Simulated data were created to illustrate how to apply mixed effects modelling when analysing QTcF data and what are the key steps to check to assess properly the modeling. APK-QTcF linear and non linear relationship is tested and evaluated.
|Context of model development:||Dose & Schedule Selection and Label Recommendation; Risk & Benefit Characterization, Outcome Prediction (Clinical & design Viability);|
|Model compliance with original publication:||Yes;|
|Model implementation requiring submitter’s additional knowledge:||No;|
|Modelling context description:||The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies. Topics included are: important study design features in a phase 1 study; modeling objectives and approach; exploratory plots; the pre-specified linear mixed effects model; general principles for model development and evaluation; and expectations for modeling analysis plans and reports. The recommendations are based on current best modeling practices, scientific literature and personal experiences of the authors. These recommendations are expected to evolve as their implementation during drug development provides additional data and with advances in analytical methodology.;|
|Modelling task in scope:||simulation;|
|Nature of research:||Early clinical development (Phases I and II);|
|Therapeutic/disease area:||CNS; Haematology; Respiratory; Cardiovascular; Immunology; Metabolism; Gastroenterology; Anti-infectives; Rheumatology; Oncology; Ophthalmology; Endocrinology; Diagnostics; Vaccines;|
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- Additional Files
- ReadMe-Case Study of a Misspecified Model V5.docx
- Misspecification Example Using LMEM V3.htm
- Misspecification Example Using LMEM V3.log
- Simulated_dataset generator output.log
- Executable_Misspecification Example using LMEM V3.sas
- Misspecification Example Using Nonlinear MEM V3.htm
- Simulated_Dataset generator.sas
- Output_simulated_Misspecification Example Using Nonlinear MEM V3.lst
- Output_simulated_Misspecification Example Using LMEM V3.lst
- Misspecification Example Using Nonlinear MEM V3.log