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EME 19/139 Mitigation of the adverse effects of health and social care interventions

 

Contents

Efficacy and Mechanism Evaluation Programme

19/139 Mitigation of the adverse effects of health and social care interventions

Closing date: 1:00pm, 16 April 2020 (two stage – Stage 1 to Stage 2)

Stage 1 applications submitted to the Mitigation of the adverse effects of health and social care interventions call close on the 16th April 2020 assessed as in remit and competitive will be considered for shortlisting at the EME Funding Committee meeting in June 2020. If shortlisted, applicants will be invited to submit a Stage 2 application for consideration at the EME Funding Committee meeting in October 2020. We anticipate informing applicants of the outcome within a month of the meeting and that contracts will be signed within approximately 9 months after the date of the outcome letter, although this is project dependent.  

Applications are sought for research to evaluate interventions for the avoidance, management or amelioration of adverse effects experienced in the implementation of established health and social care interventions. Adverse effects associated with all types of intervention within the NHS and social care services, including adverse drug reactions, adverse surgical events and adverse effects of medical testing procedures are included within the remit of this call.

Areas of interest include, but are not limited to:

  • Novel interventions to reduce adverse effects (e.g. to stop misprescribing)
  • Novel interventions to identify patients at increased risk of adverse effects
  • Studies to stratify patients to an established treatment that has very severe adverse effects
  • Development of health technologies which promise an improved safety profile.
  • Additive interventions which may improve the safety profile of existing technologies
  • Pharmacogenomic strategies to mitigate the risks of exaggerated or diminished drug responses.

In circumstances where the proposed intervention(s) is likely to have an economic impact on NHS or Social Care services, consideration may be given to collecting cost data in order to support future economic analysis.

Further information on the remit and focus of this call is given further down the page on this document.

Applicants are encouraged to consider opportunities to embed the testing of mechanistic hypotheses within the main study. Also of interest are standalone studies of the mechanisms underpinning adverse effects associated with interventions (investigational or control) used in existing CSO- and NIHR-funded trials, although applications in this area should refer to the EME Mechanisms of Action of Healthcare Interventions call.

Applications are expected to set out programmes of work which may contain distinct stages. It is expected that the initial stages of the study will, if successful, lead onto a full evaluative clinical study or trial, which is in the remit of the EME Programme. This study must also be included and clearly specified within the application. Clinical trials embedded within the programme of work must be large enough to detect a meaningful effect.

Applications to this call may include initial stages such as:

  • The limited steps needed to progress the development of an intervention to a stage suitable for use in an accredited clinical service;
  • Prospective clinical work or retrospective research utilising existing big data or clinical samples to inform the main study;
  • Pilot or feasibility studies.

As a rough guide it is expected that these initial stages will be complete within the first 18 months of the project and must not contribute more than 25% to the total cost or duration of the project.

Applicants will need to make a strong case for the future importance of the intervention through providing a measurable positive impact on health, innovation or future wealth creation and for the ultimate benefit of individual patients’ or the wider NHS. Applicants should read the details of the EME remit at https://www.nihr.ac.uk/eme

Supporting information

For the purpose of this call, an ‘adverse effect’ is considered to be any undesired harmful effect resulting from the delivery of an established, licenced healthcare intervention, including (but not limited to) pharmaceuticals, medical tests and surgical procedures.

Examples of research that might be within remit for EME under this scope include:

  1. Scientifically novel interventions as a replacement for or adjunct to treatments associated with SAE, where the investigational technology is likely to decrease risk to patients, e.g:
  • NCT03381989 – A novel surgical technique (laceration of the aortic valve leaflet) in patients at high risk of coronary artery obstruction during transcatheter aortic valve replacement. (Active, USA)
  • NCT03528564 – A phase 2 trial of erythropoietin in addition to perioperative iron, for the prevention of SAE in patients with iron-restrictive anaemia undergoing total knee or hip arthroplasty. (Active, Canada)
  1. Novel or repurposed interventions for the amelioration of SAE/side effects for licensed interventions, e.g:
  • NCT03581773 – A phase 2 trial folic acid to treat mucositis in patients receiving targeted therapy for metastatic renal cell carcinoma. (Active, Denmark)
  • NCT03111810 – Placebo-controlled trial of targeting iatrogenic Cushing's Syndrome with novel 11β-hydroxysteroid dehydrogenase type 1 Inhibition (AZD4017). (Active, UK)
  1. Novel interventions and medical tests to assist clinical decision making, thereby decreasing the risk of adverse events. e.g:
  • EME Project 11/100/78: Evaluating an experimental diagnostic approach to better determine which stroke patients are clinically eligible for thrombolytic treatment, to improve treatment rates (previous restricted by the risk of SAE).
  1. Evaluating mechanistic hypotheses underpinning SAE associated with investigational interventions, where insights may ultimately improve healthcare, e.g:
  • Association of genotypic variation with increased risk of ADR, as in previous work demonstrating: altered metabolism of warfarin, leading to gene-based dosing[1]; excessive immune reactions to medicines such as terbinafine, fenofibrate and ticlopidine, resulting in liver damage[2]

Early-phase studies focussed on the safety profile of novel technologies are not within remit for EME and may be better suited to earlier funding programmes, such as the MRC Developmental Pathway Funding Scheme (DPFS).

Novel approaches to reduce adverse effects caused by preventable medical errors are likely to focus on processes around healthcare delivery, rather than employing scientifically novel mechanisms and would not be within remit for EME (more relevant to the HS&DR programme).

Late-phase superiority/non-inferiority trial designs, systematic reviews and analysing routine data for drugs already known to be efficacious will often take account of adverse effects, however they would not be within remit for EME (more relevant to the HTA programme). However, insights into the mechanisms underpinning adverse effects for these interventions may be valuable.

Important information for applicants

Programme remit

The EME Programme funds ambitious studies evaluating interventions that have the potential to make a step-change in the promotion of health, treatment of disease and improvement of rehabilitation or long-term care. Within these studies EME supports research to improve the understanding of the mechanisms of both diseases and treatments.

The programme supports translational research evaluating a wide range of novel or re-purposed interventions. The interventions may include diagnostic or prognostic tests and decision-making tools, drugs or biological compounds, psychological treatments, medical devices, and public health initiatives delivered within the NHS. 

The EME Programme primarily supports clinical trials, and other robustly designed studies that test the efficacy of interventions. The interventions should have the potential to improve patient care or benefit the public.  The programme will only support studies where there is sufficient evidence that the intervention might work in man, i.e. that there is proof of concept

Innovative study designs involving stratification, the use of routinely collected digital data or novel methodologies are strongly encouraged.

Where appropriate, the programme encourages hypothesis-testing mechanistic studies integrated within the main efficacy study.  These studies could explore the mechanisms of action of the intervention, the causes of differing responses, or promote an understanding of any potential adverse effects and how these could be reduced; they could also contribute to understanding of the disease. The programme will also support mechanistic studies that follow on from on-going or completed clinical studies funded by the NIHR which can use data or samples from these studies.

The programme will accept applications for studies that use clinical or well-validated surrogate outcomes.  It will also consider studies that validate potential surrogate outcomes against a primary clinical outcome, within the main clinical trial. 

The EME programme WILL support:

  • Research to determine proof of clinical efficacy, size of effect, and long-term safety in a well-defined population.
  • The evaluation of a broad range of interventions that have the potential to maintain health, treat disease or improve recovery.
  • Hypothesis-testing research based on an efficacy study, to explore the mechanisms of action of interventions, causes of differing responses or disease mechanisms.  These studies use data or samples obtained and stored from both treatment and control groups of a clinical study, to arrive at conclusions that would not arise from a simple cohort study.
  • Proposals that include a series of linked stages (usually 2 to 3) with progression to the main clinical evaluation dependent on the outcome of the previous stage(s).  The criteria for progression must be clearly defined.  The main clinical evaluation should require more than 75% of the total project costs and commence within 18 months of the project start date.
  • Pilot and feasibility studies where the main study would be within the remit of the EME programme. These studies may be either stand-alone or can be the initial part of a staged project that includes the main clinical evaluation as a subsequent stage.
  • The limited steps needed to progress the development of an intervention to a stage suitable for use in an accredited clinical service when included as an initial stage prior to commencing the main clinical evaluation.
  • Studies using novel or infrequently-used study designs that increase the value of a study, by maximising the chances of demonstrating the benefit of an intervention, increasing the knowledge that can be gained through the study, or by making the study more efficient.
  • The EME Programme welcomes studies adopting novel and efficient study designs or that include the development or testing of new methodologies in an embedded methodological study (EMS). Where delivery of the EMS is integral to the main efficacy trial the additional costs should be modest and the purpose should be to explore issues that may potentially increase the efficiency of trials and value for money. The proposed work should be included in the EME application. Where the EMS requires more substantial funding and can be delivered independently from the running of the main trial, then applicants might wish to consider applying to the MRC-NIHR Methodology Research Programme (MRP). http://www.mrc.ac.uk/funding/browse/methodology-research-programme/ Any such application would be independent of the application to the EME Programme. For more information please contact the MRP programme: MRPGrants@headoffice.mrc.ac.uk

The EME Programme WILL NOT support:

  • Large effectiveness studies that test the impact of the introduction of an intervention in the wider NHS.
  • Hypothesis-generating studies based on sample or data collections from patient cohorts.
  • Confirmatory studies, equivalence studies, 'confidence in effect' studies or studies of incremental modifications to existing interventions.
  • Research into areas where the health need is primarily outside the UK.
  • Any research involving animals or animal tissues (see the NIHR research page for more information).

Guidance on applications

Applicant eligibility

Researchers in England, Northern Ireland, Scotland and Wales are eligible to apply for funding under this Programme. Anyone who considers that they can carry out high-quality research is likely to be eligible. If you have any concerns regarding your eligibility to apply we advise that you contact us before completing an application. We welcome applications from all sectors and recommend that lead applicants from Industry contact the EME office prior to submitting an application.

Studies funded by the EME Programme are generally UK based. We will consider funding an international study where the chief investigator and lead institution are based in the UK and the study is relevant to and a priority for the UK population, and where overseas recruitment is funded from other sources. It will be exceptional for NIHR programmes to fund recruitment overseas. The EME Programme is open to bids to support a UK recruitment arm of an international study where the study is relevant to and a priority for the UK population; a UK based principal investigator should be the lead applicant. Each project will be considered on a case by case basis and applicants interested in submitting a proposal for an international study should contact us for advice.

Collaboration and team expertise

Proposals should involve a multi-disciplinary team with appropriate skills and experience, including an appropriately experienced statistician on the study team. The involvement of an accredited Clinical Trials Unit (CTU) is strongly encouraged in the design of clinical trials. Where appropriate, applicants are expected to work with suitably accredited clinical research facilities.

Applications to this call should be in the form of a collaboration. All applications should include significant contributions from at least two of the following partners; industry, academia, and the NHS.  The EME Programme is particularly keen to encourage collaboration with small and medium enterprises.  The involvement of charities is also welcome, and if your research will be co-funded by a charity, you must notify the EME Programme. 

The EME Programme welcomes applications proposing joint funding arrangements. You must clearly demonstrate how the arrangement would work in practice and be explicit about where responsibility lies contractually in terms of publication, and research governance issues for example. We expect that any other organisations contributing funding would provide an ‘open grant' and not require any terms, conditions or limitations on the research. The Programme would require assurance that the funding contribution would be guaranteed for the duration of the research, and a letter of intent should be included with the application. If your application is successful, you should note that the EME Programme will require sight of the agreement between you and any other funding partners before any contract is issued.

Where your research proposal involves industry collaboration, you should ensure that the arrangements and details are determined early in the study development. The EME Programme will require assurance that any industry collaboration allows transparency in the project design and in the analysis and publication of results (including if these are negative).   If the collaboration involves the supply of reagents, drugs or other technologies, we will require written assurances that the industry collaborator will provide these products for the duration of the study.

