In a world where less than 10% of new compounds that enter clinical trials make it to market and late-stage failure is high, the pharmaceutical industry and the regulatory bodies have a unique opportunity to work together to make the process of drug discovery and regulatory evaluation more efficient.
Modelling and simulation (M&S) is one of the tools that is under the microscope as a potential way to address the challenges we face. M&S, also known as Pharmacometrics and one of the key capabilities in which AstraZeneca has invested, are quantitative methods and tools that support the development and registration of medicinal products, reducing the need for further studies and speeding up the process of getting new medicines to patients. Despite the use of these processes for over two decades, they have not had universal acceptance as a tool for drug development.
The potential for M&S as an innovative tool in the development of new drugs was explored by the European Medicines Agency (EMA) and the Federation of Pharmaceutical Industries and Associations (EFPIA), in a workshop in December 2011. Representatives from industry, academia and regulatory agencies from across Europe and beyond attended.
The aim of the workshop was to explore the current opportunities for the use of M&S within existing and future regulatory framework. A nice summary of this is provided in a series of published articles capturing the opportunities and challenges of M&S.*
For the purposes of the workshop discussions, the term M&S was used to capture a range of quantitative approaches, including pharmacometrics/systems pharmacology and other mathematical/statistical approaches, best characterised by the terms model-based drug development and model-informed regulatory assessment.
What were the opportunities identified by the group?
Currently there is a belief from both regulators and industry that M&S can increase the robustness of both regulatory and industrial decision making, with previous examples bearing this out in settings such as paediatrics and anti-infectives. Regulators are also keen to access the integrative knowledge and the potential for more quantitative decision making that M&S can offer, when involved in early discussions with industry.
What were the challenges the group identified?
Well, it has become apparent that M&S activities are underutilized in regulatory submissions with a variety of factors contributing to this. Examples include:
The need to bridge the communication gap between modelling scientists and other disciplines both within industry and between industry and regulators
Challenges inherent to M&S methodology, such as the need to standardise methods, review and reporting processes and to customise these to meet regulatory requirements. Further details of a proposed framework can be found in the workshop report*
The need to pool precompetitive data from multiple sources in order to provide a comprehensive understanding of human physiology and pharmacology, thereby building accurate mechanistic models
So how do both regulators and industry move forward with the effective use of M&S in drug development?
A number of common objectives and next steps were identified by the group:
Establish a more standardized and quantitative framework for extrapolation – further details of which can be found in EMA draft Concept Paper on extrapolation of efficacy and safety in medicines development (2012)**
Strengthen model- and data-sharing initiatives
Upgrade of current regulatory guidance on dose ranging/finding
Standardise methodology, something that would be industry led
Establish a communications strategy using existing regulatory pathways
Where are we now and what’s next?
The EMA have now established a M&S working group composed of European experts who provide support to the EMA’s scientific committees and working parties on M&S relating to medicines. They also support more general methodological discussions and qualification procedures regarding M&S.
Interest in M&S is not limited to European regulators. The FDA has, for some time, had a dedicated pharmacometrics group in the CDER Office of Clinical Pharmacology. Their role is to provide analytic support to the reviewing divisions and guidance to industry on the use of M&S in drug development and regulatory decision making.
And the model of forming public–private partnerships to promote the process of drug discovery and development has been replicated elsewhere, such as the BioMarker Consortium. This is a major public–private biomedical research partnership managed by the Foundation for the National Institutes of Health with broad participation from stakeholders across the health field. Those involved include government, industry, academia and patient advocacy and other non-profit private sector organizations.
The aim of the Executive Committee, of which I am now a member, is to bring together expertise and resources to rapidly identify, develop, and qualify potential high-impact biomarkers for the purposes of improving drug development, clinical care and regulatory decision-making.
All of these initiatives demonstrate that in the current environment, successful drug development is one that requires the active input of all stakeholders to the ultimate benefit of patients. Regulators have now clearly acknowledged the benefits associated with model-informed assessment approaches. This opens the door to truly innovative scenarios of unprecedented collaboration, leading to faster and more efficient drug development and evaluation pathways.
* Manolis E, Rohou S, Hemmings R, Salmonson T, Karlsson M, Milligan PA. The Role of Modelling and Simulation in Development and Registration of Medicinal Products: Output From the EFPIA/EMA Modelling and Simulation Workshop. CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e31