Hugo M. Vargas , Eric I. Rossman , Todd A. Wisialowski , Jill Nichols , Michael K. Pugsley , Brian Roche , Gary A. Gintant , Andrea Greiter-Wilke , Robert B. Kleiman , Jean-Pierre Valentin , Derek J. Leishman
{"title":"改进体内QTc测定:实施最佳实践以支持综合非临床临床QTc风险评估和TQT替代品的价值","authors":"Hugo M. Vargas , Eric I. Rossman , Todd A. Wisialowski , Jill Nichols , Michael K. Pugsley , Brian Roche , Gary A. Gintant , Andrea Greiter-Wilke , Robert B. Kleiman , Jean-Pierre Valentin , Derek J. Leishman","doi":"10.1016/j.vascn.2023.107265","DOIUrl":null,"url":null,"abstract":"<div><p>Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical <em>in vivo</em> electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical <em>in vivo</em> QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, <em>i.e.</em>, demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (<em>e.g.</em>, supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, <em>e.g.</em>, the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical <em>in vivo</em> QTc studies of new drug candidates. The conduct of <em>in vivo</em> QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on <em>in vivo</em> QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal).</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"121 ","pages":"Article 107265"},"PeriodicalIF":1.3000,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"Improving the in Vivo QTc assay: The value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute\",\"authors\":\"Hugo M. Vargas , Eric I. Rossman , Todd A. Wisialowski , Jill Nichols , Michael K. Pugsley , Brian Roche , Gary A. Gintant , Andrea Greiter-Wilke , Robert B. Kleiman , Jean-Pierre Valentin , Derek J. Leishman\",\"doi\":\"10.1016/j.vascn.2023.107265\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical <em>in vivo</em> electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical <em>in vivo</em> QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, <em>i.e.</em>, demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (<em>e.g.</em>, supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, <em>e.g.</em>, the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical <em>in vivo</em> QTc studies of new drug candidates. The conduct of <em>in vivo</em> QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. 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Improving the in Vivo QTc assay: The value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute
Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical in vivo QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, i.e., demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (e.g., supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, e.g., the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical in vivo QTc studies of new drug candidates. The conduct of in vivo QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on in vivo QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal).
期刊介绍:
Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.