Submission of Simulx runs to regulatory agencies
Simulx is used a part of regulatory submissions (including the FDA and the EMA) of simulations with population PK and PK/PD models. The FDA and the EMA do have access to Simulx and the modelling and simulation experts to understand, review and run Simulx. In addition, regulators are also taking part in publishing research articles with Monolix and Simulx.
Files to include for submissions
Regulatory guidelines provide only little information on the required electronic files for submission. Based on exchanges with regulatory agencies and confirmed through past regulatory submissions using Simulx, the following listed files in Table 1 and 2 are required as part of a submission package.
Table 1 lists all files needed to run Simulx and reproduce the results and diagnostic plots. A Simulx project can depend on several external files. In order to bring required file into the same folder, we strongly suggest to set Settings > Project Settings > Save the user files in the results folder, and re-save the project.
Table 2 lists the files containing the simulation results. The simulated values are by default not exported as txt file. In order to be able to include this file in your submission, set Settings > Preferences > Export simulation files and run the simulation again. If you prefer to generate a single file as formatted dataset containing both the design (covariates, doses, etc) and the simulated values, use Export > Export simulated dataset.
It is also possible to create a .zip containing all requires input files, as well as all results with Export > Share project.
Note that all files are in a human readable format. Thus, the information contained in these files can also be included into the appendices of the report creating one single document that contains everything to reproduce the results.
All MonolixSuite file types are accepted by the FDA and are listed in the "Specifications for File Format Types Using eCTD Specifications".
Table 1 Simulx files required for reproducibility of results
File | When to include | Content | File extension |
Simulx project file (.smlx) | Always | Path to external files (dataset, model, parameters, etc), defined simulation element, settings | .smlx |
All files in “DataFile” folder | If a project has been imported from Monolix | Input dataset used in imported Monolix project (and additional columns files if applicable) | .txt, .csv, .xls, .xlsx, .sas2bdat or .xpt |
All files in “External files” folder | If external files have been used and this folder exists | External files used in the definition of the simulation elements | .txt |
Model file in “ModelFile” folder | If not using a model from the libraries | Structural (and possibly statistical) model in mlxtran syntax | .txt |
Plot properties | Always (except if file not present because only default settings) | Plot stratify, settings and preferences | .smlxproperties |
Table 2 Simulx files containing the key results
File | When to include | Content | File extension |
Simulation/simulation_XXX.txt | Always | Simulated values | .txt |
simulatedData.csv | As alternative to simulation_XXX.txt | Simulated values as formatted dataset containing also the design (doses, covariates, etc) | .csv |
All files in “Endpoints” folder | If outcome/endpoints have been run | Individual outcomes and endpoints over simulation groups | .txt |
Examples of submissions
This section lists examples of Clinical pharmacology reviews (FDA) and Assessment reports (EMA) explicitly mentioning the use of MonolixSuite.
Submissions to the FDA using MonolixSuite
ZALTRAP (Aflibercept) - Sanofi - Clinical pharmacology review (link)
CORLANOR (Ivabradine) - Amgen - Clinical pharmacology review (link)
JEVTANA (Cabazitaxel) - Sanofi - Clinical pharmacology review (link)
PONVORY (Ponesimod) - Janssen - Clinical pharmacology review (link)
RYZNEUTA (Efbemalenograstim) - Evive Biotechnology Singapore - Integrated review (link)
EXBLIFEP (Cefepime and enmetazobactam) - Allecra Therapeutics - Integrated review (link)
Submission to the EMA using MonolixSuite
OSELTAMIVIR (Tamiflu) - Roche - Assesment report (link)
(Procedure No. EMEA/H/C/000402/II/0110/G – EMA/CHMP/186699/2015)BOSENTAN (Tracleer) - Actelion - Assessment report (link)
(Procedure No. EMEA/H/C/000401/II/0066 – EMA/168487/2015)ISATUXIMAB (Sarclisa) - Sanofi - Assesment report (link) and Statistical analysis plan (link)
(Procedure No. EMEA/H/C/004977/II/0003 – EMA/CHMP/186236/2021)
Publications by the FDA using MonolixSuite
This section lists a few (non-exhaustive) publications by the FDA using MonolixSuite.
“Plasma pharmacokinetics of ceftiofur metabolite desfuroylceftiofur cysteine disulfide in holstein steers: application of nonlinear mixed-effects modeling.”, J Vet Pharmacol Ther 2016 Apr;39(2):149-56, DOI: 10.1111/jvp.12245. O. A. Chiesa, S. Feng, P. Kijak,E. A. Smith, H. Li and J. Qiu.
“Quantification of disease progression and dropout for Alzheimer’s disease.”, Int. Journal of Clinical Pharmacology and Therapeutics, Volume 51 – February (120 – 131),(Doi: 10.5414/CP201787). D. William-Faltaos, Y. Chen, Y. Wang, J. Gobburu,, and H. Zhu.
“Estimation of Population Pharmacokinetic Parameters Using MLXTRAN Interpreter in MONOLIX 2.4”, D. William Faltaos, Acop 2009.
Regulatory guidelines
EMA “Guideline on reporting the results of population pharmacokinetic analyses” (CHMP/EWP/185990/06): details what should be contained in a PK or PK/PD analysis report.
FDA “Population pharmacokinetics – Guidance for industry” (2022): guidance on how to present the results of a population pharmacokinetic analysis and the information to be included. It also addresses “Electronic Files”.