A pharmacometrics-informed trial simulation framework for optimizing study designs for disease-modifying treatments in rare neurological disorders
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
05 August 2025
|
| In: |
CPT: pharmacometrics & systems pharmacology
Year: 2025, Volume: 14, Issue: 10, Pages: 1705-1714 |
| ISSN: | 2163-8306 |
| DOI: | 10.1002/psp4.70082 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1002/psp4.70082 Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/psp4.70082 
|
| Author Notes: | Yevgen Ryeznik, Ralf-Dieter Hilgers, Nicole Heussen, Emmanuelle Comets, France Mentré, Niels Hendrickx, Mats O. Karlsson, Andrew C. Hooker, Alzahra Hamdan, Xiaomei Chen, Rebecca Schüle, Matthis Synofzik, Oleksandr Sverdlov |
MARC
| LEADER | 00000naa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1946101613 | ||
| 003 | DE-627 | ||
| 005 | 20251215153701.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 251215s2025 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/psp4.70082 |2 doi | |
| 035 | |a (DE-627)1946101613 | ||
| 035 | |a (DE-599)KXP1946101613 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Ryeznik, Yevgen |e VerfasserIn |0 (DE-588)119225306X |0 (DE-627)1670583686 |4 aut | |
| 245 | 1 | 2 | |a A pharmacometrics-informed trial simulation framework for optimizing study designs for disease-modifying treatments in rare neurological disorders |c Yevgen Ryeznik, Ralf-Dieter Hilgers, Nicole Heussen, Emmanuelle Comets, France Mentré, Niels Hendrickx, Mats O. Karlsson, Andrew C. Hooker, Alzahra Hamdan, Xiaomei Chen, Rebecca Schüle, Matthis Synofzik, Oleksandr Sverdlov |
| 264 | 1 | |c 05 August 2025 | |
| 300 | |b Illustrationen | ||
| 300 | |a 10 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 15.12.2025 | ||
| 520 | |a 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. | ||
| 650 | 4 | |a clinical design optimization | |
| 650 | 4 | |a model-informed drug development | |
| 650 | 4 | |a nonlinear mixed effects model | |
| 650 | 4 | |a pharmacometrics | |
| 650 | 4 | |a simulation | |
| 700 | 1 | |a Hilgers, Ralf-Dieter |e VerfasserIn |4 aut | |
| 700 | 1 | |a Heussen, Nicole |e VerfasserIn |4 aut | |
| 700 | 1 | |a Comets, Emmanuelle |e VerfasserIn |4 aut | |
| 700 | 1 | |a Mentré, France |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hendrickx, Niels |e VerfasserIn |4 aut | |
| 700 | 1 | |a Karlsson, Mats O. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hooker, Andrew C. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hamdan, Alzahra |e VerfasserIn |4 aut | |
| 700 | 1 | |a Chen, Xiaomei |e VerfasserIn |4 aut | |
| 700 | 1 | |a Schüle-Freyer, Rebecca |d 1975- |e VerfasserIn |0 (DE-588)137544472 |0 (DE-627)695848283 |0 (DE-576)30411118X |4 aut | |
| 700 | 1 | |a Synofzik, Matthis |e VerfasserIn |4 aut | |
| 700 | 1 | |a Sverdlov, Oleksandr |e VerfasserIn |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t CPT: pharmacometrics & systems pharmacology |d London : Nature Publ. Group, 2012 |g 14(2025), 10 vom: Okt., Seite 1705-1714 |h Online-Ressource |w (DE-627)733752829 |w (DE-600)2697010-7 |w (DE-576)377477370 |x 2163-8306 |7 nnas |a A pharmacometrics-informed trial simulation framework for optimizing study designs for disease-modifying treatments in rare neurological disorders |
| 773 | 1 | 8 | |g volume:14 |g year:2025 |g number:10 |g month:10 |g pages:1705-1714 |g extent:10 |a A pharmacometrics-informed trial simulation framework for optimizing study designs for disease-modifying treatments in rare neurological disorders |
| 856 | 4 | 0 | |u https://doi.org/10.1002/psp4.70082 |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |7 0 |
| 856 | 4 | 0 | |u https://onlinelibrary.wiley.com/doi/abs/10.1002/psp4.70082 |x Verlag |z kostenfrei |3 Volltext |7 0 |
