midterm report - university of bristol

MRC HTMR ConDuCT Hub

MRC Hubs for Trials Methodology

ConDuCT Hub Collaboration and Innovation for Difficult or

Complex Randomised Controlled Trials

Mid-term Report November 2011


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Contents The MRC ConDuCT Hub .......................................................................................................................... 3

Aims ........................................................................................................................................................ 3

Hub environment .................................................................................................................................... 3

Hub structure .......................................................................................................................................... 4

Hub collaborations .................................................................................................................................. 4

Hub training ............................................................................................................................................ 5

Advisory functions .................................................................................................................................. 7

Research theme outlines ........................................................................................................................ 8

1. Developing & integrating qualitative research methods to improve RCT design and conduct ...... 9

2. Evidence synthesis and expected value of information for prioritisation of RCTs ....................... 11

3. Improving the design and conduct of RCTs .................................................................................. 14

4. Statistical methods in the design and analysis of challenging RCTs ............................................. 16

5. Economic evaluation in RCTs ........................................................................................................ 18

6. Clinical and patient reported outcomes in RCTs ........................................................................... 22

Appendices ............................................................................................................................................ 24

1. Structure of the MRC ConDuCT Hub ................................................................................................. 25

2. Collaborations ................................................................................................................................... 26

3. Workshops ........................................................................................................................................ 29

4. Publications ....................................................................................................................................... 31

5. Presentations .................................................................................................................................... 42

6. Research Grants ................................................................................................................................ 49


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Summary

The MRC ConDuCT Hub

The MRC ConDuCT (Medical Research Council Collaboration and innovation for Difficult or Complex

randomised controlled Trials) Hub was established in April 2009 as one of eight regionally distributed

research resources within the UK to improve the design, conduct, analyses, interpretation and

reporting of clinical trials. It is a multi-disciplinary team of researchers based at the University of

Bristol, led by Director, Professor Jane Blazeby, who is Professor of Surgery. The ConDuCT Hub

includes nine senior academic staff who are the grant holders, six research associates and nine

doctoral students (either Hub funded or affiliated) and it is supported by a grant of £1.9M over 5

years which was activated on 1 April 2009. Now some two and a half years into the grant the Hub is

examining its progress and strategy.

In this report we demonstrate the achievements of the Hub and the research themes, we summarise

the collaborations and support provided by the Hub regionally and nationally to trials units and

investigators and we document Hub provision of training and support for trials methodology

research and its application.

Aims The overall aim of the Hub is to provide the environment and infrastructure for collaborative

methodological research that leads to improvements in the successful design and completion of

randomised controlled trials (RCTs). The key objectives of the Hub are:

1. To establish nationally and internationally leading research programmes developing innovative

methods to permit the design, conduct and analysis of RCTs.

2. To provide a national focus for the support, design and conduct of ‘difficult’ RCTs in

collaboration with UK Clinical Research Collaboration (UKCRC) registered clinical trials units

(CTUs), National Cancer Research Initiative (NCRI)/UKCRC clinical studies groups and networks,

and other MRC Hubs.

3. To provide advanced learning opportunities and training for researchers and clinical academics

in RCT methodology.

Hub environment

The ConDuCT Hub is based in the School of Social and Community Medicine, University of Bristol, a

leading centre for health services research, public health, epidemiology, and primary care. The MRC

Centre for Causal Analyses in Translational Epidemiology (CAiTE), the academic unit of primary care,

the academic unit of psychiatry, the premier birth cohort study ALSPAC (Avon Longitudinal Study of

Parents and Children), and the UKCRC DECIPHer (Development of Complex Interventions for Public

Health Improvement) Centre, spanning Bristol, Cardiff and Swansea, are also based in the School.

The primary characteristics of the research undertaken are that it is collaborative and multi-

disciplinary.


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Hub structure

There are six interlinked themes, led by academics with established track records in the

development of methodology for RCTs in qualitative research, evidence synthesis and expected

value of information (EVI) analysis ahead of trials, trial monitoring and conduct, statistics, economic

evaluation, and outcome assessment in trials. The Hub also has a developing focus on research

methodology specifically within RCTs in surgery. Each theme includes a research associate and Hub

funded or externally funded but affiliated PhD students (Appendix 1).

Hub collaborations

Links to CTUs

The Hub has many links to regional and national CTUs via pre-existing projects, newly funded

methodological research projects, trials with applied methodologies and by support such as

membership on trial steering committees (Appendix 2). The Hub is closely linked to the Bristol

Randomised Trials Collaboration (BRTC), being situated within the School (Lane is Associate Director,

and Montgomery is Director). In this role they both support and advise on many primary care and

mental health trials being conducted in the South West Region. Peters, Brookes, Noble and Metcalfe

are also on the management committee, offering statistical and health economic oversight to

adopted trials. Montgomery is chair of the South West Region Research for Patient Benefit Advisory

Panel. Wiles and Metcalfe are also on the panel, which brings them into contact with trials experts

from across the South West region, including those from the research design service (RDS). Metcalfe

is linked to the Welsh Cancer Trials Unit End of Life Research Methodology Group. He has recently

attended two meetings to advise on a systematic review of research methodologies employed in

RCTs of end of life care. The Hub is also part of a pan Bristol trials group which meets with the two

Bristol CTUs and local RDS and this acts as another forum to exchange ideas and advice (Lane,

Montgomery, Blazeby).

Links to national trials bodies

ConDuCT Hub members are involved in the NCRI clinical studies groups (Blazeby, Heawood),

NCRI/UKCRC CTU Heads (Montgomery), the MRC /HTA (Health Technology Assessment) Trial

Managers Group (Lane) and the National Institute for Health Research (NIHR) working group for

improving recruitment into surgical trials (Blazeby). Hub members sit on various NIHR panels, the

HTA commissioning board (Donovan), the HTA clinical trials and evaluation board (Blazeby, Sterne)

and associate members (Lane, Metcalfe, Welton and Tilling), the chair of the MRC-NIHR

Methodology Research Programme Panel (Peters), and the chair of the South West RfPB

(Montgomery) and members (Metcalfe and Wiles).

Hubs for Trials Methodology Research (HTMR) network

Within the HTMR network the ConDuCT Hub has several active project collaborations. These include

working with the North West Hub with the DIRUM (Database of Instruments for Resource Use

Measurement) project (Noble, Hollingworth), and the COMET (Core Outcome Measures in


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Effectiveness Trials) initiative (Blazeby). The expected value of information theme works with the

Midlands Hub and Arthritis Research UK (ARUK) (Ades, Welton), and the outcomes theme

collaborated with the Biostatistics Hub, Cambridge, to deliver a highly popular workshop at the Royal

College of Surgeons of England to examine methods to improve recruitment into surgical trials

(Donovan, Blazeby, Mills). The ConDuCT Hub (Lane) leads the newly formed HTMR Trial Conduct

Working Group (Bristol, North West, Oxford, MRC CTU) currently exploring monitoring and retention

research interests following a survey of ongoing and planned research at the Hubs and Mills is lead

of the HTMR recruitment working group (supported by Blazeby) with a series of meetings and

projects planned for 2012.

Links to the NHS

The Hub also supports local NHS organisations including the University Hospitals Bristol NHS

Foundation Trust primarily via the surgical trials team (led by Prof A Ness, Prof J Blazeby, Mr R

Persad and Mr M Thomas) and North Bristol NHS Trust via several projects linked to each theme and

provision of methodological advice (Blazeby, Sterne, Donovan, Metcalfe, Montgomery).

Hub training

Members from each of the ConDuCT Hub research themes design and deliver training regionally and

nationally to academic researchers, trialists, healthcare professionals and policy makers. The Hub

also has nine affiliated PhD/MD students focusing on trial methodology research. The Hub training

activities are summarised below.

University of Bristol short courses

The School of Social and Community Medicine (SSCM) provides an annual programme of high quality

intensive short courses including trial related methodologies and generic research skills

(http://www.bris.ac.uk/social-community-medicine/shortcourse). During 2009/10 over 400 students

attended these courses giving good feedback. Courses with teaching and/or coordination from

ConduCT Hub members include:

Advanced meta-analysis (Sterne, Welton, 2 days)

Analysis of repeated measures (Tilling - organiser, 2 days)

Design & analysis of RCTs (Montgomery, Blazeby, Brookes, Hollingworth, Lane, Peters, Tilling, 5 days)

Introduction to economic evaluation (Hollinghurst, Hollingworth, Noble, Mckell-Redwood, Thorn, 3 days)

Introduction to linear and logistic regression (Metcalfe – organiser, Peters, Sterne, Welton, 5 days)

Introduction to qualitative research methods (Donovan, Heawood, Mills, 5 days)

Introduction to research governance (Lane, 2 days)

Introduction to stata (Macefield, 2 days)

Introduction to statistics (Tilling, Montgomery, 5 days)

Rates & survival analysis: Poisson, Cox & parametric survival models (Sterne, Tilling, Brookes, 3 days)

Questionnaire design, application and data interpretation (Lane, Macefield, 3 days)


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Other short courses and workshops

Short courses have been delivered nationally (and internationally by EVI and outcome theme

members) either as stand alone courses or workshops embedded in specialist meetings. Many

workshops and short courses have been delivered over the last two and half years with more

planned for 2012 (Appendix 3). ConDuCT Hub members have also taught on and co-organised three

MRC HTMR workshops.

