A fresh approach to Dementias research
Call for Expressions of Interest (EoI) to create a UK Dementias Research Platform under the MRC‘s ‘Stratified Medicine for Patient Benefit’ initiative.
EoIs are invited from UK cross-disciplinary teams to meet the following specification for a cohort-based UK Research Platform to address the challenge of dementias/ neurodegenerative diseases (ND).
The Platform will be used initially to record in a systematic way the progression of neurodegeneration according to age and physiological variables and to identify surrogate markers with functional readouts. Subsequently this information will form the basis on which to stratify patient groups for new therapeutic approaches.
Scientific rationale
Age-related neurodegenerative diseases and especially the dementias are one of the leading medical and societal challenges faced by our society. The MRC has identified a compelling opportunity to create a research platform as the basis for stratification of patient groups. This fresh approach is intended to accelerate research progress, stimulate the design of new strategies for treatment and, ultimately, assist in finding ways to prevent onset and progression of ND.
The current Stratified Medicine for Patient Benefit initiative is a research priority for MRC. The initiative’s initial focus has been on the prediction and understanding of variations in patient response to existing therapeutic interventions.
For ND we consider that a different approach to stratifying patient groups is necessary for the following reasons:
- few treatments are available in clinical use and these interventions treat the symptoms rather than the causes of ND
- few reliable biomarkers are available
- only a limited number of candidate drugs are in development currently, relative to other therapeutic areas, while recent clinical trial results concerning anti-amyloid strategies have proved disappointing
- current clinical classifications of the different ND are increasingly seen as being of limited utility, with the realisation that these classifications do not reflect the underlying pathophysiology and ignore the ‘whole patient’, particularly the co-existence of other conditions - diagnosis through molecular phenotyping may provide new insights into the development of ND and provide a basis for identifying new surrogate markers
- genetic studies indicate that some ND share common mechanistic pathways, with more recently discovered genes pointing to non-neuronal/systemic disease processes involving the metabolic, endocytic and immune systems.
Scientific structure of the Platform
To create the Platform it is expected that one or more existing well-characterised cohorts will form the basis for subgroup stratification, supported by additional data collection and analysis, as appropriate. The focus of the work should be on:
- staging progression using routine physiological measures (eg. metabolic, endocytic changes in peripheral organs and blood) and symptomatic (cognitive, behavioural) changes as the basis of ‘read-outs’ that can be used for experimental medicine.
- drivers of disease progression, including differential rates of progression
- joining up mechanistic understanding across neurodegenerative conditions and spanning non-neuronal processes
These measures should be underpinned by an understanding of genetic risk factors and combined with a range of appropriately tailored imaging modalities. It will be necessary to collect blood and cell samples if these are not already collected and available from the selected cohorts. Strong informatics and data handling input will be crucial.
Specifically, vascular, metabolic and immune system co-morbidities should be mapped, but other modalities could be included, if the case can be made that these are relevant.
It is anticipated that initial data collection and analysis will focus on presymptomatic participants who mostly will not have clinical symptoms of ND. However, there may be a case for including other age-groups where appropriate linkage can be achieved, and it is likely that in the longer term a range of age groups will need to be studied.
The design of the Platform should take a broad view of how ND develop in the population rather than focus exclusively on a single disorder. New insights and understanding are expected to follow from consideration of:
- common traits and mechanisms
- the extent, influence and interplay of co-morbidities
The Platform must have the ability now or in the future to access GCP-standard clinical research facilities for experimental medicine.
The use of human post-mortem and surgical brain tissue is strongly encouraged. Where appropriate, combining such studies with imaging analysis might be considered.
Our expectation is that industry scientists should be active participants in the Platform as it develops and may wish to contribute to the EoI. The precise roles for industry scientists are not pre-defined, and are expected to depend on the nature of the bids, but could include any or all of the following: advice on strategic direction; design of scientific projects; participation in scientific projects; provision of resources including compounds, tools and data.
Partnerships with other funders are welcome but are not seen as essential to the success of the EoI. MRC will assist with brokering any such partnerships as necessary after the EoI stage.
Funding mechanism
The call will operate through two stages – an initial EoI phase followed by invited full applications. Note that submission of an EoI is mandatory to proceed to the second stage).
EoIs are invited to present the concept and capabilities that will be brought together to deliver a Platform as a basis for a stratification agenda that will open new avenues for research in ND.
Up to £6M is available in principle for this call, with the anticipation that, subject to quality, MRC will make a single award to support one national platform for this activity for a period of up to five years. This Platform should be responsive to emergent findings and be able to reprioritize its activities in response to new internal and external data and opportunities.
In the final award, a proportion of the funding is expected to be used for the core activity of data or sample analyses or additional cohort ‘sweeps’ to fill important gaps, which should also cover substantive recruitment or re-contact work. The funding envelope is also expected to provide resource for a milestone-based programme of directly relevant work-packages or otherwise ‘federated’ projects, as well as for any pilot or initial scoping work that must take place before the Platform can become operational. For example to scope the project it may be necessary to:
- review existing cohorts in order to identify their suitability and capabilities, their strengths and weaknesses
- establish what data can be shared, the informatics requirements and what harmonisation may be needed
- carry out an analysis of which cohorts could be adapted as intervention platforms
In summary, the funding proposal may consist of cohort-based activity plus pilot work (if necessary) and federated projects/ work-packages.
There is potential to add value to the Platform by inclusion of relevant existing Research Council or charity research funding, or linkage to international activity.
Decision process
An Expert Panel will define the precise scope for the Platform based on the EoIs received. Further guidance will be issued at that stage.
