The broad aim of this research is to improve clinical trials in neurodegenerative diseases (NDs). In particular, the clinical meaningfulness of the information gained, our understanding of treatments and diseases, and the chances of coming to the correct conclusions about treatment effectiveness. The programme focuses on the two commonest NDs: Alzheimer's disease (AD) and Parkinson's disease (PD).
This programme has four themes. The most important is outcome measurement from the perspective of patients and their carers, the second is around alternative ways of measuring disease progression (so-called surrogate measures, particularly scans and body fluid measures), the third is around using new ways of using statistics to model diseases and treatment effects, and finally we will bring everything together with the overarching theme of clinical trial design.
This programme will deliver recommendations about what measures should be used for treatment evaluation and monitoring of disease course in AD and PD. It will pilot new ways of using electronic NHS resources to monitor services and disease progression. It will develop models of disease progression that will facilitate better clinical trials and treatment targeting, and it will come up with recommendations around how we should be conducting clinical trials in the future.
Theme one, around rating scales and outcome measures will provide the following outputs:
1 A set of core variables for measurement in clinical studies of AD and PD with clarification of their meaning.
2 Recommended scales that are clinically valid indicators of these core variables, with a synthesis of their psychometric performance, the completion of necessary analyses, and the identification and management of measurement limitations.
3 Identification of the core variables for which no suitable measurement scales exists
4 A list of scales proven empirically valuable, for whom further investment or development is warranted and empirically driven.
5 Draft generic consensus agreed empirically-driven guidelines for defining variables and selecting rating scales for clinical trials.
6 The basis for theory-referenced measurement of each core variable.
PI: Prof John Zajicek, College of Medicine and Dentistry, Clinical Neurology Research
Dr Jeremy Hobart, Peninsula College of Medicine and Dentistry
Prof David Wright, University of Plymouth
Prof Gordon Wilcock, Nuffield Department of Medicine
Dr Craig Ritchie, Camden & Islington Mental Health & Social Care Trust
Prof Ifeachor, University of Plymouth
Dr Carl Counsell, University of Aberdeen
Prof Paul Matthews, Imperial College, University of London
Dr Colin Green, Universities of Exeter and Plymouth
Prof Gavin Giovannoni, Queen Mary University, London
Prof Ray Fitzpatrick, University of Oxford
Disease Category: Neurology
Disease Name: Alzheimer's disease, Parkinson's disease
Age Range: Unknown
Sex: Either
Nature of Intervention: Any
- Charities
- Clinical experts
- Consumers (caregivers)
- Consumers (patients)
- Methodologists
- Researchers
- Statisticians
- Patient perspectives
- COS for clinical trials or clinical research
- Consensus meeting
- Focus group(s)
- Interview
- Survey
- Systematic review
Stage 1 Literature review and formation of consensus group
1.1 Review
Our review of the literature to date has reached 5 main conclusions: selection of scales for trials and studies in ND is not evidence-based; scale selection strategies are not used; few scales are developed from an explicit definition of the variable/s they seek to measure; many scales contain items measuring a range of dimensions; little work has been done to identify and define the important variables for measurement in AD or PD.
1.2 Consensus group
For this study to be accepted it needs to be widely endorsed. We will form a consensus group for both AD and PD, that will include internationally-renowned experts. The consensus groups will be inclusive and have representatives from: people with AD and PD; relevant charities; clinicians and researchers; rating scale scientists; qualitative researchers; systematic reviewers; statisticians. The consensus group will oversee the study, contribute to interpretation of information and guide the study process, developing the protocol for each stage.
Stage 2 Identification of a set of core variables for measurement in AD and PD; clarification of the clinical meaning of those variables.
Stage 2 will build on the findings of Stage 1. The broad aim is to identify a set of key variables for measurement in clinical trials in AD and PD and to be very explicit about the definitions of those variables.
2.1 Identifying core variables for measurement
Qualitative work is required to identify the core variables for measurement. The findings from stage 1 will be used to assist but not dictate this work. The qualitative work will include three broad groups of people: those with AD and PD, their carers (significant others) and experts. People with AD and PD will include people on treatments for NDs and in ongoing clinical trials. There will be focus groups and 1-2-1 interviews. Maximum variance sampling to redundancy will be used. Expert opinion will be sought concerning core variables for measurement in clinical trials of AD and PD in 3 ways: a postal survey; 1-2-1 interviews; focus groups.
This will be an iterative process in which a first round of qualitative work will be conducted, analysed, considered and presented to the consensus group. This will inform a second (and possibly further) round of qualitative work. It is likely that this process will identify many potential variables for measurement, and that some variables may be considered at different levels, or overlapping (eg sub domains of disability) One important role of the consensus group is to select a set of core variables for clinical trials in AD and PD to take forward to the next stage.
2.2 Defining the core variables
When the core variables have been identified they need to be defined explicitly. Defining of variables is a fundamental requirement for truly evidence-based selection of scales and determination of scale validity. Without explicit understandings of the variables we wish to measure, we cannot effectively and rigorously select scales to measure them.
For each core variable, we will review the literature to identify potential formal definitions of the variables and theoretical explanations of intrinsic factors that account for their variation. This information will be used to inform qualitative work in which we will seek to map out what it means to have more or less of it, and what it is like to move up and down the variable. The qualitative work will involve people with AD and PD who vary in their levels of core variables. This part of stage 2 will be a careful and iterative process of literature review, qualitative work, and consensus opinion. It will result in clear understandings of the core variables.
If is not possible to estimate accurately how many focus groups and interviews will be required for this stage which will continue until clarity of the constructs and their nature is reached. Our previous experience, and that of others, is that the numbers are relatively small. People with AD and PD will be recruited from the different regions covered by the study group.