PhD/MD studentships and other affiliated trainees

Social and Community Medicine has a thriving post-graduate programme with a track record of

successful supervision and completion of PhDs. Within the Hub there are seven ongoing PhD/MD

students, two completed studentships, one NIHR Methodology Fellowship linked to the Hub and two

academic F2 doctors (Figure 1). All students have at least one Hub supervisor who meets regularly

with students. The students, funding sources, projects and supervisors names are listed below.

i) Bowen (NIHR School for Primary Care Research (NSPCR) PhD) investigating preventable emergency

admissions in children to develop a primary care intervention (co-supervisor Heawood, qualitative

theme)

ii) Blencowe (NIHR PhD) investigating intervention protocolisation and fidelity in surgical trials,

Blazeby main supervisor (co-supervisor Mills, qualitative theme)

iii) Boulind (MD) investigating blinding in surgical trials, Blazeby main supervisor (co-supervisors

Metcalfe (statistics theme) and Francis)

iv) Coulman (NIHR PhD), one part of which aims to develop a patient core outcome set for obesity

surgery (starting January 2012), Owen-Smith main supervisor (co-supervisor Blazeby, outcomes

theme)

v) Franchini (NIHR Methodology Fellowship) MSc in Medical Statistics, mini-projects, currently

writing an NIHR doctoral fellowship application to work on mapping between depression and quality

of life outcomes to inform the design of a trial of treatments for depression by severity (co-

supervisors Welton and Montgomery)

vi) Guyot (jointly funded by MRC Methodology Research Panel grant and MapiValues) investigating

the analysis of time to event outcomes for use in cost-effectiveness analyses (co-supervisors Ades

and Welton)

vii) McNair (Royal College of Surgeons of England fellowship), PhD awarded March 2011, on

methods to communicate patient-reported outcomes (PROs) from RCT to patients using different

graphical formats. Blazeby main supervisor (co-supervisor Avery)

viii) Potter (Royal College of Surgeons of England fellowship), PhD - BRAVE - Breast Reconstruction

and Valid Evidence study – to determine the feasibility of clinical trials in breast reconstruction. This

included a review of clinical and cosmetic outcomes reported in breast reconstruction surgery

(submitted, awaiting viva). Blazeby main supervisor (co-supervisors Mills, qualitative theme)


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ix) Strong (Hub funded), MD to study the team working and the application of eligibility criteria in

RCTs, Blazeby main supervisor (co-supervisor Donovan, qualitative theme)

x) Whistance (NIHR Fellowship), PhD which aims to develop a core outcome and core disclosure set

for surgery for colorectal cancer. Main supervisor Blazeby (co-supervisors Brookes, Avery & McNair)

Advisory functions

Metcalfe is a member of the Data Monitoring Committee for a Peninsula CTU Trial: PASTIES (Pain

Solutions in the Emergency Setting; 2011-2012). Peters is a member of the NIHR Clinical Trials Unit

Standing Advisory Committee (2008 to present), and the current chair of the NIHR/MRC

Methodology Research Programme Panel (2007 to present). Wiles is a member of the Data

Monitoring Committees for two HTA funded trials: CanTalk at University College London (Clinical and

cost-effectiveness of CBT plus treatment as usual for the treatment of depression in advanced

cancer: a randomised controlled trial; 2011-2015) and IMPACT at Cambridge (Improving mood with

psychoanalytic and cognitive therapies; 2010-2014). Blazeby is chair of the Trial Steering Committee

(TSC) for an HTA funded orthopedic trial, UKuff and she is on the TSC of a Cancer Research UK

(CRUK) funded feasibility trial to compare surgical approaches for prostate cancer (LoPera) and the

Independent data monitoring committee for CHORUS, a gynaecological cancer trial run from the

MRC/CTU.

Methodology advisory service for trials

Along with the other Hubs, ConDuCT contributes to the Methodology Advisory Service for Trials

(MAST) (link person: Metcalfe), providing a formal route by which CTUs and the RDS can seek advice

on methodological issues arising in the trials they are conducting.


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Research theme outlines


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1. Developing and integrating qualitative research methods to improve the design and conduct of RCTs

Aim of theme

The overall aim of the theme is to increase the use and development of qualitative methods within

difficult to conduct RCTs to improve feasibility, design and conduct. This is being achieved by

encouraging and supporting the increasing integration of qualitative research methods into RCTs,

developing and refining innovative qualitative research methods that address key methodological

issues in trials, providing training in integrating qualitative research methods into RCTs, and securing

funding for new qualitative work within trials.

Research areas

(a) Understanding and improving recruitment to RCTs

Donovan and Mills have developed and been involved with several studies embedding a

combination of standard and innovative qualitative research methods into RCTs trials to understand

and improve the recruitment process. These include the development of a complex intervention

which resulted in high levels of randomisation and informed consent in a difficult trial (the ProtecT

study, Donovan JCE 2009); investigations into the reasons for poor recruitment in four RCTs in the

MRC Quartet study, including one in cancer treatment, one in paediatric primary care, one in cancer

follow-up, and one of patients with severe mental illness (Howard 2009); an exploration of the

informed consent procedure and the development of a model to facilitate informed consent at trial

recruitment (Wade 2009); understanding how patients’ treatment preferences were expressed and

justified during recruitment to a RCT and how they influenced participation and treatment decisions

(Mills 2011); and investigating and improving recruitment to RCTs in terminal cancer (Quartz trial),

varicose veins (CLASS), oesophageal cancer, and bladder cancer (SPARE, Paramasivan 2011).

(b) Feasibility studies to illuminate and address issues relating to the successful design and

implementation of a full scale RCT

Donovan, Mills and Heawood have designed, and are overseeing, qualitative research using various

methods within feasibility studies to expose and address issues relating to the successful design and

implementation of a full scale RCT. This includes the SMILE feasibility trial, in which qualitative

methods are used to assess the recruitment process, delivery of the intervention, and experiences

and acceptability of the intervention and outcome measures; the BRAVE study, in conjunction with

Blazeby, in which interviews were conducted with patients and clinicians to determine the feasibility

of undertaking an RCT in breast reconstruction; the ROMIO trial (with Metcalfe and Blazeby) using

qualitative research to assess the feasibility of a surgical trial in oesophagectomy; and the

mindfulness for co-morbid chronic obstructive pulmonary disorder and depression feasibility study,

which contains both qualitative and quantitative elements to determine trial feasibility.

(c) Unpacking the ‘black box’ of talk-based interventions and exploring the impact of intervention

delivery on retention and drop-out within RCTs

Alongside leading several nested qualitative studies within trials to evaluate patients’ and

professionals’ experiences of interventions, and how these may inform trial outcomes (e.g. the

SCOOP study – Emmett 2011), Heawood (with Ekberg and Barnes) is undertaking work using the


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innovative methods of Conversation Analysis (CA) to unpack the ‘black box’ of talk-based

interventions and examine how intervention delivery may relate to trial outcome. A Bupa

Foundation study is underway (OTIS), using CA to study the development of ‘therapuetic alliance’

within online CBT and how this may relate to therapy and trial outcome. The data for this study are

therapist–patient interactions during a trial of online CBT for primary care patients with depression.

Future plans/new research areas in development

(a) Understanding and improving recruitment to RCTs

Donovan and Mills are currently advancing much of our research in this area, including:

A re-analysis and synthesis of the qualitative research conducted in six major RCTs

Designing a trial to measure the effectiveness of the complex intervention to improve

recruitment developed through the ProtecT study

The development of a rating scale to measure the effectiveness of information provision

during informed consent consultations for trial recruitment

Research to identify good practice for dealing with treatment preferences at trial recruitment

Support for an MD student on understanding the recruitment process to maximise trial

participation (with Blazeby).

The following funded RCTs, all at the contracting stage, have qualitative recruitment investigations

built into them. Donovan will support these trials, most of which are in collaboration with Blazeby:

NIHR HTA funded BY-BAND trial of surgical treatments for morbid obesity (PI Blazeby)

Clinical Trials Awards and Advisory Committee (CTAAC) /CRUK funded POUT trial of surgery

and radiotherapy for ureteric cancer

NIHR HTA funded OPTIMA trial of the use of diagnostic tests to determine targeting of

chemotherapy or no chemotherapy for breast cancer

NIHR HTA funded FASHioN trial of surgery and physiotherapy for hip impingement.

(b) Feasibility studies to illuminate and address issues relating to the successful design and

implementation of a full scale RCT

The team will continue designing and overseeing existing and new research in this area including

extending the SMILE feasibility trial into a main trial to investigate the effectiveness of an

intervention for children with chronic fatigue syndrome or myalgic encephalopathy.

(c) Unpacking the ‘black box’ of talk-based interventions and exploring the impact of intervention

delivery on retention and drop-out within RCTs

Proposals are underway, led by Heawood, to develop the OTIS work by examining ‘therapeutic

alliance’ within cognitive-behavioural therapy (CBT) interventions delivered in different settings, via

different modalities (e.g. online, face-to-face), for varying groups of patients with depression. The

aim is not only to improve our understanding of the conduct of talk-based interventions such as CBT,

but to provide insight into how delivery of the intervention can impact retention and drop-out

within therapy and within the trial, a recognised methodological challenge within CBT trials. This

work will be linked to existing trials of CBT within the School of Social and Community Medicine.


