A Pharmacometrics‐Informed Trial Simulation Framework for Optimizing Study Designs for Disease‐Modifying Treatments in Rare Neurological Disorders

CPT Pharmacometrics & Systems Pharmacology, vol. 14, pp. 1705–1714

Abstract

The development of new treatments for rare neurological diseases (RNDs) may be very challenging due to limited natural history data, lack of relevant biomarkers and clinical endpoints, small and heterogeneous patient populations, and other complexities. A systematic approach is needed for comparing various design and analysis strategies to identify "optimal" approaches for a clinical trial in a chosen RND with the given resource constraints. For this purpose, we propose a pharmacometrics-informed clinical scenario evaluation framework (CSE-PMx), which includes some important research hallmarks relevant to RND clinical trials: a disease progression model for simulating individual longitudinal outcomes, the choice of a suitable randomization method for trial design, and an option to perform subsequent statistical analysis with randomization tests. We illustrate the utility of CSE-PMx for an exemplary randomized trial to compare the disease-modifying effect of an experimental treatment versus control in patients with Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). In the considered example, our simulation evidence suggests that a nonlinear mixed-effects model (NLMEM) with a population-based likelihood ratio test analysis is valid, robust, and more powerful than some conventional methods such as two-sample t-test, analysis of covariance (ANCOVA), or a mixed model with repeated measurements (MMRM). Our proposed framework is very flexible and generalizable to clinical research in other rare disease indications.

Authors 13

1. Yevgen V. Ryeznik

   Uppsala University

   Affiliation as printed

   Department of Pharmacy Uppsala University Uppsala Sweden

   Department of Pharmacy, Uppsala University, Uppsala, Sweden

2. R.-D Hilgers Aachen Department of Medical Statistics

   RWTH Aachen University

   Affiliation as printed

   Department of Medical Statistics RWTH Aachen University Aachen Germany

   Department of Medical Statistics, RWTH Aachen University, Aachen, Germany

3. Nicole Maria Heussen Aachen Department of Medical Statistics

   RWTH Aachen University · Sigmund Freud Privatuniversität Wien

   Affiliation as printed

   Department of Medical Statistics RWTH Aachen University Aachen Germany

   Medical School Sigmund Freud Private University Vienna Austria

   Department of Medical Statistics, RWTH Aachen University, Aachen, Germany

   Medical School, Sigmund Freud Private University, Vienna, Austria

4. Emmanuelle Comets

   Inserm · Université Paris Cité · Université Sorbonne Paris Nord · Université de Rennes · Infection, Anti-microbiens, Modélisation, Evolution · Institut de Recherche en Santé, Environnement et Travail · École des Hautes Études en Santé Publique

   Affiliation as printed

   Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en santé, Environnement et Travail) UMR_S 1085 Rennes France

   Université Paris Cité and Université Sorbonne Paris Nord, Inserm, IAME Paris France

5. France Mentré

   Inserm · Université Paris Cité · Université Sorbonne Paris Nord · Infection, Anti-microbiens, Modélisation, Evolution

   Affiliation as printed

   Université Paris Cité and Université Sorbonne Paris Nord, Inserm, IAME Paris France

6. Niels Hendrickx

   Inserm · Université Paris Cité · Université Sorbonne Paris Nord · Infection, Anti-microbiens, Modélisation, Evolution

   Affiliation as printed

   Université Paris Cité and Université Sorbonne Paris Nord, Inserm, IAME Paris France

7. Mats O. Karlsson

   Uppsala University

   Affiliation as printed

   Department of Pharmacy Uppsala University Uppsala Sweden

   Department of Pharmacy, Uppsala University, Uppsala, Sweden

8. Andrew C. Hooker

   Uppsala University

   Affiliation as printed

   Department of Pharmacy Uppsala University Uppsala Sweden

   Department of Pharmacy, Uppsala University, Uppsala, Sweden

9. Alzahra Hamdan

   Uppsala University

   Affiliation as printed

   Department of Pharmacy Uppsala University Uppsala Sweden

   Department of Pharmacy, Uppsala University, Uppsala, Sweden

10. Xiaomei Chen

    Uppsala University

    Affiliation as printed

    Department of Pharmacy Uppsala University Uppsala Sweden

    Department of Pharmacy, Uppsala University, Uppsala, Sweden

11. Rebecca Schüle

    University of Tübingen · University Hospital Heidelberg · German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research

    Affiliation as printed

    Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH) University of Tübingen Tübingen Germany

    Division of Neurodegenerative Diseases, Department of Neurology Heidelberg University Hospital Germany

    German Center for Neurodegenerative Diseases (DZNE), Tübingen Germany

    Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH) University of Tübingen Tübingen Germany

12. Matthis Synofzik

    University of Tübingen · German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research

    Affiliation as printed

    Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH) University of Tübingen Tübingen Germany

    German Center for Neurodegenerative Diseases (DZNE), Tübingen Germany

13. Oleksandr Sverdlov corresponding

    Novartis (United States)

    Affiliation as printed

    Novartis Pharmaceuticals Corporation East Hanover New Jersey USA

    Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA