Medicines Adaptive Pathways to Patients (MAPPs)

Introduction

After nearly a decade of discussion, analysis, and development, the Medicines Adaptive Pathways to Patients (MAPPs) initiative is beginning to see acceptance from regulators, industry, patients, and payers with the first live pilot project initiated under the guidance of the European Medicine’s Agency (EMA) in 2014. ¹ Although it is a significant achievement to see the first asset being placed into human trials under an adaptive pathway, there is much to be learned regarding the multinational and multi-stakeholder effort that has driven the growing acceptance of MAPPs as a methodology and concept, as well as the need for continued and increasing international collaboration to foster the wider adoption of MAPPs.

At their core, MAPPs are flexible development and access strategies, unique to individual medicines, that considers the total context at the time of development, and executed within the current regulatory frameworks, designed to optimize trade-offs among early patient access, public health, and societal benefits. MAPPs harness and utilize the continuing scientific innovations in targeted and stratified therapies, as new medicines are launched with the earlier authorization of a new therapy for a well-defined group of responders for whom there is sufficient confidence that benefits will outweigh risks. The initial label and target population included at the launch is adjusted (to accommodate a different target population) as the initial in-market evidence and experience base expands, ideally with the capture of multiple data sources including real-world evidence (RWE). In this way, MAPPs encompasses the entire life cycle of a medicine from development, licensing through to patient access and utilization, with the ultimate goal of providing patients with access to new drugs in a scientifically and socially responsible manner, while allowing for more efficient usage of research and development resources.

Currently, a new medicine is authorized, but not automatically reimbursed, at a point generally occurring after the successful completion of a phase III randomized controlled trial (RCT) development program. Success is defined as meeting or exceeding the targets defined in the endpoints of the trial, and the approval issued by a responsible medicines regulatory authority who clearly defines the officially sanctioned, or “licensed,” uses of the medicine for sale. In the European Union (EU), this license is granted by the European Commission after receiving the opinion of the EMA; in the US, it is the purview of the Food and Drug Administration (FDA). Similarly, other countries/regions have their own unique licensing authorities designed to meet local needs.

Between the periods of a therapy undergoing RCTs to prove efficacy and establish a certain safety baseline and its authorization/licensing for sale is a single governing regulatory decision point, which has been referred to as the “magic moment.” It is at this specific point that an authorized governmental regulatory agency, based on the data and evidence gathered in the course of a medicine’s development, makes a determination that the anticipated benefits of a new therapy outweigh the foreseen risks for the intended patients when they are taken as tested during clinical trials evaluation. At this “magic moment,” an experimental therapy transforms overnight into an approved medicine that is commercially available for use, sometimes by millions of people.

Although this system of RCTs has been the gold standard for establishing the benefit/risk profile of new therapies, increasingly, the system is not meeting the needs of the various stakeholder groups, including patients. For patients, RCTs are a lengthy process, standing between what may oftentimes be a race between the clock and the only chance of a life-changing medical solution. Case studies of MAPPs development approaches have focused on the potential power of combining other methodologies with RCTs to reduce uncertainty around benefit/risk profiles and—in the process—shorten times to patient access by 2 to 8 years. ^2,3 For payers and prescribers, RCTs are often considered inflexible, expensive, and do not always answer the questions most pertinent to their concerns. This problem is particularly acute in Europe where new therapies, once approved via the EMA, then require the lengthy process of 28 country-specific negotiations for pricing and reimbursement. This portion of the European pathway often adds additional years to the time before patients can receive needed new medicines. ⁴

A recent study by the Genetic Alliance UK has shown that, across Europe, 38% of those surveyed, all closely involved in managing a chronic disease for themselves or others, are aware of existing treatments that may be of benefit, but are currently unable to gain access to the therapy because of regulatory decisions. ⁵ Although regulatory agencies have attempted over the past several decades to reduce the barriers to the access of needed new medicines via accelerated approval, fast track, priority review, conditional marketing authorizations, and other regional specific procedures, these have been stepwise and incremental as they rely on the same “magic moment” phenomenon and do not routinely have the strong postauthorization continued learning and cooperation among key partners, resulting in, for example, managed market entry and restrained off-label use that will characterize MAPPs.