A small number (no more than three) of groupings will be invited to develop their bids on the basis of the Panel’s advice and to compete for the final funding allocation. It is likely that lead applicants from short-listed groups may be required to present their plans in person to a meeting of the Panel in Q3 2013 (exact timing will be confirmed later).
The final funding decision is currently expected to be taken in Q3/Q4 2013.
Consortia forming the Platform are expected to include international-level expertise and hands-on experience for some or all of the following areas:
- Epidemiology and cohort management
- Human physiology, pulmonary, vascular, metabolic and immunological expertise
- Informatics, record linkage and database interoperability
- Genetic risk factors and their analysis
- Imaging
- Cognitive and behavioural testing
- Early phase clinical research (experimental medicine)
- Animal and/or cellular models of human disease
- Biomarker identification
- Target validation.
EoI should define any additional skills sets that will need to be incorporated for the Platform to be fully successful.
Training
Support for training will not be allowable through this call, which is focussed on establishing the Platform. Once established, the Platform will provide a basis from which to bid to existing schemes or, potentially, to make a case for supplementary funding.
Management structures (people)
We are open to considering different management models for operation of the Platform. The main requirement is for an identified lead academic facilitator/ co-ordinator who will co-ordinate arrangements for work-packages and for industry interaction. Leaders of work-packages should be acknowledged scientific experts who are familiar with operating in an interdisciplinary environment.
Management Structures (governance)
The Platform will be expected to operate robust yet streamlined overview and day-to-day structures for steering, co-ordination, management and goal delivery.
There should be a clear strategy for working with industry. A flexible structure is encouraged, where partners are able to join at specific points of interest to them.
Progress will be measured against pre-agreed SMART targets and milestones. A case must be made for all roles which must be clearly specified, for example with industry or lay/patient input tailored in a realistic and well defined way to steering/ advisory activities or specific project input, as appropriate.
Format for EoI
General
The EoI should be submitted in pdf format using type of 11 pt Arial font single spacing. The length should be no more than 5sides of A4, with margins of 1.5 cm on all page borders. Four annexes are required in addition, as follows:
1. Gantt chart: Overview of work programme (one side of A4)
2. Schematic diagram: To illustrate the different components of the Platform (one side of A4)
3. Table of finances: Indicative costingsto the nearest £100k (one side of A4). Please use the headings provided in the MRC Applicant Handbook (p 20 to 23)
For the EoI, a case may be made for the following types of support:
- Salary costs for the portion of time dedicated to the Platform for lead investigators
- High quality research projects, innovative pilot studies or methodology development to underpin the Platform
- Start-up costs for new posts (eg technical staff, statisticians, database management, project management etc) required to fulfil the Platform’s strategy
- Start-up costs or new resources essential to deliver a successful Platform. MRC will consider start-up funding for equipment and 80% FEC running costs
- Requests for equipment over £10k should be listed under a separate heading (see p 31 of Handbook)
- Costs for translational work, co-ordinationand collaboration between disciplines, or communications, needed to bring the research closer to the patient
- Facilities: costs to enable the piloting of new facilities or methodologies to support the scientific programmes
- Public engagement: part-time support (no more than one day a week) may be included to cover communications purposes
- No costs will be available for research training.
The nature of what will and will not be allowed in terms of resources for the full application could differ. Any changes will be confirmed when a full application is requested.
4. CVs: One-side CVs (A4) are required for the proposed Co-ordinator/Facilitator/Director and each of lead investigators linked with the Platform. The CV should briefly outline career details covering the last three positions, key grant income and up to 8 major relevant publications.
No further annexes will be allowed. This means that all other diagrams, tables etc (if needed) must be included within the body of the application.
Case for support
The case should be structured under the following headings:
Title |
The title of the proposed Platform. |
Summary of mission and objectives |
Vision and strategy for building the Platform with details of the funded cohort and other resources that will lie at the core. MRC Units are eligible to apply. |
Mission of the Platform |
Under this heading the EoI should describe: How the Platform will develop its approach How the Platform will meet the stated mission The key research themes underpinning the scientific strategy, including specified aims for the future Vision, strategy and objectives for the next five years. |
Importance |
Under this heading the EoI should explain how the Platform will differ from, or be complementary to, any similar national and international activities |
Scientific case |
Research plans People and track record Environment An early indication of the expected outputs/ outcomes/ metrics of success to be achieved by the Platform over five years. Scientific justification for resources that would be requested and how these would enhance the outputs of the Platform. |
The scientific case will be the longest section of the EoI. Emphasis should be placed on how the proposed Platform will build on existing capability to become the basis for leading-edge dementias research. The case should also explain how the research activities associated with the Platform are expected to evolve over the five years of any award, and how this will be achieved.
Details of key scientific partnerships, from both inside and outside academia (e.g industry partners) should be provided.
For information, note that any full application invited will require the following details in addition to those specified within the EoI:
- Identification of any ethical issues arising from the involvement of people, human samples or personal data
- The ethical review and research governance arrangements that will apply to the work done
- A Data Management Plan
- Formal agreements with industry, depending on the nature of industry interaction/ collaboration.
Key dates
EoI should be structured as above and sent as a single, bookmarked, pdf document to: Catherine.Moody@headoffice.mrc.ac.uk
The deadline for receipt of EoI is 18.00h on Wednesday 20th March 2013.
Note that submission of an EoI is mandatory for progression to the invited full application stage
The reminder of the call timeline is as follows
Provisional date for decisions on EoI: 8 May 2013
Provisional deadline for full proposals which will be by invitation only: 1 July 2013
Provisional date for final funding decision: Q3/Q4 2013
Provisional start date for award: Q1 2014
Contact
For any scientific queries please contact Dr Catherine Moody:
Catherine.Moody@headoffice.mrc.ac.uk or 020 7395 2231