DDMODEL00000299: Garnett_2018_WhitePaper_QTcF

  public model
Short description:
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.
Original code
  • Scientific white paper on concentration-QTc modeling.
  • Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, Mehrotra D, Riley S, Sager P, Tornoe C, Wang Y
  • Journal of pharmacokinetics and pharmacodynamics, 6/2018, Volume 45, Issue 3, pages: 383-397
  • Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. christine.garnett@fda.hhs.gov.
  • 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.
Celine Sarr
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: Immunology; Cardiovascular; Vaccines; Haematology; Anti-infectives; Rheumatology; Oncology; Endocrinology; Gastroenterology; Metabolism; Diagnostics; Ophthalmology; Respiratory; CNS;
Annotations are correct.
This model is not certified.
  • Model owner: Celine Sarr
  • Submitted: Mar 29, 2019 7:33:34 AM
  • Last Modified: Mar 29, 2019 7:33:34 AM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Mar 29, 2019 7:33:34 AM
    • Submitted by: Celine Sarr
    • With comment: Updated model annotations.
 
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