Treatment for Dementia

1) Study Context and Objectives

Over the past few decades, we have witnessed medical breakthroughs transform a range of diseases from being lethal to manageable conditions. Some examples include HIV, specific types of cancers and certain orphan diseases. In each case, successful breakthroughs have been enabled and supported by diverse social, institutional, scientific and technological factors.

Given the limited progress with dementia research and innovation efforts, the UK Department of Health (DH) commissioned RAND Europe to examine breakthroughs in the treatment of four conditions of ill health and to identify potentially transferable and adaptable lessons for the dementia context. This information could, in turn, help inform levers for supportive policy development.

In line with innovation systems thinking, our study built on a conceptualisation of breakthroughs as a process that is often gradual, and that rests on cumulative knowledge and repeated experimentation. Although sudden and unexpected advances can happen, they are more often an exception than the norm.

2) Study Design and Methods

The four conditions of ill health that this study focused on are HIV/AIDS, coronary heart disease, breast cancer and Parkinson's disease. We recognise that there is no direct comparator to dementia (neither in terms of the nature of the scientific challenge, nor in terms of the wider social or financial context). Our selection of the four cases was influenced by a number of criteria. These include the existence of: (i) a clearly identifiable breakthrough; (ii) some shared features with dementia (e.g. extent to which aetiology is understood, existence of a lifestyle component); and (ii) some challenges held in common with dementia innovation efforts. We also aimed to achieve a balance in the types of challenges which our cases cover (e.g. scientific, regulatory, economic, social factors). An initial long-list of conditions was identified by the research team in discussion with health experts, and the final selection was determined in consultation with the Department of Health.

The study was primarily based on desk research and key informant interviews. For each case study, we first used desk research to identify the series of “events” that contributed to a breakthrough, and to examine their nature. Examples include scientific advancements; regulatory approvals or new legislation, dedicated research funding or financing incentives; and lobbying and advocacy, among others. We aimed to capture the relationships among key events. We then conducted interviews with experts in each of the four disease areas to validate and enrich the insights from the desk research. Finally, we interviewed leading experts in the field of dementia to discuss the perceived barriers to dementia treatment and the emerging insights from our case studies. We also discussed the implications of our case study findings for dementia research and innovation efforts.

It is important to note that it was outside the scope of our work to consider any counterfactuals. We focused on identifying factors which could potentially be useful for dementia breakthrough efforts and that were associated with breakthroughs in our case studies. We used triangulation across multiple informants, as well as desk research, to understand the contribution of specific events to the innovation process, as a proxy for exploring causation. We cannot claim that these factors would necessarily cause and “translate into” a dementia breakthrough. Rather, we suggest that there are a number of areas for policy consideration worth reflecting on further, in light of our findings.

3) Key Findings from the Case Studies of Other Health Conditions

Our case studies identified four overarching factors which enabled breakthroughs in treatment. These were found to be associated with the innovation process across the four cases and included: (i) a commitment to tackling the science associated with a disease; (ii) an active and committed advocacy community; (iii) a flexible and responsive regulatory environment; and (iv) a coordinated strategic response and collaboration across sectors. The relative importance of each of these points varied across the conditions we examined. (Their applicability to dementia challenges is discussed in the last two sections of this article.)

Commitment to tackling the science: The accumulation of scientific knowledge on various aspects of a disease was important across our cases. This included new basic science understandings (e.g. disease aetiology, nosology, pathophysiology), but also applied and clinical research on new compounds or drugs being considered for repurposing. Clinical research and experimentation often occurred in parallel to basic science activity (e.g. testing an existing drug in a new area, exploring the efficacy of a new compound). However, a relatively established basic science base was seen as a particularly important enabler for industry engagement (as was the existence of a clinical trials infrastructure which industry could feed compounds into). For example, understanding the fundamental science helped identify candidate molecules to use in drug development processes, as well as features of existing compounds which could potentially be useful for repurposing. Interdisciplinary collaboration and long-term sample studies were also central to addressing scientific bottlenecks across the research and innovation value chain.

An active and committed advocacy community: Our case studies highlighted the role that advocacy can play in prioritising a disease in policy agendas, ensuring political commitment and galvanising research and innovation investments. A strong social movement was sometimes associated with the “politicization” of a disease. Advocacy efforts often included diverse stakeholder groups (especially so in the case of HIV). These spanned patient associations, celebrities, relatives, community leaders, the media, the scientific community, central and local government, NGOs and intergovernmental organisations (IGOs). They also tended to occur at multiple levels (locally, nationally, internationally). The personal leadership and the actions of high-profile individuals who could act as champions for a given cause were closely related to successful advocacy. This leadership took many forms—political, scientific or third sector–based. Many philanthropic organisations active in disease research areas were linked to high-profile individuals.

