Submission of Monolix analysis to regulatory agencies
Monolix is used for regulatory submissions (including the FDA and the EMA) of population PK and PK/PD analyses. Monolix analyses for first in human dose estimation, dose-finding studies and registration studies have been routinely and successfully submitted to the FDA, EMA and other agencies. The FDA and the EMA do have access to Monolix and the modelling experts to understand, review and run Monolix. In addition, regulators are also taking part in publishing research articles with Monolix.
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 Monolix, the following listed files in Table 1 and 2 are required for a Monolix analysis submission package.
Table 1 lists all files needed to run Monolix and reproduce the results and diagnostic plots. Attention must be paid to use relative file path definitions (Settings > Preferences > Use relative path) to facilitate the project transfer from one computer system to another. It is also possible to create a .zip containing all requires input files, as well as all results with Export > Share project. Table 2 lists the files containing the run results.
A Monolix run will automatically produce a large number of additional files. However, the files listed in Table 1 and Table 2 are sufficient to entirely reproduce the results and share the main findings. 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 Monolix files required for reproducibility of results
File | When to include | Content | File extension |
Dataset file | Always | Input dataset | .txt, .csv, .xls, .xlsx, .sas2bdat or .xpt |
Additional columns file | If “additional columns” in data formatting module was used | Additional columns appended to the dataset | .txt, .csv, .xls, .xlsx, .sas2bdat or .xpt |
Monolix project file (.mlxtran) | Always | Path to dataset, dataset settings (column tagging, filters, etc), path to structural model, statistical model, algorithm settings, estimation tasks | .mlxtran |
Structural model file | If not using a model from the libraries | Structural model in mlxtran syntax | .txt |
Plot properties | Always (except if file not present because only default settings) | Plot stratify, settings and preferences | .mlxproperties |
Model building configuration file | If model building (covariate search) has been run via the command line | Covariate search method, settings and relationships to test | .txt |
Conv. assessment configuration file | If convergence assessment has been run via the command line | Convergence assessment settings and estimation tasks ro tun | .txt |
Bootstrap configuration file | If bootstrap has been run via the command line | Bootstrap settings | .txt |
Table 2 Monolix files containing the key results
File | When to include | Content | File extension |
summary.txt | Always | Results of population parameter, EBEs, conditional distribution, standard errors and likelihood tasks. | .txt |
populationParameters.txt | Always | Population parameters and standard errors | .txt |
ModelBuilding/ | If model building (covariate search) has been run | Overview of all tested models, their likelihood and BICc | .txt |
Bootstrap/ | If bootstrap has been run | Summary statistics of bootstrap estimates | .txt |
Assessment/ | If convergence assessment has been run | Parameter estimate of each assessment run | .txt |
Examples of submissions
This section lists examples of Clinical pharmacology reviews (FDA) and Assessment reports (EMA) explicitly mentioning the use of Monolix.
Submissions to the FDA using Monolix
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 Monolix
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”.