Edinburgh Trials Methodology Hub
Lead Research Organisation:
University of Edinburgh
Department Name: School of Clinical Sciences
Abstract
When a new drug is being developed it passes through several stages of development. After the initial preclinical development, first in man studies evaluate the safety and potential side effects. Then explanatory studies optimise the treatment, for example in terms of which patients have the greatest potential to benefit and what dose to use. Such studies look at underlying disease mechanisms, and test whether an intervention has the potential to be useful in practice. Then pragmatic studies test whether any potential benefit seen in the explanatory trials can be realised in clinical practice. For non-drug treatments the terminology is different, but the development path is similar.
There are many reasons why an intervention can fail as it progresses through the stages of development, and the aim of the Edinburgh Trials Methodology Hub is to undertake a programme of research which will help to increase the chances of success at each step of the development process. We shall attempt to learn lessons both from successful development programmes and also from others which have failed.
This will be achieved by encouraging interdisciplinary cllaboration between the scientists who are working on understanding underlying disease mechanisms and those with experience in clinical trials methodology. The end results will be to improve the design and analysis of future clinical trials, and to provide researchers with trials support and access to genetic and imaging technologies to identify patient subgroups with the greatest potential to benefit within ongoing trials.
There are many reasons why an intervention can fail as it progresses through the stages of development, and the aim of the Edinburgh Trials Methodology Hub is to undertake a programme of research which will help to increase the chances of success at each step of the development process. We shall attempt to learn lessons both from successful development programmes and also from others which have failed.
This will be achieved by encouraging interdisciplinary cllaboration between the scientists who are working on understanding underlying disease mechanisms and those with experience in clinical trials methodology. The end results will be to improve the design and analysis of future clinical trials, and to provide researchers with trials support and access to genetic and imaging technologies to identify patient subgroups with the greatest potential to benefit within ongoing trials.
Technical Summary
Our vision is to deliver more effective translation of novel scientific ideas and discoveries (both drug and non-drug) into innovative clinical practice. A major challenge in clinical medicine is to identify therapeutic interventions that can be targeted to the correct patient at the right time to substantially improve disease outcomes. Traditionally, clinical trial design has focussed on delivering a standardised intervention on a large scale to patients with a specific clinical presentation which may actually have several different underlying causes, in terms of pathophysiology. This approach has been successful to an extent, but often these interventions have modest effects for the individual patient. Ideally therefore, one would wish to develop biomarkers which can be used in clinical practice to predict which patients will have the greatest response to an intervention, whilst excluding those who are likely to respond poorly or not at all. The vision of the Edinburgh Clinical Trials Methodology Hub will be to develop technologies to achieve this aim, by exploiting knowledge gained from animal models; by developing grid based networks for image analysis and processing; by exploiting access to genomic technologies and by developing a facility for secondary analysis of existing data to develop and validate prognostic models. The end result will be to improve the design of future clinical trials and to provide researchers access to imaging and genetic technologies to identify patient subgroups who respond best within ongoing trials.
In parallel with the planned methodological developments, the Edinburgh Hub will develop a training programme which combines elements of existing programmes in translational medicine, molecular medicine and public health sciences to develop the next generation of trialists and methodologists.
In parallel with the planned methodological developments, the Edinburgh Hub will develop a training programme which combines elements of existing programmes in translational medicine, molecular medicine and public health sciences to develop the next generation of trialists and methodologists.
Publications
Hall AS
(2009)
A randomized, controlled trial of simvastatin versus rosuvastatin in patients with acute myocardial infarction: the Secondary Prevention of Acute Coronary Events--Reduction of Cholesterol to Key European Targets Trial.
in European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology
CLOTS Trials Collaboration
(2009)
Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial.
in Lancet (London, England)
Deary IJ
(2009)
Intelligence and persisting with medication for two years: Analysis in a randomised controlled trial.
in Intelligence
Stone J
(2009)
Symptoms 'unexplained by organic disease' in 1144 new neurology out-patients: how often does the diagnosis change at follow-up?
in Brain : a journal of neurology
Bates TC
(2009)
Association of KIBRA and memory.
in Neuroscience letters
Marioni RE
(2009)
Peripheral levels of fibrinogen, C-reactive protein, and plasma viscosity predict future cognitive decline in individuals without dementia.
in Psychosomatic medicine
Roozenbeek B
(2009)
The influence of enrollment criteria on recruitment and outcome distribution in traumatic brain injury studies: results from the impact study.
in Journal of neurotrauma
Hodges L
(2009)
Patient and general practitioner preferences for the treatment of depression in patients with cancer: how, who, and where?
in Journal of psychosomatic research
Brazzelli M
(2009)
No evidence of bias in the process of publication of diagnostic accuracy studies in stroke submitted as abstracts.
