, guidance is needed on when and how these novel approaches could play a role in determining the proarrhythmic risk to inform clinical development.
Moderator: Simon Authier, DVM, MBA, PhD, DSP, Director Safety Pharmacology, Citoxlab
We look forward to your participation.
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