Model informed-drug development (MIDD) is acknowledged as a vital approach in understanding drug-related benefits and risks. At the core of MIDD lies modelling and simulation (M&S), a technology providing the basis for informed, quantitative decision-making. M&S facilitates the continuous integration of information related to a drug or disease into constantly evolving mathematical models that are capable of describing and predicting the behaviour of systems. As such, M&S helps researchers, regulators and public health care bodies to answer the questions they face when bringing drugs to patients. The full adoption of MIDD is hindered by a lack of common tools, languages and ontologies, which often leads to inefficient reuse of data and duplication of effort by academic, industrial and regulatory stakeholders. IMI’s DDMoRe project set out to address that challenge.
The project’s main achievement was the development of a repository for clinical trial data models, the largest of its kind to date, which members of the modelling community can use to store and access an assortment of computational models. The repository is publicly available and contains more than 120 models so far.
As different models are executed in different software programmes, this may cause model structures to be very different too. In order to address this, DDMoRe also designed a set of common standards for developing, describing and storing models. These standards are now also available for everyone to use and are facilitating model sharing and communication between researchers.
An interoperability framework
Additionally, the project developed an interoperability framework in which scientists can perform a modelling exercise. The framework is free for anyone to download and enables scientists to re-run models, thereby replicating each other’s work. The framework uses new standards and connectors for many commonly used programming tools and languages. As such, the interoperability framework provides a consistent environment in which researchers can work, using modelling tools they know, while opening up their work to others through a standard language for describing models.
Training programme and other achievements
Other important project achievements include:
- The development of computer models in different therapeutic areas such as oncology and diabetes;
- a training programme to support the adoption of the standards, repository and the interoperability framework;
- new tools which enable scientists to build and evaluate models and use them for specific purposes, such as optimising clinical trials.
For the benefit of industry, academia and SMEs
Thanks to their participation in this project, the academic community gained access and insights into industry bottlenecks, which helped them to develop methods and models which are useful for drug development. Additionally, as part of the project, many PhD students received invaluable training and access to industry, and many of them landed jobs in the industry.
When it comes to the industry, model-informed approaches have become very important in designing clinical trials and other stages of drug development. The interoperability framework, standards and model repository have already and will further enhance the way industry implements model-informed drug development projects.
SMEs within the project benefited from expanding their customer base and gaining insights into their customers’ needs. Additionally, three SME spin-offs were created as a direct result of the project.
Before the project ended, the DDMoRe project partners set up a foundation, which is continuing some of the work. The foundation is now the primary caretaker of all important project outputs including the repository, the interoperability framework and the data standards.
Read the interview with project coordinators
Achievements & News
In drug development, computer-based models are vital for understanding drug-related benefits and risks, but until now it has been difficult for researchers to pool their knowledge and develop these models collaboratively. To facilitate the sharing of models across sectors and organisations, the DDMoRe project developed common standards and the largest repository for clinical trial data models to date. ###In an interview with the IMI Programme Office, project coordinator Lutz Harnisch of Pfizer and academic coordinator Mats Karlsson of Uppsala University explain how the project outputs are already speeding up the drug development process while at the same time making it more collaborative and transparent. ‘It was a great undertaking, a great collaboration’, said Harnisch. ‘We had a chance to have so many interactions with so many people from a similar domain and greatly fruitful interactions with parties outside of pharmacologic modelling domain. That helped us understand what we want to do and how to better achieve it.’
- Read the full interview
The IMI project DDMoRe has launched a new, open source platform that allows researchers to simply and reliably share drug and disease models with one another. Scientists often use computer-based tools to simulate both diseases and the impacts of drugs on them.### DDMoRe’s new interoperability framework uses new standards and connectors for many commonly-used programming tools and languages. As such, the interoperability framework provides a consistent environment in which researchers can work, using modelling tools they know, while opening up their work to others through a standard language for describing models. The framework is free to download and the project is keen to get feedback from users. ‘We are excited to see how new opportunities for collaboration will develop now that this platform is available for stakeholders such as academia, industry and health authorities,’ commented DDMoRe Scientific Officer Wendy Aartsen.‘ We are very keen to involve anyone with an interest in the use or further development of the platform.’ To complement this release, the DDMoRe repository enables access to curated and shared knowledge for the benefit of model-informed drug discovery, development (MID3) and therapeutic use. As of today, more than 60 models are available to the public; all are free to download and ready to be used.
PharmML stands for Pharmacometrics Markup Language, and the new exchange format for encoding of models in pharmacometrics is spotlighted in a new article in Clinical Pharmacology & Therapeutics: Pharmacometrics and Systems Pharmacology (CPT:PSP).### PharmML was developed by IMI’s DDMoRe project and is a key component of DDMoRe’s platform. PharmML-encoded models can be deposited in the DDMoRe repository, helping researchers collaborate on models to improve the design of cost effective, reliable clinical trials of new and repurposed drugs. Pharmacometric modelling is essential for designing cost-effective, reliable clinical trials to test new or repurposed medicines, but until now it has been difficult for researchers to pool their knowledge and develop these models collaboratively between organisations. PharmML, developed at the European Bioinformatics Institute (EMBL-EBI), is helping researchers collaborate on computational models of disease and drug action.