in Journal of clinical epidemiology
Whiteley W
(2009)
Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6.
in PLoS medicine
Bolton JL
(2010)
Association between polymorphisms of the dopamine receptor D2 and catechol-o-methyl transferase genes and cognitive function.
in Behavior genetics
Flynn RW
(2010)
Automated data capture from free-text radiology reports to enhance accuracy of hospital inpatient stroke codes.
in Pharmacoepidemiology and drug safety
Walker J
(2010)
Screening for suicidality in cancer patients using Item 9 of the nine-item patient health questionnaire; does the item score predict who requires further assessment?
in General hospital psychiatry
Lingsma HF
(2010)
Early prognosis in traumatic brain injury: from prophecies to predictions.
in The Lancet. Neurology
Chung PY
(2010)
Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone.
in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Walker J
(2010)
The HSCL-20: one questionnaire, two versions.
in Journal of psychosomatic research
Sandset EC
(2010)
Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and placebo-controlled clinical trial (NCT00120003).
in International journal of stroke : official journal of the International Stroke Society
Sharpe M
(2010)
Neurology out-patients with symptoms unexplained by disease: illness beliefs and financial benefits predict 1-year outcome.
in Psychological medicine
Rashid S
(2010)
The effects of uterine artery embolisation and surgical treatment on ovarian function in women with uterine fibroids.
in BJOG : an international journal of obstetrics and gynaecology
Rhatigan E
(2010)
Scoring system to identify patients at high risk of oesophageal cancer.
in The British journal of surgery
Maas AI
(2010)
IMPACT recommendations for improving the design and analysis of clinical trials in moderate to severe traumatic brain injury.
in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
McHugh GS
(2010)
A simulation study evaluating approaches to the analysis of ordinal outcome data in randomized controlled trials in traumatic brain injury: results from the IMPACT Project.
in Clinical trials (London, England)
Marioni RE
(2010)
Blood rheology and cognition in the Edinburgh Type 2 Diabetes Study.
in Age and ageing
Marioni RE
(2010)
Genetic variants associated with altered plasma levels of C-reactive protein are not associated with late-life cognitive ability in four Scottish samples.
in Behavior genetics
Vesterinen HM
(2010)
Improving the translational hit of experimental treatments in multiple sclerosis.
in Multiple sclerosis (Houndmills, Basingstoke, England)
O'Connor M
(2010)
Measuring improvement in depression in cancer patients: a 50% drop on the self-rated SCL-20 compared with a diagnostic interview.
in General hospital psychiatry
Walsh TS
(2010)
Prevalence, management, and outcomes of critically ill patients with prothrombin time prolongation in United Kingdom intensive care units.
in Critical care medicine
CLOTS (Clots In Legs Or STockings After Stroke) Trial Collaboration
(2010)
Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial.
in Annals of internal medicine
Flynn RW
(2010)
Systematic review of observational research studying the long-term use of antithrombotic medicines following intracerebral hemorrhage.
in Cardiovascular therapeutics
Van Der Worp HB
(2010)
Can animal models of disease reliably inform human studies?
in PLoS medicine
Sena ES
(2010)
Publication bias in reports of animal stroke studies leads to major overstatement of efficacy.
in PLoS biology
Marioni RE
(2010)
Associations between polymorphisms in five inflammation-related genes and cognitive ability in older persons.
in Genes, brain, and behavior
Kleiboer A
(2010)
Monitoring symptoms at home: what methods would cancer patients be comfortable using?
in Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation
Sena ES
(2010)
Factors affecting the apparent efficacy and safety of tissue plasminogen activator in thrombotic occlusion models of stroke: systematic review and meta-analysis.
in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Flynn RW
(2010)
Prescribing antiplatelet medicine and subsequent events after intracerebral hemorrhage.
in Stroke
Bembenek J
(2010)
How many patients might receive thrombolytic therapy in the light of the ECASS-3 and IST-3 data?
in International journal of stroke : official journal of the International Stroke Society
Stone J
(2010)
Who is referred to neurology clinics?--the diagnoses made in 3781 new patients.
in Clinical neurology and neurosurgery
Flynn RW
(2010)
The Tayside Stroke Cohort: exploiting advanced regional medical informatics to create a region-wide database for studying the pharmacoepidemiology of stroke.
in Pharmacoepidemiology and drug safety
Roberts CL
(2011)
Population-based trends in pregnancy hypertension and pre-eclampsia: an international comparative study.
in BMJ open
Niewada M
(2011)
Planning trials in older patients with stroke: data from the International Stroke Trial.
in Age and ageing
Laird BJA
(2011)
Cancer pain and its relationship to systemic inflammation: an exploratory study.
in Pain
Hartings JA
(2011)
Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study.