Further, there is a belief among many stakeholders that RCTs, once they have generated data and analyses validating phase III clinical endpoints, remove any doubts around efficacy, safety, and performance of new therapies, under nearly any circumstances of use. Although RCTs are the most reliable barometer of a given new therapy’s potential performance in the market, the statistical reality is that many adverse events will only occur and subsequently be identified by having access to a larger pool of data obtained by wider use of the new therapy in the market postauthorization. In addition, many patients will have comorbidities and be taking other medicines than those in the clinical trials database, thus adding potentially new safety and effectiveness factors. These realities underline postauthorization systems that will facilitate the development and dissemination of that data in a controlled manner such that patients who need the medicine have access whereas those for whom the benefit/risk profile is not favorable are not exposed. However, enactment of such a system requires transformative thinking, mastery of the use of the full range of data and analytic methods that can be applied to generate evidence for decision making, and a better understanding of perceived values, risks, and uncertainties by all stakeholder groups. ⁶

It is these challenges that have led directly to the groundbreaking MAPPs collaboration between the Massachusetts Institute of Technology (MIT) Center for Biomedical Innovation’s New Drug Development Paradigms (NEWDIGS) Initiative, the EMA, patient, payer and health technology assessment groups, the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Innovative Medicines Initiative (IMI)—a European public-private partnership. ⁷

Developing MAPPs as a Concept: How Did We Get Here?

The implementation of the EMA pilot investigating MAPPs has been the result of a multitude of efforts, initiatives, and discussions that have been global in scope for nearly a decade (Figure 1). The earliest known “adaptive pathway” was recommended by Health Canada in 2006 when they proposed a life-cycle, evidence-based approach that they called “progressive licensing” in their “Blueprint for Renewal.” ⁸ The initiative would include the input and consideration of multi-stakeholder preferences in decision making as well as an overarching goal of increased transparency, combined with well-planned, continuing accrual of reliable evidence. ⁹

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Figure 1.

MIT NEWDIGS adaptive licensing/MAPPs timeline.

Similarly, the US Institute of Medicine (IOM) helped to articulate a new approach harnessing iterative assessments across the entire life cycle of a medicine. Postmarket assessments were to be shared in a multi-stakeholder structure, and it was to feature enhanced adverse event reporting. The IOM also suggested that the FDA extend its authority to require post-marketing trials with five-year reviews for all newly approved, nongeneric medicines. ¹⁰ Separately, in 2009 the Singapore Economic Development Board convened a select group of international drug development and regulatory experts and asked them to present a series of ideas on improving the collection and submission of data on a medicine’s safety and effectiveness while evaluating new therapies. These are only a few examples of the many relevant ideas that have been presented.

Building on these initiatives in 2010, MIT NEWDIGS convened a meeting of multi-stakeholder experts and thought leaders to discuss the feasibility of an adaptive approval model based on the continuous reappraisal of data collected over the lifetime of a new therapy. The findings of this meeting included a key recommendation: to ensure the greatest chance of success for a new adaptive approval model, the implementation should be designed, piloted, and evaluated in a precompetitive environment with all key stakeholders involved in providing perspectives to improve the decision-making processes.

By 2012, NEWDIGS had matured “adaptive licensing” as a framework concept, acknowledging that flexible approaches could lead to the continuous evolution of licensing and access by basing decisions on the evolving understanding of benefits and harms to subpopulations of patients. ¹¹ The systems-oriented learning methodologies applied by NEWDIGS highlighted that adaptive licensing was not, in fact, a new regulatory pathway in the traditional sense, but rather a multi-stakeholder process framework designed to facilitate the continuous evaluation of a therapy over its entire life cycle. It was also recognized that how the framework was designed and implemented would be highly context dependent, and the stakeholders involved would tailor it appropriately for the disease, the medicine, and/or the geography.

