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
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
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
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
Gregson BA
(2012)
Update on the Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II): statistical analysis plan.
in Trials
Guest RV
(2012)
Application of Variable Life Adjusted Display (VLAD) to risk-adjusted mortality of esophagogastric cancer surgery.
in World journal of surgery
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
Harman NL
(2015)
Exploring the role and function of trial steering committees: results of an expert panel meeting.
in Trials
Harris B
(2012)
Systematic review of head cooling in adults after traumatic brain injury and stroke.
in Health technology assessment (Winchester, England)
Hartings JA
(2011)
Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study.
in The Lancet. Neurology
Higgins JP
(2013)
A tool to assess the quality of a meta-analysis.
in Research synthesis methods
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
Hopkins C
(2016)
UK publicly funded Clinical Trials Units supported a controlled access approach to share individual participant data but highlighted concerns.
in Journal of clinical epidemiology
Horne MA
(2016)
Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data.
in The Lancet. Neurology
Ilodigwe D
(2013)
Sliding dichotomy compared with fixed dichotomization of ordinal outcome scales in subarachnoid hemorrhage trials.
in Journal of neurosurgery
IST-3 Collaborative Group
(2013)
Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial.
in The Lancet. Neurology
IST-3 Collaborative Group
(2012)
The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.
in Lancet (London, England)
Kirkpatrick PJ
(2014)
Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial.
in The Lancet. Neurology
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
Lacroix J
(2015)
Age of transfused blood in critically ill adults.
in The New England journal of medicine
Laird BJ
(2011)
Characterization of cancer-induced bone pain: an exploratory study.
in Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
Laird BJ
(2011)
Pain, depression, and fatigue as a symptom cluster in advanced cancer.
in Journal of pain and symptom management
Laird BJA
(2011)
Cancer pain and its relationship to systemic inflammation: an exploratory study.
in Pain
Lane PW
(2013)
Methodological quality of meta-analyses: matched-pairs comparison over time and between industry-sponsored and academic-sponsored reports.
in Research synthesis methods
Legg LA
(2011)
Non-pharmacological interventions for caregivers of stroke survivors.
in The Cochrane database of systematic reviews
Lingsma HF
(2010)
Early prognosis in traumatic brain injury: from prophecies to predictions.
in The Lancet. Neurology
Lone NI
(2013)
Surviving intensive care: a systematic review of healthcare resource use after hospital discharge*.
in Critical care medicine
Lone NI
(2016)
Five-Year Mortality and Hospital Costs Associated with Surviving Intensive Care.
in American journal of respiratory and critical care medicine
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
Maas AI
(2013)
Advancing care for traumatic brain injury: findings from the IMPACT studies and perspectives on future research.
in The Lancet. Neurology
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
Marioni RE
(2009)
Peripheral levels of fibrinogen, C-reactive protein, and plasma viscosity predict future cognitive decline in individuals without dementia.
in Psychosomatic medicine
Marioni RE
(2011)
Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts.
in Behavior genetics
Marioni RE
(2010)
Associations between polymorphisms in five inflammation-related genes and cognitive ability in older persons.
in Genes, brain, and behavior
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)
McMillan TM
(2011)
Death after head injury: the 13 year outcome of a case control study.
in Journal of neurology, neurosurgery, and psychiatry
Mendelow AD
(2013)
Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial.
in Lancet (London, England)
Mendelow AD
(2011)
Surgical trial in lobar intracerebral haemorrhage (STICH II) protocol.
in Trials
| 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 |