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
Niewada M
(2011)
Planning trials in older patients with stroke: data from the International Stroke Trial.
in Age and ageing
Marioni RE
(2010)
Blood rheology and cognition in the Edinburgh Type 2 Diabetes Study.
in Age and ageing
Fox K
(2013)
Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart failure.
in American heart journal
Lone NI
(2016)
Five-Year Mortality and Hospital Costs Associated with Surviving Intensive Care.
in American journal of respiratory and 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
Walker J
(2013)
Prevalence of depression in adults with cancer: a systematic review
in Annals of Oncology
Evangelou E
(2014)
A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.
in Annals of the rheumatic diseases
Bolton JL
(2010)
Association between polymorphisms of the dopamine receptor D2 and catechol-o-methyl transferase genes and cognitive function.
in Behavior genetics
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
Marioni RE
(2011)
Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts.
in Behavior genetics
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
Moss JG
(2011)
Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results.
in BJOG : an international journal of obstetrics and gynaecology
Tudur Smith C
(2015)
How should individual participant data (IPD) from publicly funded clinical trials be shared?
in BMC medicine
Thanacoody HK
(2013)
Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP).
in BMC pharmacology & toxicology
Braganza G
(2011)
Effects of short-term treatment with atorvastatin in smokers with asthma--a randomized controlled trial.
in BMC pulmonary medicine
Roberts CL
(2011)
Population-based trends in pregnancy hypertension and pre-eclampsia: an international comparative study.
in BMJ open
Chiswick CA
(2015)
Efficacy of metformin in pregnant obese women: a randomised controlled trial.
in BMJ open
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
Stephen J
(2014)
Time dependence of biomarkers: non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer.
in British journal of cancer
Thekkumpurath P
(2011)
Screening for major depression in cancer outpatients: the diagnostic accuracy of the 9-item patient health questionnaire.
in Cancer
Ananthakrishnan G
(2013)
Randomized comparison of uterine artery embolization (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): subanalysis of 5-year MRI findings.
in Cardiovascular and interventional radiology
Flynn RW
(2010)
Systematic review of observational research studying the long-term use of antithrombotic medicines following intracerebral hemorrhage.
in Cardiovascular therapeutics
Sandercock P
(2011)
The authors say: 'The data are not so robust because of heterogeneity' - so, how should I deal with this systematic review? Meta-analysis and the clinician.
in Cerebrovascular diseases (Basel, Switzerland)
Whiteley W
(2011)
Blood biomarkers for the diagnosis of acute cerebrovascular diseases: a prospective cohort study.
in Cerebrovascular diseases (Basel, Switzerland)
Flynn RW
(2012)
Persistence, adherence and outcomes with antiplatelet regimens following cerebral infarction in the Tayside Stroke Cohort.
in Cerebrovascular diseases (Basel, Switzerland)
Salvilla SA
(2013)
Disease-specific health-related quality of life (HRQL) instruments for food allergy: protocol for a systematic review.
in Clinical and translational allergy
Stone J
(2010)
Who is referred to neurology clinics?--the diagnoses made in 3781 new patients.
in Clinical neurology and neurosurgery
Coupar F
(2011)
Predictors of upper limb recovery after stroke: a systematic review and meta-analysis
in Clinical Rehabilitation
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)
Roozenbeek B
(2011)
The added value of ordinal analysis in clinical trials: an example in traumatic brain injury.
in Critical care (London, England)
Lone NI
(2013)
Surviving intensive care: a systematic review of healthcare resource use after hospital discharge*.
in Critical care medicine
Roozenbeek B
(2012)
Prediction of outcome after moderate and severe traumatic brain injury: external validation of the International Mission on Prognosis and Analysis of Clinical Trials (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models.
in Critical care medicine
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
Walsh T
(2013)
Restrictive Versus Liberal Transfusion Strategies for Older Mechanically Ventilated Critically Ill Patients A Randomized Pilot Trial*
in Critical Care Medicine
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
Fowkes F
(2013)
Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events
in European Journal of Preventive Cardiology
Combadière C
(2013)
Comment on "Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration" by Luhmann et al. (Exp. Eye Res. 2013; 107: 80.doi: 10.1016)
in Experimental Eye Research
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
| 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 |