In 2013, broad discussions were initiated about ways to further evaluate the adaptive licensing approach in the EU. In the course of these discussions, relevant stakeholders agreed to modify the name under which the collaboration would proceed in the EU to MAPPs in order to more accurately reflect the broader scope of implications of the framework.

NEWDIGS Scenario Design Sessions: Creation of an Environment to Exchange Stakeholder Perspectives and Obtain Consensus

From 2010 through 2014, NEWDIGS conducted multi-stakeholder sessions in a neutral, precompetitive “safe haven” environment allowing ideas to be freely exchanged, refined, and discussed in a collegial manner. Such an atmosphere is often the exception rather than the norm for interactions among members of the pharmaceutical industry and external stakeholders. Each workshop was conducted under guiding principles that established expectations and ensured a level of mutual comfort required for candid dialogue. The thoughts and perspectives expressed by each participant were acknowledged not to reflect those of their employer organization, but rather represented the opinion of a functional expert, and no binding decisions were made at the workshop, further promoting stimulating, frank, and open discussion. Most importantly, specific comments, findings of fact, and outcomes determined to be nonconfidential were shared outside the workshop under the Chatham House rule. ¹²

To date, 13 investigational therapies have been discussed by member companies at NEWDIGS workshops with the goal of designing a possible MAPPs development program that would meet the needs of all stakeholders. These potential medicines, which were actual development candidates when presented, represented a range of therapeutic areas and stages of development (Table 1). No therapeutic area, to date, has been determined to be unsuitable to be placed into MAPPs, and proposals have been presented for compounds in preclinical development, through pre–phase III and all stages in between. It is the current consensus that the greatest benefits of multi-stakeholder input are realized between preclinical and early phase II stages of development.

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Table 1.

Characterization of Development Candidates Presented at NEWDIGS Scenario Design Sessions.

NEWDIGS Identification Number	Therapeutic Area/Indication	Phase of Clinical Development	Number of Scenario Design Sessions
N0511-1	Antibiotic for drug-resistant gram-positive bacteria	Phase 2	3
N0811-1	Multidrug regimen for drug-resistant TB	Pre–phase 1	4
N1111-1	Dyslipidemia therapeutic	Phase 2	2
N1211-1	ADPKD therapeutic	Phase 2	1
N1211-2	MAb to treat PML	Pre–phase 1	1
N1211-3	Vaccine	Phase 1	1
N0312-1	siRNA for treatment of ATTR	Phase 2	2
N0612-1	Novel-novel oncology combination for the treatment of rare cancers	Phase 2	1
N0912-1	Therapeutic vaccine for B-cell lymphoma	Preclinical	2
N0912-2	Anti-inflammatory for the treatment of ACS	Pre–phase 3	1
N0213-1	Oncology therapeutic and companion diagnostic	Phase 1	1
N0613-1	Broad amyloidosis therapeutic	Phase 1	3
N0414-1	Pain therapeutic	Phase 2	1

Abbreviations: ACS, acute coronary syndrome; ADPKD, autosomal dominant polycystic kidney disease; ATTR, transthyretin amyloidosis; MAb, monoclonal antibody; NEWDIGS, New Drug Development Paradigms; PML, progressive multifocal leukoencephalopathy; TB, tuberculosis.

Overall, NEWDIGS scenario design sessions confirmed the recognition that MAPPs strategies are not a one-size-fits-all development approach. Design and implementation considerations varied widely depending upon the context within which they were being applied and will also be influenced by therapeutic areas, international cultures and jurisdictions, and health care delivery systems.

From Scenario Designs to Pilots: Crystallizing Initial Findings and Next Steps

MAPPs, as explored in NEWDIGS Scenario Design sessions, leverage existing accelerated access regulatory and payer pathways in a theoretical model. These pathways have been in use for many years in the US, the EU, and other regions. ¹³ However, there is little or no benefit to the patient when a medicine has an accelerated regulatory approval, but the payers will not provide reimbursement or a medicine is removed postauthorization because of inappropriate use, making benefit/risk profiles negative.

