The EMA and FDA PBPK Guidance Documents: Perspectives from a Software Provider

Transcription

1 The EMA and FDA PBPK Guidance Documents: Perspectives from a Software Provider John DiBella, M.S.E. Vice President, Marketing & Sales john.dibella@simulations-plus.com April 27 th, 2017

2 EMA and FDA PBPK Guidance Drafts EMA guidance: Large emphasis on model and especially platform qualification Also includes guidance on what should be included in the PBPK modeling report FDA guidance: Focused strictly on the content of the PBPK modeling report 2

3 3 EMA PBPK Guidance Document

4 Qualification Process Approach 1: CHMP Procedure Would make subsequent applications easier: Straightforward application of qualified platform for given purpose Higher confidence in the outcome from sponsor companies Fewer resources required at regulatory agency to review subsequent applications Very lengthy and very expensive process Especially if different types of applications need to go through separate qualification procedures 4

5 Qualification Process Approach 1: CHMP Procedure cont. Before starting the qualification process, Simulations Plus needs more information on: How much software capability can be covered in a single CHMP application? For example: Can software be qualified to predict absorption in general? Would it have to be split for different drug subgroups (high/low permeability compounds, compounds with high contribution of paracellular absorption, etc.)? Can software be qualified for metabolism- or transporter-based DDI in general, or specific to certain types of compounds? Would the model for every standard compound supplied with the software have to be qualified separately? Need a clear path for qualification of subsequent program versions: Will a complete CHMP procedure be required with each new version of the program or could it be a simpler comparison of results with previously qualified version? What would be the cost of the requalification through the CHMP procedure? 5

6 Qualification Process Approach 2: For specific purpose within application Could be faster to compile the information for a specific application More uncertainty in the outcome less confidence in the outcome from the sponsor companies Less efficient for the regulatory agency - reviewers may end up reviewing the same information repeatedly Approach 3: Recommendations through learned societies Software providers have very little influence on the process Can EMA provide guidance on the type of publication and detail needed in the publication for it to be sufficient for qualification process? 6

7 Qualification Datasets The guidance asks for large qualification datasets but: Does not specify: what is considered to be a large dataset? Simulations Plus thinks that higher emphasis should be placed on diverse (where applicable) rather than large dataset Datasets for DDI predictions are described in detail but there are still some uncertainties: To qualify inhibitor models, need to show predictions with qualified substrates; to qualify substrate models, need to show predictions with qualified inhibitors where do we start (chicken vs. egg)? How many different substrate models are required to qualify the inhibitor models and vice versa? We have submitted comments on the draft guidance pointing out these (and number of additional) issues/questions. 7

8 What can Simulations Plus do to help GastroPlus users address the qualification requirements in their regulatory submissions to EMA? 8

9 Qualifying PBPK Platform Scientific qualification: Are the models (equations) implemented in the software predictive? Physiological information provide confidential report on sources of physiological parameter values for built-in physiologies Population simulations provide confidential comparison of physiologies generated by the program and reported physiological variabilities Compound models included with the software we can provide reports describing the compound models (input parameters, in vivo data used to calibrate and validate the compound model) We are reviewing and compiling information from publications with GastroPlus applications that could be supplied as additional support for model predictions and could provide list of publications related to a specific application area As all of these summaries are not ready and take time to compile At the moment, they would be handled on case-by-case basis and the sponsor company would need to give us some time to compile the information required for a specific application 9

10 Qualifying PBPK Platform Technical qualification: Is the code doing what it is supposed to be doing? It is a part of the standard QC process for each version release We can compile the information in the format that could be submitted with the application It would be provided upon request from the regulatory agency Decision on whether Simulations Plus will proceed with full CHMP qualification procedure will depend on the responses to questions raised in previous slides Resources that will be required for this process are not trivial and will need to be covered Consideration of cost/benefit what is reasonable and adequate? 10

11 Example of Platform Qualification: Pediatric Predictions Provide the summary of physiological parameters in pediatric physiologies Show accuracy of pediatric predictions for compounds eliminated by a specific pathway. For each validation compound, include summary of: Compound-specific input parameters Model calibration and validation in adults Accuracy of predictions in different pediatric groups Ideally, full plasma concentration-time profiles would be used to evaluate the accuracy of prediction If Cp-time profiles are not available (often not reported in public sources) a comparison could be made on the basis of available PK endpoints (AUC, CL, Vss, etc.) 11

12 Guidance on PBPK report Fairly straightforward description of what should be included in the PBPK report Provides examples of figures and workflows to include in the report to describe the model building process The key points for the report are: The model assumptions need to be explained The important input parameters need to be described, including their sources Sensitivity analysis needs to be included 12

13 13 FDA PBPK Guidance Document

14 Focused on PBPK report content Describes the exact structure and format of the report Describes what information needs to be included when using commercial software or a custom modeling tool Similar to EMA guidance, sensitivity analysis is highlighted as important part of model verification The executable model files need to be submitted along with the report We are in discussions about the GastroPlus file formats with FDA and it appears that they will try to make the electronic file submission more straightforward 14

15 Advancing the Science Together 15 Continued open communication between regulatory agencies, pharmaceutical companies, universities, and software providers will help validate new M&S applications: Food effect modeling Disease state populations Oral/non-oral delivery of drug products virtual BE Simulations Plus investing in publishing more Peer-reviewed journal publications Formal white papers Always encourage users to publish and open to collaborations