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Submission of Monolix2018 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 [3] and other agencies. Some of the agencies like the FDA or the EMA do have Monolix and the modelling experts to understand, review and run Monolix. Regulators are also taking part in publishing research articles with Monolix [2].
Regulatory guidelines [1] 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) are required for a complete Monolix analysis submission package. The Monolix analysis submission package listed in Table 1 has all the files needed to run Monolix without any implementation work and to reproduce the results. Attention must be payed to use relative file path definitions to facilitate the project transfer from one computer system to another (Monolix documentation). Further, it is important to consider that Table 1 represents the Monolix submission package for a typical analysis. There might be modelling cases that require the submission of additional material. Each submission should be treated separately and carefully reviewed for completeness cases by cases.

Table 1 Monolix analysis submission package

File Explanation File type, format
Report (.pdf) Report detailing all of the modelling according to the EMA or FDA guidelines [1] PDF
Data (.txt or .csv) Data file containing all the observations, dosing history, patient specific information and other information provided via the data file Text file, CSV
Project file (.mlxtran) Defines what data file, model file, algorithm settings, graphics settings and parameters have been used to generate the results Text file, Mlxtran

In addition, some Monolix files define project independent parameters that are applied to all projects run on the same computer account. In all but the most special cases users will have these parameters set to the default values. In case these parameters are modified, they should also be communicated. They can be found in the following files:

Table 2 Optional but recommended files 

File Explanation File type, format
Model file (.txt) The structural model in Mlxtran syntax if not one of the MonolixSuite library Text file, Mlxtran
Properties file (.properties) Properties of the graphics. It allows the project to reload all the graphical properties to be able to exactly reproduce the same graphics (in terms of color, split by categories, …)  Text file, .properties

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. 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.

References

[1] Applicable 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 “Guidance for Industry Population Pharmacokinetics”: takes a larger scope also addressing “Data Integrity and Computer Software’ and ‘Electronic Files”.
  • FDA “Exposure-Response Relationships – Study Design, Data Analysis, and Regulatory Applications”.

[2] FDA publications 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.

[3] Submission with Monolix analyses to the EMA

  • Procedure No. EMEA/H/C/000402/II/0110/G – EMA/CHMP/186699/2015 –  Tamiflu – International non-proprietary name: OSELTAMIVIR. (link)
  • Procedure No. EMEA/H/C/000401/II/0066 – EMA/168487/2015 – Tracleer –  International non-proprietary name: BOSENTAN. (link)