Although some proposals, such as those made by Tapestry Networks, ¹⁴ have offered simultaneous regulatory and health technology assessment (HTA) input, having key stakeholders engaged at the start of the design phase, including patients and clinicians, is vital to the implementation of MAPPs. This highlights the value of multi-stakeholder discussions early and continuously across the life cycle of the therapy in order to more fully serve the needs of patients.

Another key principle of MAPPs is that the current handling of uncertainty will change significantly. Specifically, uncertainty will be handled transparently and reduced explicitly and progressively throughout the life span of the product, and will be managed in a more coordinated manner across stakeholders. In many cases, for example, the initial license will be granted for a specific population with a smaller overall accompanying evidence of safety package. This will require regulators and payers to have greater confidence in the performance capacity and reliability of the postauthorization data capture and analysis “systems” to extrapolate and assess from RCT data the potential outcomes (both positive and negative) that will be seen in real-world usage. These challenges are offset as a result of a smaller prescribing population of the initial authorization under MAPPs, making the collection of such data, in theory, easier in comparison to the much larger challenges of current approaches.

Mechanisms and capabilities that will need to be enhanced or newly developed over current capabilities in order to overcome the current uncertainty barrier will include reliable, high-quality, and timely postmarket evidence generation; efficient and effective communication of emerging product information to all stakeholders; and minimizing/eliminating off-label use of new medicines during the initial authorization phase. All stakeholders will play a role in improving postauthorization evaluation and systems as well as define processes that make possible the reliable use of RWE and other postmarketing data.

NEWDIGS has recently launched the Janus Initiative, which is focused on developing a set of open access, interactive simulation tools designed to help structure multi-stakeholder discussions and evidence evaluation in the near term. ¹⁵ It is also hoped that Janus will enable the rapid adoption of new game-changing technologies, processes, and policies as they emerge. The ongoing research into RWE to collect, analyze, and communicate information to stakeholders to support better decision making is a potential early platform for Janus to investigate. By advancing RWE research, it may be possible to develop a standardized approach to evaluating and advancing the use data systems to support life cycle–based management of benefit, risk, and uncertainty.

MAPPs, NEWDIGS, IMI, EFPIA, and EUROPE: A Transatlantic Initiative

NEWDIGS is collaborating with the EU’s IMI and EFPIA to identify and undertake additional research to support the implementation of the MAPPs framework. Already, NEWDIGS has a geographic reach that includes perspectives from around the globe (Figure 2). IMI is one of the world’s largest public-private partnership research programs in life science; the next phase under IMI2 launched in 2014 with a budget of €3.3 billion, with €1.4 billion being contributed by EFPIA ⁷ for the period 2014-2024. One of the actions funded by IMI is an enabling platform with relevant stakeholders to coordinate the MAPPs activities in IMI2, as well as to help engaging a dialogue between, patient groups, regulators, researchers, industry, and medical practice. The challenge in implementing MAPPs is that it touches all aspects of regulatory science, HTA assessment, and reimbursement simultaneously. IMI2 will provide an appropriate neutral platform to investigate and identify the missing and enabling evidence and tools to put MAPPs into practice across all points of the MAPPs ecosystem. This includes providing deeper understanding to key questions such as the following:

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Figure 2.

Geographic reach of MIT NEWDIGS.

In addition to projects in IMI2, EMA’s announcement on March 19, 2014, inviting companies to submit plans for ongoing medicine development programs for consideration as prospective MAPPS pilots should help shed light on some of these important questions. The pilot project was launched as a confidential “safe harbor” and received 34 applications as of December 22, 2014, of which 6 have been selected for further discussion. ¹⁶ The intention in the pilot is to expedite products through early authorization in a narrowly defined patient population and then manage iterative phases of RWE gathering that allow the marketing authorization to be adapted, ideally expanding to broader patient populations.