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2. Evidence synthesis and expected value of information for prioritisation of

RCTs

Aim of theme

To develop a programme of technical statistical and health economics research, that provides the

inputs and computational tools required for Expected Value of Information (EVI) calculations, which

measure the net expected returns from a future RCT of a given design. Evidence synthesis and cost-

effectiveness analyses will be derived for a wide range of examples, through which computational

methods can be developed. Links with CTUs will provide the opportunity to use EVI analyses to guide

trial design before initiating a RCT, for example as part of a feasibility study. We will also provide

training on EVI and evidence synthesis methods for the clinical and academic community.

Research areas

(a) Intravenous Immunoglobulin for severe sepsis (HTA funded project)

This was a collaborative project with the Intensive Care National Audit Centre (ICNARC) and the

Centre for Health Economics (York). Welton carried out a systematic review and network meta-

analysis that explored treatment definitions and risk of bias. The results from this synthesis were

used as inputs to the cost-effectiveness model developed in York, and Welton collaborated with

Soares (York) on the Expected Value of Sample Information (EVSI) calculations to assess the value of

a new trial evaluating Intravenous Immunoglobulin for severe sepsis in adults in the UK. The report is

currently under editorial review by the HTA and papers are planned on quality indicators to explore

heterogeneity in a network meta-analysis, and how the results can be used in cost-effectiveness

analysis.

(b) Electronic aids for smoking cessation (HTA funded project)

This was a collaborative project with the Universities of Birmingham and Bath. The systematic review

was carried out in Birmingham, and Madan and Welton carried out a network meta-analysis with

complex interventions and heterogeneously reported outcomes (repeated measures, continuous

abstinence and point prevalence). Madan developed a cost-effectiveness model and performed the

cost-effectiveness analysis and EVPI calculations. The report is currently under editorial review. Two

papers are being written: a methodology paper for synthesis with complex interventions and

heterogeneously reported outcomes, and an economic paper to include VoI analysis.

(c) Fluid expansion as supportive therapy for malaria (the FEAST trial)

This project was a collaboration with the FEAST trial group, led by Professor K Maitland of Imperial

College, London. We used the evidence available from pilot studies of fluid resuscitation conducted

by Professor Maitland and her team to perform a network meta-analysis, cost-effectiveness analysis

and EVI analysis. The initial aim was to see how the EVI analysis could have been used

(retrospectively) to design the FEAST trial. However, the example has proved methodologically

interesting, and our primary focus now is to use it as a motivating example for a methodology paper

on methods for linearising strategies in order to avoid nested simulation in EVI computations. We


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are in the process of writing a methodology paper on linearising strategies for the efficient

computation of Expected Value of Partial Perfect Information (EVPPI) using this example to illustrate.

(d) Biologic therapies in inflammatory joint diseases (initiated since initial proposal)

This collaboration with ARUK was a result of a request to the Hubs Network coordinator for training

on network meta-analysis to help with research prioritisation. This led to a workshop (jointly funded

by HTMR network funds and ARUK) held in September 2010 with presentations on network meta-

analysis, cost-effectiveness analysis and EVI for biologic therapies, followed by discussion. The

presented papers were published in a supplementary issue of Rheumatology (including 3 papers by

ConDuCT Hub members). Further funding (from the same sources) has been obtained to hold two

further workshops aimed at obtaining consensus on the structure of and inputs to a cost-

effectiveness analysis model that can be used as an “off-the-shelf” model for rheumatoid arthritis.

The expected output will be a grant application to build the model and perform EVI to identify

research needs in this field.

The first of the two consensus meetings is to be held in November 2011 with a follow-up meeting

planned. We will write a paper on the process of eliciting a consensus model from experts. We will

be involved in a grant application to build the consensus model and carry out EVI calculations.

(e) Analysis and synthesis of time-to-event data from cancer trials in the assessment of cost-

effectiveness (initiated since initial proposal)

This project is a collaboration with industry (MapiValues) funded via an MRC MRP grant, with

researcher and PhD student Guyot. Guyot has completed a look-back review of the analysis of time

to event outcomes in effectiveness and cost-effectiveness analyses. She has also developed an

algorithm to allow the reconstruction of Kaplan-Meier data from digitised published survival curves

to allow different survival model assumptions to be explored in secondary analyses.

We plan to write a paper setting out a re-analysis of the Kaplan-Meier data from the published

survival curves from a range of examples with typical “shapes” of the survivor curve seen in cancer

patients. We also plan to explore how external data can be used to provide additional information

on the shape at the end of the survival curves which are typically based on small samples. This is

important for the use of survival curves in cost-effectiveness analyses because the key input is the

mean survival time, or area under the curve, which is highly sensitive to assumption on the shape of

the tail of the curve. Finally, we plan to combine all of the methods above in an evidence synthesis of

several survival curves to obtain a pooled estimate of the survival curve for use in a cost-

effectiveness analysis. An example cost-effectiveness in cancer will illustrate the methods.

(f) Widening the spectrum of health outcomes used in health technology assessment: integrated

synthesis and mapping to QALYs (initiated since initial proposal)

This is an MRC Methodology Research Programme (MRP) grant, with Ades and senior research

fellow Lu, who have developed methods for synthesising evidence from trials reporting different

(but related) outcome measures. For example, depression scores on various scales. Prof Lewis

(Bristol) has obtained an NIHR programme grant looking at treatment of depression by severity

thresholds. We will contribute to the programme with an EVI analysis and, because the existing

evidence base will include studies measuring outcomes on different depression scales, the mapping

work will be integral to that analysis.


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(a) EVI for surrogate outcomes/biomarkers

What is the added value of obtaining information on the primary outcome rather than a shorter-

term surrogate outcome? The Net Benefit of Sampling can then indicate whether the additional cost

of running a trial with longer follow-up to obtain the primary outcome is cost-effective compared

with a shorter-trial measuring a surrogate outcome.

(b) EVI when the evidence is subject to flaws in methodological quality

How to adjust for potentially biased evidence in cost-effectiveness analyses that feed into EVI

analyses. IVIg for severe sepsis can be used as an illustrative example.

(c) EVI to inform the choice of follow-up times in trials with time-to-event outcomes

Cost-effectiveness models need to extrapolate beyond the follow-up seen in trials in the evidence

base, and there is usually considerable uncertainty in this extrapolation – especially if the treatment

may have long-lasting effects. What is the value in funding longer trials that can reduce this

extrapolation uncertainty? What are the ethical implications of running longer trials? Electronic aids

for smoking cessation can be used as an illustrative example.

(d) Research prioritisation in the absence of a cost-effectiveness model

A major barrier to the use of EVI methods is that at the point at which studies are being designed a

cost-effectiveness model has not yet been developed. The aim of this project would be to explore

how the uncertainty in parameters in an effectiveness model can be used to help identify those

parameters in which there is likely to be most value in conducting further research, whilst stopping

short of a full cost-effectiveness model.

(e) Building a consensus cost-effectiveness analysis model for biologic therapies for rheumatoid

arthritis

This is a grant proposal that is an expected output from the planned consensus workshops on

biologic therapies for arthritis (see 2(d) above). As well as building a cost-effectiveness analysis

model there will be an EVI analysis component to the grant, and we would be involved in that work.

(f) EVI for Markov Models

Markov models are commonly used in cost-effectiveness models, but result in highly non-linear net-

benefit functions. We plan to explore methods for EVI for these models with typical data formats

that inform the parameters. Challenges will be efficient computational methods that can short-cut

the need for nested simulations.

(g) EVI when several treatments currently approved, and policy is cost-minimisation

What would be the format of an EVI analysis in this case? In order to change policy, it will be

necessary to show that one (or more) of the existing treatments is significantly inferior to the others.

Classical tests of statistical significance are therefore necessary in addition to cost-effectiveness.


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3. Improving the design and conduct of RCTs to maximise trial performance and ensure timely and accurate results

Aim of theme

This theme aims to improve the design and conduct of RCTs to maximise trial performance and

ensure timely and accurate results. The theme focuses on developing and evaluating tools and

systems that can be utilised across trial designs and disease sites, in particular addressing key issues

of quality assurance, participant retention and study cohesion.

Research areas

(a) Site conduct and monitoring

A systematic review of on-site monitoring methods in healthcare RCTs has been completed by

Macefield (under revision at Clinical Trials). The review identified the diversity of systems used

worldwide in the 52 papers representing organisations (e.g. NCI) or individual trials and the lack of

robust evidence for current practice.

A new on-site monitoring method (PRIME – Peer Review Intervention for Monitoring and Evaluation

of Sites) has been developed and evaluated in the ProtecT prostate cancer treatment trial. The

method focuses on mentoring, training and improving site performance without the more

customary source data verification at site visits. The PRIME process has been further piloted in two

other studies by providing training and advice during site visits:

South East Wales Trials Unit (SEWTU): Project SFP Cymru, Chief Investigator (CI) Prof

Laurence Moore, Cardiff University

BRTC & SEWTU: DUTY, CI Dr Alastair Hay, University of Bristol.

