Modelling, Extrapolation and Simulation approaches for rare diseases - Review of two case-studies in the INVENTS project

Objective The objective of this work was to review the modelling and simulation methods used in two selected case-studies from the Invents project, with a focus on longitudinal data modelling, simulation methods and extrapolation approaches (across populations, across indications or across similar drugs) applied during the later phases of drug development.

We included publications based on relevance to the case-studies involved in Invents, extending the search to articles reporting results of modelling, simulation, or extrapolation approaches for the two drugs secukinumab and tocilizumab through keyword-based literature searches.

When outcomes were measured repeatedly during the study, the focus of the analyses was usually along the lines of improvement at a given time-point, with other time-points included in secondary analyses. When PK (pharmacokinetic) or PK/PD (pharmacodynamic) models were developed, they were generally simple, with compartmental models for PK and direct or indirect response models for PD. Clinical questions addressed in the studies selected in this review were mainly centered on efficacy (57%, including exposure-response relationships and efficacy concerning patient-reported outcomes) and safety (34%). Besides the few studies investigating PK, other clinical questions focused on finding predictors of response, either biomarkers related to changes in the outcome under study, molecular characteristics of certain groups of patients, or prognostic factors at baseline. Finally, a couple of studies were more methodological. We found almost no paediatric study, despite modelling and simulation analyses being put forward in the Paediatric Investigation Plan, which could be due to the time needed to perform these studies, lack of interest in obtaining paediatric approval, waivers or failure to publish.

Despite the clear focus on longitudinal modelling and simulation in our search, we found very few examples of published PK or PK/PD models for the two case-studies considered, and almost no extrapolation approaches for paediatric or disease applications. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was performed within the project INVENTS, which has received funding from the European Union's Horizon Europe Research and Innovation programme under grant agreement 101136365, the Swiss State Secretariat for Education, Research and Innovation (SERI) and by the UKRI Innovative UK under their Horizon Europe Guarantee scheme. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes emmanuelle.comets{at}inserm.fr moreno.ursino{at}inserm.fr Data Availability All data produced in the present study are available upon reasonable request to the authors.