Although the uptake in EMA’s safe harbor pilot is impressive, it also serves to underscore the challenges of implementing MAPPs, and the need for the development of tools under IMI2 that would utilize greater creative intelligence than is routinely seen in clinical development approaches today. Safe harbor allows applicants to discuss their objectives in confidence, and the pilot should make it possible to inject adaptive approaches and designs into the pathways. However, most of the applications are still thinking in a linear way, of going from A to B to C in the regulatory pathway. Tools are needed to stimulate thinking and broaden understanding of trade-offs and impacts within and between stakeholders, in designing nonlinear pathways. ¹⁶

The challenge for MAPPs is to find ways to more effectively communicate among stakeholders how the uncertainties in knowledge base at any time have affected their decision making and their expectations for future uncertainty reduction in order to ensure continued access. Some have pointed out that an ongoing process of re-evaluation of a product is likely to make it difficult to define value in terms of price at launch. ¹⁶ The challenge then for MAPPs is to develop robust tools and processes that address this and other such concerns through multi-stakeholder agreements and discussions before the new therapy is placed into the market.

To avoid patient exclusion or national expenditures rising in an unsustainable fashion, managed entry agreements are seen as a viable option, but these will need to be tested. As well, patient registries will assist in defining price and access and help payers to understand where the investment in health will be most cost effective. ¹⁶ However, these will also need to be investigated and piloted in collaboration with the EU member states, perhaps via IMI2, Janus, EMA, or all of the above.

Regarding patient involvement in assessing benefit/risk, a recent research study conducted in partnership with the UK-based mobile health company Patients Know Best found that 73% of their users would be willing to participate and volunteer in clinical research to evaluate benefit/risk and determine if new medicines were effective. ¹⁷ The ongoing challenge is to incorporate these decision-making processes into MAPPs methodologies, to ensure the appropriate balance is struck between earlier access to new medicines, a given regulator’s willingness to facilitate that to occur, a health care provider’s willingness to accept more focused data before prescribing a new medicine, as well as the provider’s correlating willingness to restrict their off-label prescribing practices and to participate in real-world clinical research to progressively reduce uncertainties, a given payer’s willingness to purchase such medicines, and having strong multifaceted postauthorization systems in place to facilitate all of this in as safe and dependable a manner as possible.

The central difficulty remains that implementation of MAPPs requires that all elements in the ecosystem be dealt with at the same time. And although all stakeholders may align on the need for change from the current approach to bringing new therapies to market, their motivations may be different. This problem is most acute when discussing flexible pricing, as MAPPs imply that a given therapy’s theoretical price could be going down in one country with a strategy focused on volume buying, whereas at the same time another country using an outcome evaluation measure could see prices rising based on performance metrics, or that price may change (up or down) as further information is gathered and real-world benefit and risk become clearer.

Although challenges certainly exist, the ongoing international collaboration, idea sharing, and partnership between NEWDIGS, EMA, EFPIA, and IMI and other stakeholder groups is changing the nature of the discussion and debate. MAPPs have now emerged into a full-blown international effort to redefine the entire clinical evaluation pathway in a collaborative multi-stakeholder fashion.

On October 21, 2014, an international group of 140 experts was invited to the Royal College of Physicians in London to discuss how MAPPs, adaptive clinical regulatory pathways, sources of evidence, and evolving data on real-world patients can be used both to expedite the development of drugs and improve their quality and access. ¹⁶ Jointly hosted by NEWDIGS, EFPIA, and IMI, the event received international coverage in the media and was a watershed moment establishing MAPPs as a major international research agenda for new medicines.

With the launch of IMI2, Europe is spearheading the international multi-stakeholder approach to improve the way new medicines are developed, ultimately for the benefit of patients as well as for the future sustainability of health care systems.

The initiation of the MAPPs pilot program by EMA in early 2014 provides the setting for the collection of real-world experience to determine the perceived benefits and potential risks of the new approach with multiple development candidates. It is believed that the learnings from this pilot can be used to refine MAPPs and advance the implementation enablers that will drive meaningful and sustainable value for all stakeholders, both in the EU and in other regions around the world.

The required evolution of the system mandates flexibility and collaboration of all stakeholders. Increased patient involvement will be a very important step. Our common goal to serve patients and society must drive systemwide progress. Joint learnings from the EMA pilot projects in adaptive licensing and the IMI projects over the next 1 to 3 years will be significant milestones on this path.