This research will continue by approaching newly funded RCTs at regional CTUs to assess and refine

the PRIME process further. A robust evaluation of the PRIME system, including a remotely delivered

version, will be evaluated in several nested RCTs embedded in pragmatic phase III trials. A

preliminary assessment of wider suitability of PRIME for trials was recently made with trial managers

at the NIHR trial managers network annual meeting in October through a survey and discussions. An

MRP grant application has been submitted to support this research with regional CTUs (SEWTU,

Wales CTU), experienced trialists (Aberdeen) and other Hubs (North West, London) as collaborators.

We are collaborating with the North West Hub (Tudur-Smith) on a cross-hub grant to investigate UK

site monitoring practice and to run a site monitoring workshop in spring 2012.

(b) Improving adherence and retention

Measurement of adherence to dietary interventions was assessed in a feasibility trial of prostate

cancer prevention by green tea and tomatoes (ProDiet trial, BRTC). Clinician reported and patient

reported measurements of adherence to capsules or dietary modification were compared against

returned capsule counts and biomarkers. In-depth interviews explored the facilitators and barriers to

adherence such as taking capsules at mealtimes. This research will be written up as a paper.


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Factors influencing follow-up questionnaire response rates were investigated with a mixed methods

approach. The impacts of three interventions on response rates in the ProtecT trial were analysed,

including in-depth interviews with participants about follow up procedures. Reminder letters and

telephone calls from the clinical centre staff were successful, whereas a study pen had no effect.

Interviews revealed that most men were willing to complete questionnaires although some men saw

less need over time and if they were cured of the disease. This research will be written up as a

paper.

A proposal to develop an online theory driven retention strategy toolkit, led by SEWTU (Nuttall, Lane

as co-applicant) has also been submitted to MRC MRP programme.

(c) Trial data quality and management

Source data verification (SDV) of trial data against medical records is a major activity in site

monitoring by commercially sponsored trials. However, the value of SDV had been questioned by

many academic trialists and our systematic review found little evidence of benefit to trials. We have

investigated the value of SDV for data completeness by comparing outcome case report forms (CRF)

completed by ProtecT nurses with CRFs completed by ProtecT data managers using medical records.

We will also aim to identify problematic data types and provide advice for trialists designing CRFs.

Future plans/new research areas in development (joint with outcomes theme)

(a) Measurement and reporting of harms (adverse events)

There are regulatory requirements to report serious adverse events (harms) in Investigational

Medicinal Product (IMP) and non-IMP trials and these events can also form secondary outcomes of

trials. The levels and types of regulatory and outcome reporting of harms varied for cancer trials in

the USA but much less is known for other disease sites and trial designs. Event reporting rates in the

ProtecT trial will be analysed by site in comparison with data from outcome CRFs. A systematic

review of the literature may also be beneficial. This problem for academic trials was identified in

discussions with Hood (SEWTU) and we will also discuss these ideas with the other regional CTUs.


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4. Statistical methods in the design and analysis of challenging RCTs

Aim of theme

To establish the best way of applying novel statistical methods to the design or analysis of

challenging RCTs. Where novel methods are likely to offer advantages over established techniques,

theme members will implement these and investigate their practical application in ongoing and

completed RCTs, in this way providing advanced statistical support in the design and analysis of

difficult RCTs to CTUs and the RDS.

Research areas

(a) Unbiased estimates of treatment efficacy when not all RCT participants comply with their

allocated treatment

The ProtecT trial is comparing surgery, radiotherapy and active monitoring in the management of

screen-detected and clinically localised prostate cancer, with a primary outcome of mortality due to

prostate cancer and an anticipated reporting date in 2015/2016. We have been conducting

methodological work in preparation for a secondary analysis of the ProtecT primary outcome data,

aimed at unbiased estimates of the relative treatment effects in men who complied with their

allocated treatment. Hampson (research associate (RA) with ConDuCT May 2009 until July 2011) and

Metcalfe have been leading this work which has compared different methods of unbiased

estimation in real and simulated data sets, and has extended the methods to allow adjustment for

baseline variables. This work has been presented at high profile meetings (Royal Statistical Society

Primary Care Research Group, London 2010; International Society for Biostatistics in Ottowa 2011),

and Statistics in Medicine have asked for a revision of the manuscript describing this work

(Hampson, 2011).

(b) Process and barriers to sharing trial data for methodological research

Brookes and Montgomery are co-ordinating a collaboration between the eight centres of the

National School for Primary Care Research. They are seeking funding for a project centred around an

exploration of the processes for and barriers to making trial data available for methodological

research. Three methodological projects will motivate the initial sharing of data, with ConDuCT

leading on a comparison of methods for futility analysis.

(c) Unbiased estimation of cost-effectiveness when not all RCT participants comply with their

allocated treatment

Metcalfe, Montgomery, Wiles and Peters collaborated with members of the “Economic Evaluation in

RCTs” theme to apply for grant funding to develop methods for the unbiased estimation of cost-

effectiveness when not all RCT participants comply with allocated treatment. This application to the

MRC Methodology panel was unsuccessful. A scoping review, conducted in preparation for a re-

application, was the subject of a poster presentation at the MRC Clinical Trials Methodology

Conference in Bristol, October 2011.


17

(d) Statistical precision of cost-effectiveness analysis

Metcalfe and Hampson contributed to this work which is described more fully under the “Economic

Evaluation in RCTs” theme.


(a) Analysis and reporting of non-inferiority trials

Sterne and Metcalfe, in collaboration with the Cambridge Hub, are planning to review the analysis

and reporting of non-inferiority trials. Initially a systematic review will be conducted of reporting of

different types of analysis in published non-inferiority trials with a critical appraisal of current

recommendations (eg Consolidated Standards of Reporting Trials (CONSORT)) and how they have

been interpreted. Suitable data from completed BRTC trials will be sought to establish the relative

merits of intention to treat and per protocol analyses, and whether it is feasible to use causal

inference methods. This is a possible project for the new Statistics Theme RA or a PhD student.


18

5. Economic evaluation in RCTs

Aim of theme

To develop and improve methods for the design and analysis of economic evaluations alongside

RCTs. This will be achieved through reviews of literature, using our links with trialists through our

applied work to evaluate research questions, and collaborating with other health economists in

areas of shared interests.

Research areas

(a) Using existing cost-effectiveness trial data to estimate the frequency with which efficiency is

considered in sample size calculations and whether RCT-based economic evaluations are likely

to come to inconclusive results at odds with the clinical findings

A review of cost-utility analyses conducted alongside RCTs has been conducted to: 1) determine the

extent to which cost-effectiveness is considered when calculating sample sizes, 2) estimate the

frequency and extent to which economic conclusions differ from clinical conclusions, 3) assess

whether economic evaluations are more likely to come to indeterminate results and 4) discuss the

circumstances in which economic sample size calculations might be appropriate. This work was

presented at the Society for Social Medicine Meeting (September 2011) and the MRC Clinical Trials

Methodology Conference (October 2011). The manuscript is currently under review in Clinical Trials.

The review found that trialists rarely assess the extent to which their trial might resolve the key

uncertainties about the efficiency of interventions. Economic evaluations conducted alongside RCTs

are valuable, but often present inconclusive evidence. Our review makes recommendations about

when it is, and is not, appropriate to consider economic outcomes in the sample size calculation of

an RCT. This work provided some of the groundwork for an MRC MRP grant application (jointly with

the statistics theme). The application was not funded, but our future plans include revising and

resubmitting this application based on reviewer feedback.

(b) Creating a repository of resource-use questionnaires for adoption in and adaptation to future

trials

In collaboration with colleagues from the Midland and North West Hubs, money through the HTMR

was obtained; the database (DIRUM) http://www.dirum.org/ is live and has 32 resource use

measures uploaded. There have been almost 1200 visits and in excess of 300 downloads taken from

the website. A successful workshop on “Resource-use measurement based on patient recall: Issues,

challenges and DIRUM” took place in October 2011, the proceedings of which are currently being

written up for publication.

A paper in relation to DIRUM was accepted for the Health Economics Study Group (HESG)

conference in Bangor and a paper is currently under review with Value in Health.

We plan to use DIRUM to generate ideas for a MRC MRP grant application in the areas of

questionnaire validation, reliability and missing data reduction. In preparation for this grant

application a systematic review of the evidence on collecting resource use data from patients will be

conducted.

http://www.dirum.org/


19

(c) Feasibility of using routine data to supplement resource use data in multi-centre trials

In collaboration with colleagues within the school: Turner, Martin, Donovan, Metcalfe, Lane, and

Macleod; and externally, Verne (South West Public Health Observatory), Oliver (University of York),

Van Staa (General Practice research database), Neal ( University of Cambridge) and Hamdy

(University of Oxford), a second stage full grant proposal has been submitted to the NIHR HSR, the

aim of which is to evaluate the feasibility, validity and costs of utilising routine NHS electronic

databases compared with using data from detailed review of medical records and nurse interviews

within two linked population-based RCTs.

If the Hospital Episode Statistics (HES) data are proved to be valid, this has the potential for long

term individual patient data to be used in economic evaluations of RCTs, and also as a way of

validating economic models. Potentially older trials which used models to extrapolate from the RCT

will be sought. If the original consent allows then HES information would be obtained for the

datasets, and the long term costs of these trials would be estimated and compared with the original

model estimate.

