Submission of PKanalix runs to regulatory agencies
PKanalix is used for regulatory submissions (including the FDA and the EMA) of NCA, BE and CA analyses. The FDA and the EMA do have access to PKanalix and the experts to understand, review and run PKanalix. In addition, regulators are also taking part in publishing research articles with PKanalix.
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 PKanalix, the following listed files in Table 1 and 2 are required for a PKanalix analysis submission package.
Table 1 lists all files needed to run PKanalix 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 key 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.
All MonolixSuite file types are accepted by the FDA and are listed in the "Specifications for File Format Types Using eCTD Specifications".
Table 1 Pkanalix 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 |
PKanalix project file (.pkx) | Always | Path to dataset, dataset settings (column tagging, filters, etc), NCA/BE/CA settings | .pkx |
Compartmental model file | If using CA and not using a model from the libraries | Compartmental model in mlxtran syntax | .txt |
Plot properties | Always (except if file not present because only default settings) | Plot stratify, settings and preferences | .pkxproperties |
Table 2 PKanalix files containing the key results
File | When to include | Content | File extension |
nca/ | If NCA has been run | Individual NCA parameters and exclusion flags | .txt |
nca/ | If NCA has been run | Individual concentrations and points included in terminal slope (lambdaZ) regression | .txt |
be/ | If BE has been run | Confidence intervals for NCA parameters include din the BE analysis | .txt |
ca/ | If CA has been run | Individual CA parameters | .txt |
ca/ | If CA has been run | Cost function and likelihood of CA model | .txt |
The other output files (nca/concentrations.txt, nca/ncaIndividualParametersSummary.txt, be/anova.txt, be/estimatedCoefficients.txt, be/variationCoef.txt, ca/caIndividualParametersSummary.txt) can also be included if needed.
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)