in The Lancet. Neurology
Braganza G
(2011)
Effects of short-term treatment with atorvastatin in smokers with asthma--a randomized controlled trial.
in BMC pulmonary medicine
Dennis M
(2011)
The timing, extent, progression and regression of deep vein thrombosis in immobile stroke patients: observational data from the CLOTS multicenter randomized trials.
in Journal of thrombosis and haemostasis : JTH
| Description | Arthritis Research UK |
| Amount | £756,791 (GBP) |
| Organisation | Versus Arthritis |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2010 |
| End | 06/2013 |
| Description | Arthritis Research UK |
| Amount | £723,692 (GBP) |
| Funding ID | 19403 |
| Organisation | Versus Arthritis |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2010 |
| End | 02/2016 |
| Description | CSO funding Health Services Research |
| Amount | £224,999 (GBP) |
| Organisation | Chief Scientist Office |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2011 |
| End | 03/2013 |
| Description | CSO funding Health Sevices Research |
| Amount | £400,000 (GBP) |
| Organisation | Chief Scientist Office |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2010 |
| End | 04/2012 |
| Description | Chief Scientist Office (CSO) |
| Amount | £47,030 (GBP) |
| Organisation | Chief Scientist Office |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | EME Programme |
| Amount | £3,070,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2012 |
| End | 06/2014 |
| Description | HTA Programme |
| Amount | £2,140,000 (GBP) |
| Funding ID | 11/01/1930 |
| Organisation | National Institute for Health Research |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2012 |
| End | 05/2017 |
| Description | MRC Clinician Scientist Fellowship |
| Amount | £834,329 (GBP) |
| Funding ID | G0902303/95197 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2010 |
| End | 09/2015 |
| Description | MRC Efficacy and Mechanism Evaluation Programme (EME) |
| Amount | £1,000,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2010 |
| End | 06/2014 |
| Description | MRC Methodology Research Panel |
| Amount | £120,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2010 |
| End | 06/2012 |
| Description | MRC NIHR |
| Amount | £1,369,437 (GBP) |
| Organisation | National Institute for Health Research |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2011 |
| End | 04/2016 |
| Description | Medical Research Council Clinician Scientist Fellowship |
| Amount | £834,329 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2010 |
| End | 09/2015 |
| Description | NIHR HTA |
| Amount | £485,908 (GBP) |
| Organisation | National Institute for Health Research |
| Department | Health Technology Assessment Programme (HTA) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2011 |
| End | 08/2013 |
| Description | NIHR HTA |
| Amount | £2,940,842 (GBP) |
| Organisation | National Institute for Health Research |
| Department | Health Technology Assessment Programme (HTA) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | Project Grant |
| Amount | £1,340,000 (GBP) |
| Funding ID | SP/12/2/29422 |
| Organisation | British Heart Foundation (BHF) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2013 |
| End | 05/2018 |
| Title | Ordinal Analysis of Clinical Trial Outcomes |
| Description | A number of methodological studies, now supported by relevant publications, have demonstrated the strengths and limitations of ordinal analysis in clinical trials of head injury and stroke. |
| Type Of Material | Data analysis technique |
| Year Produced | 2009 |
| Provided To Others? | Yes |
| Impact | An ordinal approach has been adopted as the primary analytical approach in a number of on-going clinical trials. |
| Description | Edinburgh Clinical Trials Unit |
| Organisation | University of Edinburgh |
| Department | Edinburgh Clinical Trials Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The senior statisticians with the Hub work closely with the Trials Unit, giving statistical input for trial protocols and grant applications. |
| Collaborator Contribution | The collaboration has been a source of research questions for the Merthodology Hub and given the opportunity to evaluate and promote methodological developments emerging from the Methodology Hub. |
| Impact | The principal outputs to date have been grant applications for clinical trials which have been funded - including awards through MRC EME, Arthritis Research UK, and CSO. |
| Start Year | 2009 |
| Description | Scottish Mental Health Research Network |
| Organisation | Scottish Mental Health Research Network (SMHRN) |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | Hub statisticians are involved in giving statistical advice to researchers via the SMHRN's Protocol Development Groups. |
| Collaborator Contribution | The protocols developed via the SMHRN provide a source of methodological research problemsand also a testbed for methodological innovations. |
| Impact | The outputs to date have been grant applications being worked up for submission. |
| Start Year | 2009 |
| Description | Scottish eHealth Informatics Research Centre |
| Organisation | Scottish School of Primary Care |
| Department | Scottish eHealth Informatics Research Centre |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | This is at a very early stage, with the eHIRC just having been funded. |
| Collaborator Contribution | Sheikh is a grant holder for the eHIRC. The grant application to extend the Hub funding beyond 2013 has eHealth as a major research theme. |
| Impact | It is too early for this collaboration to have produced outputs |
| Start Year | 2012 |