(d) Missing data in economic evaluation of RCTs

Treatment of missing data: A literature review was conducted as background work to establish what

missing data techniques were currently in use in cost effectiveness analyses of RCTs. This led to a

paper at the HESG conference and a subsequent publication in Health Economics.

In order to assess which method should be used to analyse missing data there is a need to know why

the data are missing. In relation to clinical outcomes it is thought that information is often missing

because patients have deteriorated. This may not be the case in relation to resource use. Using data

already collected from the Bristol helicobacter project, information from the resource use

questionnaire (RUQ) and the General Practitioner (GP) records review will be evaluated as to

whether those who had incomplete data in respect of GP visits in the RUQ had fewer GP visits as

derived from the medical records.

Prevention of missing data: This project was in collaboration with the NIHR Restore programme

team, led by Professor Ashley Blom of the School of Clinical Sciences. As part of the APEX

(Arthroplasty pain experience study) pilot study, an RCT examining the use of a resource use log in

reducing the amount of missing data in resource use questionnaires was conducted. The abstract

has been accepted for two conferences and is currently being written up for publication.

There is very little evidence as to what might reduce the amount of missing data from resource use

questionnaires. The following are ideas for randomised controlled trials which in collaboration with

trialists could be conducted in feasibility studies of RCTs to enlarge the evidence base.

Sending the RUQ separately rather than combining it with the main study questionnaire

Patients to be randomised to one of two versions of RUQs:

o Initial design state prior to validation

o One which has been validated

Placement of resource use questions within the main trial questionnaire

Placement of questions within the resource use questionnaire.


20

(e) Timely and complete publication of economic evaluations alongside RCTs

Trials which intended to conduct an economic evaluation were identified in the International

Standard Randomised Controlled Trial Number (ISRCTN) register. The subsequent effectiveness and

economic evaluation paper were sought in order to determine whether economic evaluations are

subject to publication bias by considering whether economic data are as likely to be reported, and

reported as promptly, as effectiveness data. This work was presented at the Society for Social

Medicine Meeting (September 2011). The paper is currently under review with Pharmacoeconomics.

(f) A comparison of using reference costs versus finance department costs in trial data

Within randomised controlled trials, the economic evaluation analysis is often delayed because of a

lack of cost data. In a study using data from the CAP (Comparison Arm for ProtecT) trial, (Primary

investigator (PI), Richard Martin), inpatient resource use of patients in the last year of life is being

evaluated. Two ways of obtaining costs for the resource use (hospital finance and healthcare

resource group (HRG) codes) are being examined to see whether the type of approach matters, and

assess the time it takes to do both approaches i.e. the time to apply HRG codes to trial data, and the

time taken to obtain information from finance departments.

Once the results of this study are known, there is a potential to join with other academics currently

working in this area, e.g. Dakin (University of Oxford), and to produce guidelines in relation to

costing resource use within trials.

(g) Unbiased estimation of cost-effectiveness when not all RCT participants comply with their

allocated treatment

Hollingworth contributed to this work which is described more fully under the “Statistical methods

in the design and analysis of challenging RCTs” theme.


a) Feasibility of using routine data (e.g. HES) to supplement resource use data in multi-centre

trials

A second stage full grant proposal (Primary investigator (PI) Emma Turner ) has been submitted to

the NIHR HSR, the aim of which is to evaluate the feasibility, validity and costs of utilising routine

NHS electronic databases compared with using data from detailed review of medical records and

nurse interviews within two linked population-based RCTs.

b) The impact of different methods of valuing productivity changes in economic evaluation in

different settings.

General guidelines exist on how best to deal with productivity changes in economic evaluation.

There have however been no investigations into their appropriateness in different settings, e.g. a

condition with low prevalence which prevents patients from working for long durations will have a

different pattern to that with high prevalence and short durations of time off work. Data from two

contrasting trials PhysioDirect and COBALT will be used to: estimate productivity losses using

different methods; investigate the effect of different methods of valuation in different populations

and settings and refine existing guidelines in the light of the results


21

c) To explore within trials involving children how best to value their time off from school.

There has been little research how to value Children’s time off from school for use in health

economic evaluations. People may value their child’s time off from school differently depending on

the age of the child and the nature of this absenteeism i.e. if the child is off for weeks at a time

compared with a day a week. A systematic review of the literature is therefore needed as

background for a grant application in which it will be proposed that Willingness to Pay exercises are

conducted within current children centred trials within the BRTC and then within a general

population sample.

d) To evaluate the face validity, feasibility and responsiveness of the EQ-5D-5L, EQ-5D-3L, ICECAP

in clinical trials

Established health utility measures are often considered unresponsive for patients in clinical trials. Newer measures of health state preferences (e.g. EQ-5D-5L) or capabilities (e.g. ICECAP-O) may be more valid and responsive. In a proposed cohort study of 1,500 patients undergoing cataract surgery, the responsiveness of existing and emerging health economic indices will be compared. Patients will receive the ICECAP-O questionnaire at baseline and follow-up (3 months) and will be randomly (1:1) assigned to receive either the traditional 3 level EQ-5D, or the recent 5 level EQ-5D (potentially more responsive).


22

6. Developing and establishing methods to improve the integration and reporting of clinical and patient reported outcomes in RCTs to influence clinical decision-making

Aim of theme

The overall aim of the theme is to develop and establish methods to improve the integration and

reporting of clinical and patient reported outcomes (PROs) in RCTs. This is being achieved by

supporting the integrated use of PROs alongside clinical outcome in RCTs, by developing methods for

clinicians to use to communicate PROs and clinical outcomes from RCTs in practice with patients, by

collaborating nationally and internationally to agree standards of PRO reporting in RCTs and by

training and influencing clinicians, clinical trialists and clinical researchers in the above.

Research areas

(a) Understanding PROs reporting in clinical trials to identify methods for improvement

A systematic review examining standards of PRO reporting (and its integration with clinical

outcomes) in RCTs in curative treatment for gastro intestinal cancer has identified that many trials

lack hypothesis driven measurement of PROs and therefore results are rarely integrated with clinical

findings, often being published in separate journal articles and many months apart. Methods to

communicate PRO and clinical results from RCTs with patients have been piloted in hypothetical

settings. Assessment of patient understanding, interpretation and preference for graphical and

narrative data formats were performed and checked with a blinded observer. Results showed that

patients had a high degree of understanding and preferred graphical data over narratives.

(b) Designing RCTs with integrated PRO measurement to clinical influence decision-making

Theme members have designed and are overseeing PRO measurement in RCTs using standard and

rigorous methods in collaboration with local, regional and national trials units. This includes cancer

trials, the OEO5 and STO3 trials collaborations with the MRC CTU, the COUGAR, COG and Enrol trials,

collaborations with Cambridge and Oxford, the New EPOC and BOXIT trials collaborations with CTUs

in Southampton and London, the SCOPE1 and ROCs trials collaborations with the Welsh Cancer Trials

Unit and the 123-Go trial in development in collaboration with the CTU in Leeds. Theme members

are also leading recently funded RCTs with dual primary clinical and PRO end points to encourage

the use of PRO assessment to influence clinical decision-making. This includes the BY-BAND (PI

Blazeby), ROMIO (PI Metcalfe and Blazeby) and ROCS (co-applicant Blazeby) trials.

(c) Exploring methods for blinding of patients, professionals and outcome assessors in trials

An affiliated theme MD student (Boulind) with supervisors Blazeby, Avery and Metcalfe have

investigated and tested methods to achieve blinding in two feasibility RCTs in surgery, the EWIC and

Enrol trials (Research for Patient Benefit (RfPB) and CRUK funded in collaboration with Yeovil District

Hospital and the Octo CTU, Oxford, respectively). Participants and staff are blinded to the

interventions by use of large wound bandages (Enrol trial) and a double dummy technique for

infusion of pain relief (EWIC) and the success of blinding tested with a modified Bang Blinding test

and with in-depth qualitative interviews conducted with patients and staff to probe what informed


23

responses to the Bang Blinding Index. A systematic review of methods to test blinding in non-

pharmaceutical trials has also been initiated.

(d) Continued development of better methods for assessing PROs and other outcomes in RCTs

European Organisation for Research and Treatment of Cancer (EORTC) questionnaire modules: Work

completing and further testing the psychometric and clinical testing of EORTC questionnaire

modules for superficial bladder cancer, primary liver cancer and the Mexican version of the

oesophago-gastric cancer module has been completed with collaborations with the BOXIT trial, PI

Prof Kelly, London CTU, Prof W Chu Chei (National University of Singapore and the EORTC Quality of

Life Group) and Dr Oñate-Ocaña (National Cancer Institute, Mexico City).

Core outcome sets: Development of clinical and patient core outcome sets that will be used as a

minimum set of outcomes in trials to reduce outcome reporting bias and improve data synthesis are

under development for oesophageal cancer, colorectal cancer, breast reconstruction and bariatric

surgery. Work completed so far includes literature reviews summarising the heterogeneity of

outcome reporting and the need for core outcome sets. Links to the COMET initiative with cross Hub

funding (North West Hub, All-Ireland Hub and Prof Altman) are established and an MRP grant

application submitted to continue this project. The core outcome sets in development will be

completed and it is planned to work with stakeholders to ensure their update and use. The COMET

initiative plans to undertake work to establish methods to assess the quality of core outcome sets

and to support the widespread use of this approach for improving outcome assessment in trials.