DDMoRe will hold a workshop during the 24th PAGE meeting in Crete, Greece on 2 June 2015. Using real model examples from the pharmaceutical industry and academic world, DDMoRe consortium partners will give an overview of the project’s concept and demonstrate its platform.### Information from a wide array of sources can be integrated into models to describe and predict the behaviour of complex disease/biological systems and drug actions. The goal of the DDMoRe platform is to improve the quality, efficiency and cost effectiveness of model-informed decision making in drug development and therapeutic use of marketed drugs. The added value of DDMoRe and how it can support Model Informed Drug Discovery and Development (MID3) and Model Informed Patient Care (MIPC) will be discussed. The elements that make up the DDMoRe platform are the Model Repository, Model Certification, Exchange Standards, Interoperability Framework, Pharmacometric Workflow and Training. The workshop is free of charge and registration is now open
The DDMoRe project is launching a series of courses introducing the principles of model-informed drug development, covering a range of therapeutic areas, via the newly-developed DDMoRe interoperability framework platform.###
The first course, ‘Model-informed drug development in oncology (beginners)’ will be held in Berlin in March. Designed for PhD students and postdocs, the course will cover model-informed anti-cancer drug development and will include an introduction to the DDMoRe framework (new modelling & simulation language, model repository, interoperability platform. The week long course will include lectures, group work, and student presentations.
The DDMoRe project is working to build and maintain a universally applicable, open source, model based framework, intended as the gold standard for future collaborative drug and disease modelling & simulation.
The models describe and predict drug exposure‐response‐relationships in patients across a variety of diseases. The repository currently showcases a range of 'proof of concept' models describing drugs and diseases. Over time, DDMoRe will make available safety models and new models in key therapeutic areas including diabetes, oncology, central nervous system, and infectious diseases. ‘It's open access, so more people will be able to build on the models and cite the original authors' work – that means it’s also helping people who make models receive additional credit for their work,' says DDMoRe repository developer Mihai Glonț of EMBL‐EBI. 'But more importantly, the new repository makes it much easier for modellers to collaborate, so people working in different places can pool their talents to create computer‐based methods for predicting the effects of drugs in a range of conditions.’
IMI data management project DDMoRe has launched a suite of new computer modelling languages designed to facilitate quantitative decision-making at all stages of drug development.### Among other things, the project has developed a universal Modelling Description Language (MDL), which describes models and related tasks and is designed to be easily read and written by scientists. Related to the MDL are an Integrated Development Environment (MDL-IDE) and a new exchange language standard called the Pharmacometrics Markup Language (PharmML). The MDL-IDE provides a user-friendly framework where MDL code can be created and edited, while the new markup language PharmML will make it easier to exchange and reuse models/objects, annotations, and associated tasks. MDL, MDL-IDE, and PharmML are all under active development and the project is keen to gather feedback on these first releases from users outside the DDMoRe project.
DDMoRe’s Nadia Terranova, who recently completed her PhD at the University of Pavia, was awarded a Lewis Sheiner award at the recent conference of PAGE (‘Population Approach Group in Europe’).### The Lewis Sheiner award is a distinguished prize which recognises work performed by MSc and PhD students; winners receive €300 and present their work during a special session at the conference.
Dr Terranova’s award-winning work, carried out under DDMoRe, focuses on combination therapies which are widely used to treat cancer. ‘We developed a new mathematical model to describe tumour growth in mice treated with two drugs given in combination, and asses the strength of the drug effect interaction.’ explains Dr Terranova. On DDMoRe, Dr Terranova comments: ‘I think that the possibility to work within a public-private partnership gives a great added value especially for young people like me. The partnership allows the identification of the most strategic points of action for improving modelling approaches, and offers the opportunity to compare, present and share research activities and in some cases experimental data.’
DDMoRe focuses on facilitating Model Based Drug Development (MBDD), which enables the integration of information collected from diverse sources during drug development to describe and predict the behaviour of complex diseases, biological systems and drug actions. As such, MBDD provides decision-makers with a rationale to select drug candidates, targets, trial designs, dose regimens, patient populations and suitable endpoint measures.
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Some outcomes from the education and training team are highlighted in a white paperpublished recently in the Nature journal CPT: Pharmacometrics & Systems Pharmacology.###
DDMoRe’s focus is on Modelling and Simulation (M&S), a technology providing the quantitative basis for informed decision-making across all stages of drug development. This model-based drug development is acknowledged as a vital approach in understanding drug-related benefits and risks.
The white paper presents a survey developed by DDMoRe which targeted stakeholders who are either directly or indirectly involved in Drug Disease Modelling and Simulation (DDM&S) in academia, industry, or the therapeutic usage of medicines. The survey provides insights into the current impact, benefits, weaknesses, and potential hurdles as perceived by the different stakeholders and identifies requirements for effective decision-making and knowledge integration management. The insights gained from the survey results will be used as the basis for developing a framework of competencies, and will contribute towards future educational and training efforts in pharmacometrics and systems pharmacology and DDM&S.