Timescales and funding

There are no fixed limits on the duration of projects and proposals should be tailored to fully address the questions posed. Applicants should be aware that they are competing for limited funds and proposals should represent good value for money. All funding requested should be clearly justified, but there is no upper limit.

Public involvement

The EME Programme expects patient and public involvement in study design, implementation and dissemination of results.  Applications must demonstrate how patients or members of the public have been involved in the study design and how they will be involved in the conduct and management of the trial.  Patient, public or carer representation is required on management and steering committees. Comments from public and patient reviewers will be obtained during peer review and at the EME Board.  For further guidance please see the EME website.

Project management and monitoring of studies

Where appropriate, projects funded through this call may be organised into distinct stages (usually up to three). At the end of each stage there should be clearly delineated go/no-go decision points with measurable criteria which will allow an assessment of whether the stage has completed successfully. The purpose of this delineation is to clearly identify critical points that determine whether the research should proceed to the next stage. It is anticipated that there will be a significant number of projects that will fail to meet criteria in the early stages. The EME Programme retains the right to reassess project progress in light of other new developments in the research area before subsequent stages of funding are released.

For all projects it is expected that there will be a number of milestones which will allow the project team and EME Programme to track progress through routine project reporting. Applicants will need to demonstrate a clear management plan for all stages of the project as well as detailed plans for how they will actively manage individual stages.

Where appropriate, projects funded through this call should be organised into distinct stages (usually up to three). At the end of each stage there should be clearly delineated go/no-go decision points with measurable criteria which will allow an assessment of whether the stage has completed successfully. The purpose of this delineation is to clearly identify critical points that determine whether the research should proceed to the next stage.  It is anticipated that there will be a significant number of projects that will fail to meet criteria in the early stages. The EME Programme retains the right to reassess project progress in light of other new developments in the research area before subsequent stages of funding are released.

Within each stage it is expected that there will be a number of milestones which will allow the project team and EME Programme to track progress through routine project reporting. Applicants will need to demonstrate a clear management plan for all stages of the project as well as detailed plans for how they will actively manage individual stages.

Research networks

The EME Programme expects that applicants will work, where appropriate, with the relevant NIHR Clinical Research Network..

Governance and regulation

Applicants should follow the Medical Research Council’s Good Clinical Practice guidelines in planning how studies, particularly RCTs, will be supervised.

Note that trials involving medicinal products must comply with ‘The Medicines for Human Use (Clinical Trials) Regulations 2004’. In the case of such trials, the NIHR expects the employing institution of the chief investigator to be nominated as the sponsor. Other institutions may wish to take on this responsibility or agree co-sponsorship with the employing institution. The NIHR is prepared to accept the nomination of multiple sponsors. Applicants who are asked to submit a full proposal will need to obtain confirmation of a sponsor(s) to complete their application. The NIHR reserves the right to withdraw from funding the project if they are not satisfied with the arrangements put in place to conduct the trial.

The MHRA (info@mhra.gsi.gov.uk) can provide guidance as to whether your trial would be covered by the regulations. The Clinical Trials Toolkit also contains the latest information about Clinical Trials regulations and a helpful FAQ page.

Application assessment process and criteria for assessment

For information about the Application Assessment Process and Criteria for Assessment, please see https://www.nihr.ac.uk/eme

Additional resources for applicants

For additional resources to support the development of your applications, please see https://www.nihr.ac.uk/eme

Making an application

If you wish to submit a stage 1 proposal please refer to the individual call.

Further information

Further information on applying to the EME Programme is available on the NIHR website. The EME team welcomes enquiries at eme@nihr.ac.uk  or 023 8059 4303.

In line with the government’s transparency agenda, any contract resulting from this tender may be published in its entirety to the general public.

 

[1] Pratt, V. et al. (2012 - ) Medical Genetics Summaries, Bethesda (MD)

[2] Nicoletti, P et al. (2017) Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology 152(5):1078-89