An extension to ConSORT for PRO reporting in trials: A Hub network grant has been obtained to

establish a CONSORT extension to set standards for reporting of PROs in RCTs, in collaboration with

the West Midlands Hub, CONSORT, and ISOQOL (the International Society of Quality of Life

Research). A survey of views of different aspects of trial design has been undertaken and a

consensus meeting is planned for January 2012.

(e) Undertaking studies to examine PROs in clinical settings

Reporting and analyses of PROs and clinical outcomes in various clinical settings (non RCT designs)

have continued, and these provide opportunities to examine different methods for presenting data,

although the work is more applied than methodological. Work in surgery for pancreatic cancer,

resection of hepatic metastases from colorectal cancer has been completed. Exploratory work

analysing the prognostic value of baseline and changes in PROs over time has also been undertaken

which may have relevance to RCTs if baseline PROs differ between study arms.


An NIHR program grant is under development to include outcomes research specific to surgical

trials. This will include completion and implementation of the core outcome sets and development

of sets for emergency surgery and other cancer sites. Within these projects methodological work

examining ways to optimise core outcome set development (e.g. methods to identify long list of

outcomes looking at literature reviews) will be undertaken. The program will contain work around

recruitment into surgical trials looking at methods to optimise screening logs and a theme that will

develop methods (an intervention) for clinicians to use to communicate PRO and clinical results from

RCTs with patients during decision making for cancer surgery.


24

Appendices


Director

Prof J Blazeby

1. Developing & integrating qualitative research methods to improve RCT design

Leads:

Prof J Donovan Dr A Heawood

Research fellow:

Dr N Mills

Other members:

Dr S Paramasivan Prof R Campbell Dr S Audrey

MD student with outcomes theme:

Dr S Strong

Affiliated PhD student:

Ms L Bowen


Leads:

Dr S Noble Dr W Hollingworth

Research assistants:

Ms D McKell-Redwood Dr J Thorn Other member: Dr S Hollinghurst

2. Evidence synthesis & EVI analysis for prioritisation of RCTs

Leads:

Prof T Ades Dr N Welton

Research associate:

Dr J Madan

Affiliated PhD student:

Ms P Guyot

Affiliated NIHR Fellow:

Mr A Franchini

4. Statistical methods in the design and analysis of RCTs

Lead:

Dr C Metcalfe

Research associate:

Dr L Hampson, left 2011 Dr L Odondi, starting Nov 2011

Other members:

Dr ST Brookes Dr A Montgomery Prof T Peters Prof J Sterne Prof K Tilling Dr N Welton Dr N Wiles

Affiliated MD student with outcomes theme:

Dr C Boulind

3. Improving trial design & conduct

Lead:

Dr A Lane

Research associate with outcomes theme:

Ms R Macefield

Other member with outcomes theme:

Dr K Avery

Affiliated NIHR PhD student with outcomes and qualitative theme:

Dr N Blencowe

6. Improving clinical and patient reported outcome measurement in RCTs

Lead:

Prof J Blazeby

Research associate with conduct theme:

Ms R Macefield

Other members:

Dr S Brookes

Affiliated NIHR PhD students:

Dr R Whistance Ms K Coulman

Affiliated PhD students:

Dr S Potter Dr A McNair

Affiliated academic F2:

C Davis J Ward

1. Structure of the MRC ConDuCT Hub


2. Collaborations External collaborations between the ConDuCT Hub and regional and national clinical trials units

1. Bristol Randomised Trials Collaboration, Bristol University

Study details Collaborating Hub theme(s)

HTA funding for ROMIO trial. Feasibility surgical trial with integrated qualitative research to optimise recruitment, development of core clinical outcome set and in-theatre study of surgical protocol and methods to measure adherence to it

Outcomes, statistics, qualitative methods, economics

DUTY trial with integrated PRIME method for improving trial monitoring Trial Conduct

APEX study is a feasibility study including an RCT examining the use of a resource use log in reducing the amount of missing data in resource use questionnaires.

Economics

Feasibility trial of chemoradiotherapy versus surgery. Integrated qualitative methods to optimise recruitment

Qualitative, outcomes and economics

Anticipate – feasibility trial of antenatal CBT intervention Economics

Feasibility of RCT of interventions for CFS/ME with integrated qualitative work around recruitment. Full trial recently funded Lindbury and Ashden Trust

Qualitative

OTIS: Negotiating a 'therapeutic alliance' during online CBT: an analysis of patient-therapist interactions Qualitative

2. Clinical Trials & Evaluation Unit, Bristol University


HTA funding for BY-BAND trial. Full trial with in-built feasibility stage, integrated qualitative research to optimise recruitment and development of a core clinical outcome set.

Outcomes, qualitative

3. Wales Cancer Trials Unit, Cardiff University


Co-applicant and HRQOL expert on CRUK SCOPE 1 trial and HTA funded ROC trial, comparing radiotherapy in addition to stenting for oesophageal cancer palliation

Outcomes


27

4. Peninsula Clinical Trials Unit, Peninsula Medical School


Qualitative study linked to online trial of CBT for depression; using conversation analysis. Qualitative

5. South East Wales Trials Unit


Project SFP Cymru, integrated PRIME method for improving trial monitoring Trial conduct

6. OCTO clinical trials unit, Oxford


Co-applicant and HRQOL expert on Enrol trial and integrated study testing success of blinding Outcomes

7. Southampton clinical trials unit


HRQL expertise and co-applicant New EPOC trial Outcomes

8. Warwick CTU


HRQL expertise and co-applicant COUGAR trial Outcomes

9. London MRC CTU


HRQL and surgical expertise and co-applicant OEO5 and STO3 (CRUK funded) and AddAspirin trial Outcomes


28

10. ICR CTU London


Qualitative study within SPARE to optimise recruitment, a CTAAC funded trial of surgery versus non surgical treatment for bladder cancer

Qualitative

HRQL expertise and co-applicant of BOXIT trial, trial questionnaire validation completed. Outcomes

Blazeby on trial steering committee of Lopera also run by this trials unit Hub director

11. Priment CTU


Member of IDMC of HTA funded CanTalk trial of cognitive behavioural therapy Statistics

12. Cambridge


Member of IDMC of Impact trial Statistics theme

13. Aberdeen


Chair of Trial Steering Committee of UKuff Hub director

Qualitative recruitment study within the CLASS trial, an HTA funded trial of treatment for varicose veins Qualitative

Qualitative study looking at the acceptability of the intervention within the SCOOP trial (MRC/ARC), evaluating the effectiveness of a screening programme for prevention of fractures in elderly women.

Qualitative

14. Norwich, University of East Anglia


SCOOP: Screening of older women for prevention of cancer Qualitative


3. Workshops

a) MRC HTMR workshops

Economic evaluation

‘The use of ICECAP measures in clinical trials and economic evaluation’ (Birmingham, February 2011

led by Midlands Hub)

‘Resource-use measurement based on patient recall: Issues, challenges and DIRUM (Database of

Instruments for Resource-Use Measurement)’ (Noble, Hollingworth, Birmingham, October 2011, led

by ConDuCT, North West and Midland Hubs)

Qualitative research and outcomes

‘Methods to improve recruitment and study design of surgical trials’ (Blazeby, Donovan, Mills,

London, September 2011 led by ConDuCT Hub and Cambridge)

Planned workshops for 2012

Expected Value of Information ‘Consensus decision models for biologic arthritis therapies’ (Welton

and Ades led by ConDuCT)

‘How qualitative methods can contribute to the design and conduct of randomised trials’ (Mills,

Blazeby, Donovan led by ConDuCT, planned for March 2011)

‘Trial monitoring: towards establishing best practice’ (Lane, Macefield, led by North West)

‘Integrating PROs into RCTs’ planned for Autumn 2012

b) Other workshops that Hub members have contributed to

‘Methods for evaluating service delivery models for end of life care (EoLC): development of best

practice guidance’ Health Economics expert think tank (Manchester, May 2011).

Evidence Synthesis and Decision modelling (Ades, Welton, Venice, June 2009).

Expected Value of Information for Research Prioritisation and Trial Design. (Welton, half day, Bern,

February 2009).

Indirect and Mixed Treatment Comparisons. (Ades, Welton, 3 days, in Leicester August 2009, London

September 2010, Leicester September and November 2011).

An Introduction to Bayesian Methods for Health Technology Assessment. (Welton, half day, Dublin,

June 2010).

Mixed Treatment Comparisons in Health Technology Assessment. (Welton, 1 day, Canada, May

2010)

L


30

Biologic Therapies in Inflammatory Joint Diseases: Models for Decision Making (Ades, Madan,

London, September 2010)

Network Meta-Analysis in Clinical Guidelines and Cost-Effectiveness Analyses. 1-day workshop for

the NICE Clinical Guidelines Development Groups (Ades, Welton, London, October 2011).

Blazeby with Calvert (Midlands Hub) and Brundage have run a half day workshop, “Improving the

Design, Conduct and Reporting of Quality of Life in Randomized Clinical Trials” Denver, October

2011).

Integrating qualitative research with RCTs. Invited lecture and workshop (Donovan, HSR Unit,

University of Aberdeen, May 2010).