A flexible and responsive regulatory environment: Collaborative and responsive regulatory authorities can play an important role in facilitating scientific breakthroughs and in incentivising the involvement of the pharmaceutical industry. The key regulatory provisions highlighted as important for research and innovation relate to accelerated review and drug approval processes. Some of the participants in this research emphasised that conducive regulatory interventions become important once there are tractable drug targets. However, our evidence suggests that paving the way for effective regulation can be done even when the scientific base is in the early stages of development. Some of the issues that are likely to be relevant can be foreseen a priori, and supportive regulation can also act as an incentive for innovation. In addition, some regulatory interventions (e.g. those associated with patent pools and drug repurposing efforts) might be important at earlier stages of breakthrough efforts than others (e.g. expedited approval). Regulation was part of a broader mix of factors that contributed towards scientific progress and to a breakthrough in treatment.

A coordinated strategic response and collaboration across sectors: Coordination is distinct from, but related to, collaboration. Our case studies highlight the importance of both coordination and collaboration for enabling breakthroughs in treatment. Coordination between national and international organisations at all levels, and across sectors and stakeholders, was important for the scale and pace of research and innovation activity. Collaboration between the public and private sectors was also crucial. Although overcoming research and innovation bottlenecks in the basic science underlying a disease was important for incentivizing the downstream engagement of industry, paving the way for this engagement could happen before the basic science was addressed. For example, a moral imperative associated with the scale of a public health burden, the visibility of a disease, and substantial public investment have encouraged pharmaceutical commitment in the past. The promise of supportive regulation also reduced barriers to industry engagement. Academic research institutions, clinical service providers and the pharmaceutical industry collaborated on diverse aspects of a breakthrough challenge and across various stages of innovation pathways. This included prompting and accelerating initial breakthroughs, sustaining innovation efforts over time (e.g. improved treatments, dealing with side effects, dosage issues), and ensuring access to treatments in post-breakthrough phases.

Applicability of Case Study Insights to the Dementia Context

Our interviews with experts in the dementia field tested the applicability of insights from our case studies to the dementia context and led us to identify four key messages:

The lack of understanding of the “basic science” behind dementia creates a major challenge for innovation, but supporting basic science should not occur at the expense of parallel efforts in applied and clinical research. Understanding the key biological mechanisms of dementia and its nosology (i.e. disease classification) was seen a key obstacle to achieving a medical breakthrough. The gap in basic science knowledge hampers prospects for identifying biomarkers for new drug development and challenges rational drug design models which have applied to other conditions, such as breakthroughs in Parkinson's disease. It also hampers industry prospects for selecting existing compounds to test for repurposing value. The challenge is compounded by the fact that many different types of dementia exist and that these may have different aetiologies. This implies there is a need for multiple and diverse treatments and combinations thereof. Evidence from both our case studies and our interviews with dementia experts highlight several potential strategies for tackling scientific bottlenecks. These include: (i) mobilisation of an interdisciplinary community of researchers, health and social care professionals who are committed to dementia research and are able to address the multiple facets of the disease; (ii) incentives to make dementia research more attractive to young scientists and/or to redirect the focus of established researchers towards a “critical mass” of investigators; and (iii) dedicated funding committed by investors across the public, private and third sectors. In addition, and according to one key expert in the field, radical breakthroughs may also require explicit support of some experimentation with less scientifically validated potential solutions (e.g. through observational studies involving multiple treatments initially studied on a case-by-case basis).

Commitment to and support from an advocacy community is growing and could be prioritised further, potentially through a more nuanced advocacy approach. The case for enhanced advocacy in the dementia field is strong. A number of studies have highlighted the high economic burden associated with dementia and the fact that the number of people and families affected by dementia is considerable and is projected to rise substantially. Despite a recognised need, ensuring a stronger social movement around dementia is particularly challenging given the difficulties of engaging those affected by the disease, and it not being seen as an urgency in the same way that disease outbreaks are. There is also a need for the high level of political will to be sustained and matched by funding commitments. Evidence from both our case studies and our interviews with dementia experts identified a series of opportunities for strengthening advocacy for dementia research and innovation. These include: (i) establishing more coordinated efforts (nationally, regionally, internationally); (ii) recognising the diversity of goals in an advocacy agenda (e.g. highlighting the magnitude of the challenge, setting and sustaining dementia as a policy priority and communicating the economic case); (iii) considering who the most effective advocates might be and engaging champions of change; and (iv) improving the nature and degree of patient/carer involvement in dementia research.

