Aims: DDMoRe is a consortium of European Federation of Pharmaceutical Industries and Associations (EFPIA), Academic and Small Medium Enterprise (SME) partners founded in 2011 with the vision to improve quality, efficiency and cost effectiveness of model-informed drug discovery and development (MID3) (1) and therapeutic use (2). This can be achieved by creating standards, tools and a model sharing repository.
Methods: The core DDMoRe products are: i) an open, pre-competitive drug and disease model repository allowing access to curated and shared knowledge; ii) an open source interoperability framework providing a platform for bridging modelling tools and methodologies; iii) training and education supporting adoption of the repository and the framework.
Results: The Model Description Language (MDL) and the Pharmacometrics Markup Language (PharmML) (3) standards have been developed to convey information about pharmacometric models and tasks. The goal of each language is to ensure models and tasks are described consistently between modellers (using MDL) and between software target tools (using PharmML). The model repository holds a diverse range of models encoded using the standards (MDL and/or PharmML) in a controlled environment. With scientific quality in mind, models submitted to the repository have to fulfil minimal requirements prior to their publication. The interoperability framework is an integrated infrastructure enabling use of MDL models across target software. The user interacts with the interoperability framework via the MDL Integrated Development Environment (MDL-IDE) graphical user interface, which includes an editor supporting MDL. During task execution, MDL is first translated to PharmML and then converted to the target software code, e.g. NMTRAN or MLXTRAN. Each task produces a standard output (SO) object which enables consistency in assessment, review and reporting of the modelling and simulation tasks across different target software. The user interacts with the MDL model and SO objects via R, allowing an interface with existing pharmacometrics packages such as Xpose and mlxR. Standards for describing provenance have been defined to capture the modelling context and provide knowledge management for the workflow tasks, to provide an audit trail, track assumptions and ensure reproducibility.
Conclusion: In support of MID3, the core DDMoRe products provide a vital improvement to transparency in model informed decision making, enhancing knowledge-sharing and scientific communication. An indexed, easily accessible and fully searchable drug and disease model repository enables sharing, comparison and integration of existing model knowledge to be applied to new projects/compounds. The use of a universal modelling language to describe models enhances a common understanding of purpose and hence facilitates model re-use. The interoperability framework provides a platform to streamline modelling, providing consistency and reproducible quantitative research. Altogether, the deliverables of the DDMoRe project provide a quantitative framework for prediction and extrapolation, centred on knowledge and inference generated from integrated models of compound, mechanism and disease level data, improving the quality, efficiency and cost effectiveness of decision making.
References: 1. EFPIA MID3 Workgroup. Marshall SF, et al. Good practices in model-informed drug discovery and development (MID3): practice, application and documentation. CPT Pharmacometrics Syst. Pharmacol. 2016;5(3):93-122. DOI: 10.1002/psp4.12049. 2. Harnisch L, Matthews I, Chard J, Karlsson MO, on behalf of the DDMoRe Consortium Partners and Contributors. Drug and disease model resources: a consortium to create standards and tools to enhance model-based drug development. CPT Pharmacometrics Syst. Pharmacol. 2013;2(3):e34. DOI: 10.1038/psp.2013.10. 3. Swat MJ, et al. Pharmacometrics markup language (PharmML): opening new perspectives for model exchange in drug development. CPT Pharmacometrics Syst. Pharmacol. 2015;4(6):316-319. DOI: 10.1002/psp4.57.
Acknowledgement: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115156, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. The DDMoRe project is also financially supported by contributions from Academic and SME partners.