The IMI-funded DDMoRe consortium came together to overcome the lack of common tools, languages and ontologies for M&S, as well as the limited access to stored information which created significant gaps in the use of knowledge within drug development. The consortium builds and maintains a universally applicable, open source, model-based framework, intended as the gold standard for future collaborative drug and disease M&S. More general information on DDMoRe can be found in another article in the same issue of the journal.
• Read DDMoRe’s white paper
• Learn more about DDMoRe
Learn more about DDMoRe at the PAGE workshop
IMI’s DDMoRe project will hold a workshop in Lisbon, Portugal on 7 June 2016 as part of the 25th Populations Approach Group Europe (PAGE) meeting. The theme of the DDMoRe workshop is ‘Get inspired … get started … get into the world of DDMoRe’. ### As such, the one-day event will consist of presentations and hands-on sessions to familiarise participants with the different elements of the DDMoRe platform. The diverse products will be demonstrated live with real model examples, showing the different elements and intended workflows. The added value of the products to efficiently apply model-based approaches and knowledge exchange - supporting the concept Model Informed Drug Discovery and Development (MID3) - will be discussed in the closing session of the workshop. Information from a wide array of sources can be integrated into models to describe and predict the behaviour of complex disease/biological systems and drug actions. The goal of the DDMoRe platform is to improve the quality, efficiency and cost effectiveness of model-informed decision making in drug development and therapeutic use of marketed drugs.
Sign up for the DDMoRe course on model-informed drug development in oncology
July 2015 - Registration is open for a DDMoRE project course on model-informed drug development in oncology which will be held in Pavia, Italy on 7-11 September 2015. ###The programme covers model-informed drug development in the area of oncology and will include a two-day introduction to the DDMoRe framework (new modelling & simulation language, model repository, interoperability platform). The course will feature lectures, hands-on sessions, student group work, workshops, and student presentations. The course is intended primarily for PhD students and postdoctoral fellows doing research in the quantitative life sciences field. The most important prerequisite is a willingness to actively participate in the course and give constructive feedback to further improve the DDMoRe developments.
- Deadline for applications: 3 August 2015
- Details of how to apply can be found on the DDMoRe website
ParticipantsShow participants on map
- Astrazeneca AB, Södertälje, Sweden
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
- Institut De Recherches Internationales Servier Iris, Suresnes, France
- Merck Kommanditgesellschaft Auf Aktien, Darmstadt, Germany
- Novartis Pharma AG, Basel, Switzerland
- Novo Nordisk A/S, Bagsvaerd, Denmark
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Takeda Pharmaceuticals International AG, Glattpark-Opfikon (Zurich), Switzerland
- UCB Pharma SA, Brussels, Belgium
Universities, research organisations, public bodies, non-profit groups
- Consiglio Nazionale Delle Ricerche, Roma, Italy
- European Molecular Biology Laboratory, Heidelberg, Germany
- Freie Universitaet Berlin, Berlin, Germany
- Institut National De Recherche En Informatique Et Automatique, LE CHESNAY Cedex, France
- Universidad De Navarra, Pamplona, Spain
- Universita Degli Studi Di Pavia, Pavia, Italy
- Universite Paris Diderot - Paris 7, Paris, France
- Universiteit Leiden, Leiden, Netherlands
- University College London, London, United Kingdom
- Uppsala Universitet, Uppsala, Sweden
Small and medium-sized enterprises (SMEs)
- Certara Uk Limited, London, United Kingdom
- Cyprotex Discovery Ltd, Macclesfield, United Kingdom
- Lixoft SAS, Orsay, France
- Mango Business Solutions Limited, Stevenage, United Kingdom
- Optimata LTD, Ramat Gan, Israel
- Institut National De La Sante Et De La Recherche Medicale, Paris, France
|Name||IHI funding in €|
|Certara Uk Limited||145 000|
|Consiglio Nazionale Delle Ricerche||358 628|
|Cyprotex Discovery Ltd||333 357|
|European Molecular Biology Laboratory||1 391 410|
|Freie Universitaet Berlin||369 910|
|Institut National De Recherche En Informatique Et Automatique||570 533|
|Interface Europe (left the project)||477 891|
|Lixoft SAS||270 753|
|Mango Business Solutions Limited||1 794 522|
|Martin-Luther-Universitat Halle-Wittenberg (left the project)||1 182|
|Optimata LTD||147 278|
|Universidad De Navarra||189 312|
|Universita Degli Studi Di Pavia||942 620|
|Universite Paris Diderot - Paris 7||176 826|
|Universiteit Leiden||1 103 588|
|University College London||189 560|
|Uppsala Universitet||1 805 231|
|Name||Funding in €|
|Institut National De La Sante Et De La Recherche Medicale||131 825|
|Total Cost||10 399 426|