There is also a need to better articulate what the aims of a treatment for dementia are and what would constitute a successful breakthrough. This could influence the direction of innovation efforts and of advocacy campaigns. A discrete diagnosis which recognises the diversity of diseases within dementia (as opposed to addressing dementia as one condition) may help with more targeted advocacy efforts. The innovation pathway for a solution that would alter the progression of disease might be different than that for innovation efforts targeted at improving the quality of care or preventing the onset of dementia. Similarly, the scope of what is meant by success merits attention. Efforts to find a breakthrough for one type of dementia (e.g. frontotemporal dementia) may have distinct features to efforts for breakthroughs in another dementia type (e.g. Alzheimer's disease). While there are some commonalities, many of the scientific aspects of different types of dementias are unique (e.g., as suggested by a senior expert, those associated with risk factors or neurobiology). At present, the majority of investment support has been focused on Alzheimer's disease (which is not surprising given its degree of burden). The scientific challenges related to breakthroughs for other types of dementia may call for more specific advocacy campaigns that rest on mobilising champions around a cause that is directly relevant to them.

A flexible and responsive regulatory environment will be important to ensure innovation. Although the “basic science” behind dementia still needs to be tackled, foundations for supportive regulation can be put in place proactively so as to prevent delays in future translation efforts. Our interviewees highlighted several steps that could be worth considering. These include: (i) more staggered models of clinical trial design and such flexible arrangements as adaptive trials and conditional licensing; (ii) better streamlined clinical trial procedures (possibly drawing on lessons from the field of breast cancer, where combination therapy was successfully introduced); (iii) rapid review processes and fast tracking of approvals of promising drugs; and (iv) exploration of prospects for using existing infrastructure from other disease areas to facilitate R&D and trials in the dementia field. A responsive regulatory environment should be seen as an enabler of innovation efforts, within a wider policy mix. None of the interviewees suggested that legal and regulatory adjustments alone would be able to overcome fundamental challenges, such as the need for scientific advances and the availability of funding. Some regulatory interventions may be of more value once promising drug targets and compounds or combinations of compounds arise. However, other interventions—such as patent pools—may have been applicable even in the absence of immediate breakthroughs. Similarly, regulation around assistive technologies that could provide breakthroughs in the quality of care and quality of life for those afflicted with dementia are an important policy agenda.

A coordinated strategic response and multi-sector, interdisciplinary collaboration are essential. Overcoming the dementia challenge will strongly depend on successful cross-sectoral and cross-organisational collaboration and on a well-coordinated national and global effort. Initiatives such as the National Institute for Health Research's (NIHR) Dementia Translational Research Collaboration and the Medical Research Council (MRC) Dementias Platform UK support this approach.^[1] Our evidence suggests that a national strategy, coordinating agency/agencies, and a monitoring and evaluation framework are central to well-coordinated national initiatives. There may be merit in mapping the ecosystem of dementia research activity, as a first step towards leveraging synergies between different initiatives and minimizing duplication of effort. In terms of the collaboration landscape, interviewees saw public—private partnerships (PPPs) as one important way of stimulating innovative solutions. However, a range of uncertainties associated with PPP design would need to be addressed. These relate to stakeholder incentives, network size, governance models, intellectual property (IP)/ownership arrangements, stakeholder influence on the direction of research, breadth of activity, legal arrangements and benefit distribution. The Structural Genomics Consortium model may offer relevant lessons for partnerships being considered in the dementia space, given its focus on pre-competitive R&D through a unique open access model, its scale and its multiple-stakeholder governance.

Policy Considerations and Potential Areas for Action

Finally, we propose some “action areas” for policy consideration (Table 1). These are based on the insights from this study and are informed further by our wider experience of the science, innovation and health policy issues raised in the study. These action areas aim to open discussion and encourage further constructive dialogue and exchange of ideas in order to make progress on the dementia challenge.

Note

[1] It is worth noting that charities represent an indispensable part of these efforts, as illustrated by the following two UK-based examples. Alzheimer's Research UK recently launched a Drug Discovery Alliance, setting up new drug discovery centres. Similarly, Alzheimer's Society UK has recently partnered with the Alzheimer's Drug Discovery Foundation in a new research initiative (Alzheimer's Drug Discovery Foundation, n.d. Foundations partner on $3m initiative to accelerate research and discover treatments for Alzheimer's. As of 31 March 2015: http://www.alzdiscovery.org/news-room/view/foundations-partner-on-3m-initiative-to-accelerate-research-discover-treatm).

The research described in this article was prepared for the UK Department of Health and conducted by RAND Europe.