QualiTi workshops - Biannual training workshops on integrating qualitative methods into RCTs led by

Heawood and Mills (49 members currently) (2009-ongoing).

Integrating qualitative research methods into randomised controlled trials (SOSCM short course run

by theme members: planned for Spring 2013)


31

4. Publications

Most relevant publications for each theme

N.B. authors in bold text indicate ConDuCT Hub members


N.B. Heawood publishes as Shaw Donovan JL, Lane JA, Peters TJ, Brindle L, Salter E, Gillatt D, Powell P, Bollina P, Neal DE, Hamdy FC,

ProtecT Study Group. Development of a complex intervention improved randomization and

informed consent in a randomized controlled trial. J Clin Epidemiol 2009; 62: 29-36.

Mills N, Donovan JL, Wade J, Hamdy FC, Neal DE, Lane JA. Exploring treatment preferences

facilitated recruitment to randomized controlled trials. J Clin Epidemiol 2011; 64: 1127-1136.

Paramasivan S, Huddart R, Hall E, Lewis R, Birtle A, Donovan JL. Key issues in recruitment to

randomised controlled trials with very different interventions: a qualitative investigation of

recruitment to the SPARE trial. Trials 2011; 12:78.

Thompson EA, Shaw A, Nichol J, Hollinghurst S, Henderson AJ, Thompson, Sharp D. The feasibility of

a pragmatic randomised controlled trial to compare usual care with usual care plus individualised

homeopathy, in children requiring secondary care for asthma. Homeopathy (in press)

DOI:10.1016/j.homp.2011.05.001.

Wade J, Donovan JL, Lane JA, Neal DE & Hamdy F. It's not just what you say, it's also how you say it:

opening the black box of informed consent appointments in randomised controlled trial Soc Sci Med

2009; 68: 2018-28.

2. Evidence synthesis and expected value of information for prioritisation of RCTs

Griffin S, Welton NJ, Claxton KP. Exploring the research decision space: the expected value of

information for sequential research designs. Medical Decision Making 2010; 30: 155-162.

Price MJ, Welton NJ, Briggs A, Ades AE. Model averaging in the presence of structural uncertainty

about treatment effects: impact on treatment decision and Expected Value of Information. Value in

Health 2011; 14: 205-218.

Soares M, Welton NJ, Harrison DA, Peura P, Shankar Hari M, Harvey SE, Madan J, Ades AE, Palmer

SJ, Rowan KM. An evaluation of the feasibility, cost and value of information of a multicentre


32

randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic

shock) (08/70/01). Health Technology Assessment 2011 (In press).

Welton NJ, Ades AE. Research decisions in the face of heterogeneity: what can a new study tell us?

Health Economics 2011 (In press).

Welton NJ, Madan J, Ades AE. Are head-to-head trials of biologics needed: the role of value of

information methods in arthritis research. Rheumatology 2011; 50: iv19-iv25.


Donovan JL, Lane JA, Peters TJ, Brindle LA, Salter L, Gillatt D, Powell P, Bollina P, Neal DE, Hamdy FC.

Development of a complex intervention to improve randomisation and informed consent in

randomised controlled trials. J Clinical Epidemiology 2009; 62: 29-36.

Down L, Metcalfe C, Avery K, Noble S, Lane JA, Neal DE, Hamdy FC, Donovan JL. Practice-level

factors distinguishing General Practitioners who more readily participated in a large randomised

trial. J Clinical Epidemiology 2009; 62: 67-73.

Lane JA, Wade J, Down L, Bonnington S, Holding P, Lennon T, Jones A, Salter CE, Neal DE, Hamdy FC,

Donovan JL. Peer review intervention for monitoring and evaluating sites (PRIME) that improved

randomised trial conduct and performance. J Clinical Epidemiology 2011; 64: 628-636.

Macefield R, Beswick A, Blazeby JM, Lane JA. A systematic review of on-site monitoring methods for

healthcare randomised controlled trials. (Submitted to Clinical Trials; under revision).


Metcalfe C. The analysis of cross-over trials with baseline measurements. Stat Med 2010; 29: 3211-

3218.

Montgomery AA, Astin MP, Peters TJ. Reporting of factorial trials of complex interventions in

community settings: a systematic review. Trials 2011; 12: 179.

Noble SM, Hollingworth W, Tilling K. Missing data in trial-based cost-effectiveness analysis: the

current state of play. Health Econ 2011 (In press).

Cooper NJ, Peters J, Lai MC, Juni P, Wandel S, Palmer S, Paulden M, Conti S, Welton NJ, Abrams KR,

Bujkiewicz S, Spiegelhalter D, Sutton AJ. How valuable are multiple treatment comparison methods

in evidence-based health-care evaluation? Value Health 2011; 14: 371-80.

Sterne JA, Sutton AJ, Ionnidis JP, et al. Recommendations for examining and interpreting funnel plot

asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343: d4002.


33


Hollingworth W, Cohen D, Hawkins J, Hughes RA, Moore LAR, Holliday JC, et al ‘Reducing smoking in

adolescents: cost-effectiveness results from the cluster randomised ASSIST (A Stop Smoking In

Schools Trial)’ Nicotine and Tobacco Research 2011 (In press).

Hollinghurst S, Emmett C, Peters TJ, Watson H, Fahey T, Murphy D, Montgomery A. Economic

evaluation of the DiAMOND randomized trial: cost and outcomes of 2 decision aids for mode of

delivery among women with a previous caesarean section. Medical Decision Making 2010; 30(4):

453-63 DOI: 10.1177/0272989X09353195.

Hollingworth W, McKell-Redwood D, Hampson L, Metcalfe C. Cost utility analysis conducted

alongside RCTs: Are economic endpoints considered in sample size calculations and does it matter?

(Submitted to Clinical Trials.)

Noble SM, Hollingworth W, Tilling K. Missing data in trial-based cost-effectiveness analysis: the

current state of play. Health Economics 2010; DOI: 10.1002/hec.1693.

Thorn J, Noble S, Hollingworth W. Timely and complete publication of economic evaluations

alongside randomised controlled trials. (Submitted to PharmacoEconomics.)


Davis CR, McNair AG, Brigic A, Clarke MG, Brookes ST, Thomas MG, Blazeby JM. Optimising

methods for communicating survival data to patients undergoing cancer surgery. Eur J Cancer 2010;

46(18): 3192-9.

McNair AG, Brookes ST, Davis CR, Argyropoulos M, Blazeby JM. Communicating the results of

randomized clinical trials: do patients understand multidimensional patient-reported outcomes? J

Clin Oncol 2010; 28(5): 738-43.

Potter S, Brigic A, Whiting PF, Cawthorn SJ, Avery KN, Donovan JL, Blazeby JM. Reporting clinical

outcomes of breast reconstruction: a systematic review. J Natl Cancer Inst 2011; 103(1): 31-46.

Potter S, Harcourt D, Cawthorn S, Warr R, Mills N, Havercroft D, Blazeby J. Assessment of cosmesis

after breast reconstruction surgery: a systematic review. Ann Surg Oncol 2011; 18(3): 813-23.

Whistance RN, Conroy T, Chie W, Costantini A, Sezer O, Koller M, Johnson CD, Pilkington SA, Arraras

J, Ben-Josef E, Pullyblank AM, Fayers P, Blazeby JM, European Organisation for the Research and

Treatment of Cancer Quality of Life Group. Clinical and psychometric validation of the EORTC QLQ-

CR29 questionnaire module to assess health-related quality of life in patients with colorectal cancer.

Eur J Cancer 2009; 45(17): 3017-26. Epub 2009 Sep 16.

http://www.ncbi.nlm.nih.gov/pubmed/20728342











34

All other publications

N.B. Heawood publishes as Shaw

In press/published

Ades AE, Madan J, Welton NJ. Indirect and mixed treatment comparisons in arthritis research.

Rheumatology 2011; 50: iv5-iv9.

Ades AE, Mavranezouli I, Dias S, Welton NJ, Whittington C, Kendall T. Network meta-analysis with

competing risk outcomes. Value in Health 2010; 13: 976-983 (voted 2010 best paper by Value in

Health editorial board).

Ades AE. Bayesian Evidence Synthesis. In M Kattan (Ed), Sage Encyclopedia of Medical Decision

Making, 2009: Sage Publications Inc, pp59-63.

Andrews RC, Cooper AR, Montgomery AA, Norcross AJ, Peters TJ, et al. Diet versus diet plus physical

activity versus usual care in patients with newly diagnosed type 2 diabetes: the Early ACTID

randomised, controlled trial. The Lancet 2011; 378: 129-139.

Araya R, Montgomery AA, Fritsch R, Gunnell D, Stallard P, Noble S, Martinez V, Barroilhet S,

Vohringer P, Guajardo V, Cova F, Gaete J, Gomez A and Rojas G. School-based intervention to

improve the mental health of low-income, secondary school students in Santiago, Chile (YPSA): study

protocol for a randomized controlled trial. Trials 2011; 12: 49.

Avery K, Hughes R, McNair A, Alderson D, Barham P, Blazeby J. Health-related quality of life and

survival in the 2 years after surgery for gastric cancer. Eur J Surg Oncol 2010; 36(2): 148-54.

