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Mechanistic studies, explanation and examples



MRC-NIHR funding collaboration

EME encourages hypothesis-testing mechanistic studies. These studies can 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 process.

We will fund hypothesis driven studies that can be tested using sample analysis, images, or other data. Commonly these mechanistic studies use the difference between treatment groups in a randomised clinical trial to explore the mechanism of action of the treatment, but we welcome other designs involving interventions used with therapeutic intent in patients.

It is important that applicants have a clear hypothesis about the mechanisms under study, and can demonstrate how the proposed tests or data analysis will confirm or refute the hypothesis. The rationale for the hypothesis will need to be justified to persuade the Funding Committee that there is sufficient grounds to fund the research.

In addition, the application must evidence how:

  • The proposed study would add to the existing body of knowledge
  • The proposed costs of the research are reasonable and commensurate with the proposed work involved. It is expected that applications to the Mechanisms of Action of Health Intervention call would typically be under £350K    
  • The study design will answer the research question proposed
  • The proposed study is feasible and deliverable
  • The team has the necessary skill mix and experience and project management of the study is sound
  • The proposed mechanistic evaluation will not undermine the delivery of the underlying efficacy or effectiveness trial (if it is still ongoing)

In general, where the investigation primarily aims to identify mechanisms of pathophysiology or disease, or to demonstrate proof-of-concept evidence of the validity and importance of new discoveries or treatments this would fall under the remit of the Medical Research Council (MRC) schemes for funding. Where the investigation aims to identify mechanisms of an intervention for which there are existing proof of concept or efficacy data, this would fall under the remit of the EME scheme for funding.

We will not fund exploratory analyses of samples or data to seek out previously unknown analytes or unexpected associations with outcomes. Examples of exploratory analyses that EME would be unlikely to fund are “biomarker discovery”, “proteomics”, “peptidomics”, “genome-wide association studies”, and similar strategies. EME may fund collection, processing and storage of samples from patients for the duration of an RCT or other NIHR-funded study testing a therapeutic intervention in patients, for future hypothesis driven analyses where these samples represent a unique collection that would otherwise not be available. In keeping with principles of open access, we would expect samples to be made available for use for other investigators, and would expect to see an initial plan for sample sharing to be submitted alongside any proposal.

We do not fund any research involving animals or animal tissues.

How we support mechanistic studies

We support mechanistic studies in three ways:

  1. We fund mechanistic studies integrated within a main efficacy study (see studies EME 08/43/03EME 13/50/17 and others as examples).
  2. We also support mechanistic studies that use samples or data from eligible on-going or completed RCTs or other studies that are funded by the NIHR testing a therapeutic intervention in patients (see study EME 14/205/01 below for an example)
  3. In addition, the remit has expanded to also include mechanistic studies using patients and samples collected from non-NIHR funded projects, for example, from MRC, Wellcome Trust, equivalent funding from the Devolved Administrations, and major charities that include external review processes if recruitment has been completed.

Applications for stand-alone mechanistic studies using samples or data are submitted in a two-stage application process. Please see the relevant commissioning brief for further information.

We will potentially fund mechanistic studies regardless of whether the result from the completed clinical study has shown benefit, no difference or harm.

Examples of EME funded studies with mechanistic components

Studies where determinants of the treatment response are investigated

An investigator studied the clinical effectiveness of intermittent parent-determined montelukast as a treatment in pre-school wheezing children. The amount of enzyme that determines the production of the target molecule for montelukast varies with different genotypes of the promoter gene. The investigator designed a study that investigated the effect of intermittent parent-determined montelukast treatment on pre-school wheeze, whilst simultaneously determining if the treatment effect was modified by the child’s genotype. (EME 08/43/03)

A team of researchers are studying the efficacy of an IL-1 receptor antagonist in pustular psoriasis. It is possible that patients with pustular psoriasis have a deficiency in interleukin-36 receptor antagonist (IL36RA) leading to unrestrained IL-36 signalling and increased IL-1 production. The investigators will investigate the abnormal IL-1 signalling caused by IL-36 and other gene mutations to determine if they predict response to IL-1 receptor blockade. (EME 13/50/17)

Studies where the mechanism by which a treatment works is investigated

A study is using standard clinical pain assessment tools to test whether morphine provides analgesia and increased physiological stability during retinopathy of prematurity screening in neonates. In addition to standard clinical pain assessment the investigators are using recently developed electrophysiological techniques to examine the effects of morphine on the underlying brain and spinal cord activity evoked by the painful procedures, to determine how nociceptive information is transmitted to and processed by the cortex and where morphine interacts with this pathway. (EME 14/187/01)

In a study of ulipristal acetate against a levonorgestrel-releasing intra-uterine system (Mirena) for the long-term treatment of heavy menstrual bleeding a sub-set of patients will undergo imaging of the uterus using high resolution MRI of the uterine matrix and fibroids and Dynamic Contrast Enhanced MRI to measure uterine perfusion. This will determine if ulipristal influences menstrual bleeding via a reduction in uterine blood flow. (EME 12/206/52)

Studies using data or samples from other NIHR-funded trials

Intravenous tranexamic acid may reduce the severity of traumatic brain injury by reducing the severity of intracranial bleeding. It is also possible that tranexamic acid has a direct anti-inflammatory action on the brain which may also be beneficial in patients with a brain injury. An investigator is using brain microdialysis techniques in a sub-set of patients recruited to the HTA-funded CRASH-3 study to determine whether markers of brain inflammation are changed by tranexamic acid and whether this is related to outcome. (EME 14/205/01)

An EME-funded study aims to understand the mechanisms of change in group-based weight loss and related behaviour change interventions. The investigators are using recordings of group sessions from two randomised controlled trials and a feasibility study, all NIHR funded. Qualitative research methods are being used to extract target features at group level and then determine if they are associated with successful weight loss. (EME 14/202/03)

Examples of mechanistic components that would be outside EME’s remit

An investigator proposes testing a new intervention to treat exacerbations of refractory asthma with a control group treated according to standard BTS guidelines. She proposes collecting urine specimens at randomisation on all patients. Using physicochemical protein capture and high-performance liquid chromatography with tandem mass spectrometry she proposes to characterise the urinary proteome and then look for as yet unknown differences between “responders” and “non-responders” to the new treatment. Any identified biomarkers might provide the basis for future stratified care.

Comment: there is no proposed mechanism or identified analyte. This is a “biomarker discovery” project. EME would consider funding the sample collection and storage but would not fund the analysis.

A researcher proposes a study of an on-line, self-administered cognitive behavioural therapy (CBT) programme against an attention control for patients with obsessional-compulsive disorder. He requests funding for functional MRI studies in all patients to confirm previous findings that, in patients with obsessional-compulsive disorder, there is an abnormality of fMRI-determined amygdala activation to human face images.

Comment: there is no hypothesis that relates to the intervention under study, the researcher is requesting funding to study the whole cohort to confirm previous studies in this disease.

A very large effectiveness study funded by the NIHR is looking at an agent that may reduce the number of patients who develop metastatic deposits of colonic adenocarcinoma after primary resection. The agent may work via a mechanism involving endothelial cell surface antigens. A researcher proposes an add-on mechanistic study. This involves measuring the expression of these markers in venous biopsies in both groups to see how the treatment changes the surface markers of interest, and parallel work involving in vitro studies on endothelial cell cultures from an immortalised cell line.

Comment: the venous biopsy component would be within EME’s remit as it examines one possible mechanism of action of the treatment. Parallel laboratory studies not involving patient material or data are out of remit.

An investigator proposed a study of a structured exercise regimen for rehabilitation of patients with lung cancer treated with pulmonary resection. The control group was “care as usual”. She proposed a mechanistic study that included measures of muscle strength, maximal oxygen consumption during exercise (VO2max) and ultrasound-determined quadriceps mass.

Comment: the mechanistic component in this study would simply confirm the intervention had the expected effect on measures of physical fitness and does not explore novel mechanisms.