Progress in the life sciences and related technologies offers the potential to bring a wide range of beneficial therapies to patients over the coming years. There will be more personalised or stratified medicines, combinations, borderline products, and advanced therapies that will require new ways of evaluation and new ways of managing utilisation in clinical practice.

The current paradigms of bringing innovation to patients are also challenged by transformative environmental developments:

• Growing patient demand for timely access to promising therapies, exacerbating the ‘access versus evidence conundrum’. In turn, this will require more flexibility and increased numbers of iterations of regulatory and reimbursement decisions;
• Increased fragmentation of treatment populations due to better disease stratification, challenging the established clinical development pathways, e.g. large conventional phase III studies;
• Rising payer influence on product accessibility and growing concerns over budget impact of new treatments; financial pressures on health systems and sustainability challenges are raising questions regarding prioritisation of investment and value of innovation.
• Pressure on pharma/investors to ensure sustainability of drug development as pharmaceutical R&D attrition rates remain high and the cost of biopharmaceutical R&D continues to rise; this limits the absolute number of candidate drugs that can be brought forward.

To address these environmental changes while fully realizing the potential of scientific progress for patients in a timely and sustainable way will require major adaptations to current paradigms. The changes required go far beyond the well-defined remit of regulatory evidence standards. We posit that all decision makers and stakeholders in the healthcare ecosystem will need to explore a life-span approach to new pharmaceutical treatments with drug development, licensing, reimbursement, use in clinical practice and monitoring viewed as a continuum. The life-span approach is hereafter referred to as Medicines Adaptive Pathways to Patients (MAPPs). Detailed definition of the MAPPs concept, its key features, potential merits and weaknesses have been described elsewhere (ref. 1-4).

Strong public health drivers, enabling technologies, and our own collective experience convince us that there are sufficient opportunities for making the MAPPs approach a reality – now. There is, however, the “O2 problem” with MAPPs that is defined by the related Opportunities and Obstacles. A major task for ADAPT-SMART is the identification of these two Os, and to provide a framework for MAPPs that will overcome the latter and seize the former.

At present, we see the following key opportunities:

• The research-based industry’s pipelines are filling up: a number of innovative therapies are at advanced stage of development;
• Next Generation Sequencing, capture of phenotypic and behavioural data (digital biomarkers), and other predictive markers enable increasingly precise definition of the “right patient”;
• In turn, this is expected to result in better effect sizes, improved individual benefit-risk, and lower numbers-needed-to-treat with higher value in a given treatment-eligible population;
• Progress in advanced therapies (e.g. gene therapies) will make possible one-time curative interventions;
• Innovative clinical trial designs allow for more efficient and seamless knowledge generation;
• Improved understanding of disease processes (e.g. background rates of disease progression), and better knowledge management combined with modelling and simulation (M&S) increase the efficiency of knowledge generation, within randomised controlled trials (RCTs) and observational studies;
• Rapid learning systems in the healthcare environment enable improved knowledge generation post initial licensing;
• In turn, this allows decision makers to migrate from prediction to monitoring, supporting the MAPPs concept;
• More active contributions from patients/patient organisations provide opportunities for better definition of patient preferences and acceptable uncertainty about benefits, harms, and value of new products at the time of launch;
• Availability of increasingly effective tools to steward appropriate, targeted prescribing (in some healthcare environments);
• Cultural change with multi-stakeholder platforms already established, with more opportunities for data and information sharing across regions and groups.

At the same time, we recognise that important obstacles need to be addressed if MAPPs is to become a reality. At present, we identify the following key obstacles:

• The MAPPs concept, involving earlier access for (some) patients with more limited data will not be acceptable for some stakeholders; perception that (too) early launch could lead to serious safety problems and undermine public trust in the system;
• More drugs for more, but smaller, patient subpopulations (with differing levels of evidence) will make it difficult to achieve sustainability for both the research enterprise and healthcare payers; debates over price and budget-impact will become ever more contentious, willingness of payers to accept the MAPPs concept with early access and initially limited data is likely to be poor;
• In some cases, limited data exclusivity duration after the initial (narrow) license may be a disincentive to drug developers;
• There is a risk that the concept of MAPPs will find uneven acceptance across EU member states; this may in part be a result of existing diversity of patient access across the EU (e.g. Eastern versus Western EU member states).
• The political will and legal tools to limit access to an approved drug to a subset of the population, as foreseen by MAPPs, may not be in place in some healthcare environments; avoidance of off- label use after an initial authorisation may be challenging;
• It may be politically difficult to remove a drug from the market or restrict payment should the initial benefit risk balance or value proposition not be confirmed post approval;
• MAPPs concept may present specific challenge for orphan drugs in light of the terms of EU orphan legislation (e.g. the concept ‘significant benefit’ which is unique to orphan designations);
• Resistance to flexible or outcome based reimbursement strategies due to practicalities and costs associated with implementing them;
• Perception that MAPPs concept entails a shift from evidence generation by way of RCTs to observational studies which have lower evidence standard;
• MAPPs will cause extra work load/new expertise requirements for regulators, HTA bodies, and payers, in light of repeat cycles of assessment and negotiations with sponsors (may lead to resistance to change);
• Legal, healthcare systems, and other differences across jurisdictions may challenge global evolution towards MAPPs principles (given global nature of firms and diseases);
• Need for capacity building and support for all stakeholders in order to fully integrate the contribution of patients and patient organisations across the R&D cycle.

Currently, several initiatives are exploring new pathways to market. These initiatives include the EMA Adaptive Licensing Pilot project, the New Drug Development Paradigms (NEWDIGS) initiative at Massachusetts Institute of Technology (MIT, USA), and the UK’s Early Access to Medicines Scheme (EAMS). Parties directly involved with these initiatives, related IMI projects such as IMiPACT and GetReal, and several EU national developments, are joining forces in ADAPT-SMART with the aim of defining and helping to implement the MAPPs concept.

ADAPT-SMART is thus aligning a limited number of major stakeholders eager to progress towards MAPPs implementation. The consortium will mobilise its network of additional relevant stakeholders to adequately involve all players in the innovation life span. The ADAPT-SMART Coordination and Support Action (CSA), will act as a neutral collaborative framework to establish the platform that will engage with all relevant stakeholders, including patients, industry, SMEs (Small and Medium sized Enterprises), regulators, Health Technology Assessment bodies (HTAs), payers (national and European Networks), clinicians, governments/policy makers (national authorities as well as European Commission’s DG SANTE and DG GROW, and European Networks).

In addition to engaging in a dialogue with relevant stakeholders, the ADAPT-SMART consortium will contribute to align understanding of the impact of MAPPs, to share learnings between all stakeholders, and to allow the field to actively work towards MAPPs implementation. This will increase the probability of successful innovation and accelerate access to crucial therapies, thus improving the position of both the patients in need of novel treatments and the research-based pharmaceutical industry.