| 951 | |a AR | ||
| 992 | |a 20251215 | ||
| 993 | |a Article | ||
| 994 | |a 2025 | ||
| 998 | |g 137544472 |a Schüle-Freyer, Rebecca |m 137544472:Schüle-Freyer, Rebecca |d 910000 |d 911100 |e 910000PS137544472 |e 911100PS137544472 |k 0/910000/ |k 1/910000/911100/ |p 11 | ||
| 999 | |a KXP-PPN1946101613 |e 4828155171 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"id":{"doi":["10.1002/psp4.70082"],"eki":["1946101613"]},"relHost":[{"note":["Gesehen am 22.01.15"],"physDesc":[{"extent":"Online-Ressource"}],"titleAlt":[{"title":"CPT: pharmacometrics and systems pharmacology"}],"id":{"zdb":["2697010-7"],"eki":["733752829"],"issn":["2163-8306"]},"origin":[{"publisherPlace":"London","dateIssuedDisp":"2012-","publisher":"Nature Publ. Group","dateIssuedKey":"2012"}],"disp":"A pharmacometrics-informed trial simulation framework for optimizing study designs for disease-modifying treatments in rare neurological disordersCPT: pharmacometrics & systems pharmacology","title":[{"title":"CPT: pharmacometrics & systems pharmacology","title_sort":"CPT: pharmacometrics & systems pharmacology"}],"recId":"733752829","type":{"media":"Online-Ressource","bibl":"periodical"},"language":["eng"],"pubHistory":["1.2012 -"],"part":{"year":"2025","text":"14(2025), 10 vom: Okt., Seite 1705-1714","pages":"1705-1714","extent":"10","volume":"14","issue":"10"}}],"origin":[{"dateIssuedDisp":"05 August 2025","dateIssuedKey":"2025"}],"note":["Gesehen am 15.12.2025"],"person":[{"role":"aut","display":"Ryeznik, Yevgen","given":"Yevgen","family":"Ryeznik","roleDisplay":"VerfasserIn"},{"given":"Ralf-Dieter","role":"aut","display":"Hilgers, Ralf-Dieter","roleDisplay":"VerfasserIn","family":"Hilgers"},{"display":"Heussen, Nicole","role":"aut","given":"Nicole","family":"Heussen","roleDisplay":"VerfasserIn"},{"given":"Emmanuelle","role":"aut","display":"Comets, Emmanuelle","family":"Comets","roleDisplay":"VerfasserIn"},{"family":"Mentré","roleDisplay":"VerfasserIn","display":"Mentré, France","role":"aut","given":"France"},{"given":"Niels","display":"Hendrickx, Niels","role":"aut","family":"Hendrickx","roleDisplay":"VerfasserIn"},{"roleDisplay":"VerfasserIn","family":"Karlsson","display":"Karlsson, Mats O.","role":"aut","given":"Mats O."},{"roleDisplay":"VerfasserIn","family":"Hooker","given":"Andrew C.","role":"aut","display":"Hooker, Andrew C."},{"role":"aut","display":"Hamdan, Alzahra","given":"Alzahra","family":"Hamdan","roleDisplay":"VerfasserIn"},{"role":"aut","display":"Chen, Xiaomei","given":"Xiaomei","roleDisplay":"VerfasserIn","family":"Chen"},{"family":"Schüle-Freyer","roleDisplay":"VerfasserIn","given":"Rebecca","display":"Schüle-Freyer, Rebecca","role":"aut"},{"role":"aut","display":"Synofzik, Matthis","given":"Matthis","family":"Synofzik","roleDisplay":"VerfasserIn"},{"family":"Sverdlov","roleDisplay":"VerfasserIn","given":"Oleksandr","role":"aut","display":"Sverdlov, Oleksandr"}],"physDesc":[{"extent":"10 S.","noteIll":"Illustrationen"}],"language":["eng"],"type":{"bibl":"article-journal","media":"Online-Ressource"},"name":{"displayForm":["Yevgen Ryeznik, Ralf-Dieter Hilgers, Nicole Heussen, Emmanuelle Comets, France Mentré, Niels Hendrickx, Mats O. Karlsson, Andrew C. Hooker, Alzahra Hamdan, Xiaomei Chen, Rebecca Schüle, Matthis Synofzik, Oleksandr Sverdlov"]},"title":[{"title":"A pharmacometrics-informed trial simulation framework for optimizing study designs for disease-modifying treatments in rare neurological disorders","title_sort":"pharmacometrics-informed trial simulation framework for optimizing study designs for disease-modifying treatments in rare neurological disorders"}],"recId":"1946101613"} | ||
| SRT | |a RYEZNIKYEVPHARMACOME0520 | ||