Baxter H, Winder R, Chalder M, Wright C, Sherlock S, Haase A, Wiles NJ, Montgomery AA, Taylor AH,

Fox KR, Lawlor DA, Peters TJ, Sharp DJ, Campbell J, Lewis G. Physical activity as a treatment for

depression: the TREAD randomised trial protocol. Trials 2010; 11: 105.

Beattie A, Shaw A, Kaur S, Kessler D. Primary care patients’ expectations and experiences of online

Cognitive Behavioural Therapy (CBT) for depression: a qualitative study. Health Expectations 2009;

12(1): 45-59.

Beaver K, Hollingworth W, McDonald R, Dunn G, Tysver-Robinson D, Thomson L, Hindley AC,

Susnerwala SS, Luker K. Economic evaluation of a randomized clinical trial of hospital versus

telephone follow-up after treatment for breast cancer. Br J Surg 2009; 96(12); 1406-15 DOI:

10.1002/bjs.6753.

Blazeby JM, Blencowe NS, Titcomb DR, Metcalfe C, Hollowood AD, Barham CP. Demonstration of the

IDEAL recommendations for evaluating and reporting surgical innovation using minimally invasive

oesophagectomy. Br J Surgery 2011; 98: 544-51.

Blazeby JM, Morton D, Sharples L, Donovan JL. Recruiting patients into randomised controlled trials

in surgery. Br J Surg 2011 (In press).




35

Blazeby JM, Soulsby M, Winstone K, King PM, Bulley S, Kennedy RH. A qualitative evaluation of

patients' experiences of an enhanced recovery programme for colorectal cancer. Colorectal Dis

2010; 12(10 Online): e236-42.

Blencowe NS, Strong S, McNair AGK, Brookes ST, Crosby T, Griffin SM, Blazeby JM. Reporting of

short-term clinical outcomes following esophagectomy: A systematic review. Annals of Surgery 2011

(In press).

Bryan S, Dormandy E, Roberts TE, Ades AE, Barton P, Juarez-Garcia A, Andronis L, Karnon J, Marteau

TM. The cost-effectiveness of primary care screening for sickle cell and thalassaemia. British Journal

of General Practice 2011 (In press).

Burch J, Paulden M, Conti S, Stock C, Corbett M, Welton NJ, et al. Antiviral drugs for the treatment of

influenza: a systematic review and economic evaluation. Health Technology Assessment 2009;

13(58).

Caldwell DM, Welton NJ, Ades AE. Mixed treatment comparisons methods provide internally

coherent treatment effect estimates based on overviews of reviews, and may reveal inconsistency.

Journal of Clinical Epidemiology 2010; 63: 875-88.

Calvert M, Blazeby JM, Moher D, Brundage M. Improving health-related quality of life reporting in

clinical trials: why do we need a CONSORT extension? The Lancet 2011 (In press).

Chu Chie, JM Blazeby, CF Hsiao, H Chia Chiu, RT Poon, N Mikoshiba, G Al-Kadhimi, N Heaton, J

Calara, P Collins, K Caddick, A Constantini, V Vilgrain, L Trinquart, C Chiang. International cross-

cultural field validation of an EORTC questionnaire module for patients with primary liver cancer, the

EORTC QLQ-HCC18. In press Hepatology

Cooper NJ, Morris D, Sutton AJ, Ades AE, Welton NJ. Addressing between-study heterogeneity and

inconsistency in mixed treatment comparisons: Application to stroke prevention treatments in

individuals with non-rheumatic Atrial Fibrillation. Statistics in Medicine 2009; 28: 1861-1881.

Cooper NJ, Peters J, Lai MCW, Juni P, Wandel S, Palmer S, Paulden M, Conti S, Welton NJ, Abrams

KR, Bujkiewicz S, Spiegelhalter D, Sutton AJ. How valuable are multiple treatment comparison

methods in evidence-based healthcare evaluation? Value in Health 2011 (In press).

Dakin HA, Welton NJ, Ades AE, Collins S, Orme M, Kelly S. Mixed treatment comparison of repeated

measurements of a continuous endpoint: An example using topical treatments for primary open-

angle glaucoma and ocular hypertension. Statistics in Medicine 2011; 30: 2511-2535.

Davis CR, McNair AG, Brigic A, Clarke MG, Brookes ST, Thomas MG, Blazeby JM. Optimising

methods for communicating survival data to patients undergoing cancer surgery. Eur J Cancer 2010;

46: 3192-9.

Dias S, Welton NJ, Ades AE. Study designs to detect sponsorship and other biases in systematic

reviews. Journal of Clinical Epidemiology 2010; 63: 587-588.

Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in Mixed Treatment Comparison

Meta-analysis. Statistics in Medicine 2010; 29: 932-944.




36

Dias S, Welton NJ, Marinho VCC, Salanti G, Higgins J, Ades AE. Estimation and adjustment of Bias in

randomised evidence using Mixed Treatment Comparison Meta-analysis. JRSSA 2010; 173: 613-629.

Djärv T, Metcalfe C, Avery KN, Lagergren P, Blazeby JM. Prognostic value of changes in health-

related quality of life scores during curative treatment for esophagogastric cancer. J Clin Oncol 2010;

28(10): 1666-70.

Donovan JL, Lane JA, Peters TJ, Brindle L, Salter E, Gillatt D, Powell P, Bollina P, Neal DE, Hamdy FC

for the ProtecT Study Group. Development of a complex intervention improved randomization and

informed consent in a randomized controlled. J Clin Epidemiol 2009; 62: 29-36.

Dormandy E, Bryan S, Gulliford M, Roberts R, Ades AE, Calnan M, Atkin K, Karnon J, Barton P, Logan

J, Kavalier F, Harris H, Johnston T, Anionwu E, Jones P, Davis V, Wild B, Dick M, Marteau M. Antenatal

screening for haemoglobinopathies in primary care: a cluster randomised trial to inform a simulation

model. Health Technology Assessment 2010; 14(20).

Down L, Metcalfe C, Avery K, Noble S, Lane JA, Neal D, Hamdy F, Donovan J. Practice level factors

distinguishing general practitioners who more readily participated in a large randomised trial were

identified. J Clin Epidemiol 2009; 62: 67-73.

Edwards SJ, Clarke MJ, Wordsworth S, Welton NJ. Carbapenems versus other beta-lactams in the

treatment of hospitalised patients with infection: a mixed treatment comparison. Current Medical

Research & Opinion 2009; 25(1): 251-61.

Emmett C, Redmond N, Peters T, Clarke S, Shepstone Lee, Lenaghan E, Shaw A. Acceptability of

screening to prevent osteoporotic fractures in older women: a qualitative study. Family Practice

2011; 0:1–8. DOI:10.1093/fampra/cmr069.

Ford A, Bergh C, Sodersten P, Sabin M, Hollinghurst S, Hunt L, Shield J. Treatment of childhood

obesity by retraining eating behaviour: a randomised trial. BMJ 2010; 340: b5388.

Frost J, Shaw A, Montgomery A, Murphy D. Women’s views on the use of decision aids for decision

making about the method of delivery following a previous caesarean section: qualitative interview

study. British Journal of Obstetrics and Gynaecology 2009; 116: 896–905.

Govan L, Ades AE, Weir CJ, Welton NJ, Langhorne P. Controlling ecological bias in evidence

synthesis of trials reporting on collapsed and overlapping covariate categories. Statistics in Medicine

2010; 29: 1340-1356.

Guyot P, Welton NJ, Ouwens, MJNM, Ades AE. Survival time outcomes in randomised controlled

trials and meta-analyses: the parallel universes of efficacy and cost-effectiveness. Value in Health

2011 (In press).

Harrington R, Taylor G, Hollinghurst S, Reed M, Kay H, Wood VA. A community-based exercise and

education scheme for stroke survivors: a randomized controlled trial and economic evaluation.

Clinical Rehabilitation 2010; 24: 3-15 DOI: 10.1177/0269215509347437.




37

Harvey RF, Lane JA, Nair P, Egger M, Harvey I, Donovan J, Murray L. Clinical trial: prolonged

beneficial effect of Helicobacter pylori eradication on dyspepsia consultations – the Bristol

Helicobacter Project. Aliment Pharmacol Ther 2010; 32: 394-400.

Hollinghurst S, Peters TJ, Kaur S, Wiles N, Lewis G, Kessler D. Cost-effectiveness of therapist-

delivered online cognitive-behavioural therapy for depression: randomised controlled trial. Br J

Psych 2010; 197: 297-304 DOI: 10.1192/bjp.bp.109.073080.

Howard L, de Salis I, Tomlin Z, Thornicroft G, Donovan JL. Why is recruitment to trials difficult? An

investigation into recruitment difficulties in an RCT of supported employment for people with severe

mental illness. Contemporary Clinical Trials 2009; 30: 40-46.

Jarvik JG, Comstock BA, Kliot M, Turner JA, Chan L, Heagerty PJ, Hollingworth W, Kerrigan CL, Deyo

RA. Surgery versus non-surgical therapy for carpal tunnel syndrome: a randomised parallel-group

trial. Lancet 2009; 374: 1074-1081.

Jones R, Jones RO, McCowan C, Montgomery AA, Fahey T. The external validity of published

randomized controlled trials in primary care. BMC Family Practice 2009; 10: 5.

Kallmes DF, Comstock BA, Heagerty PJ, Turner JA, Wilson DJ, Diamond TH, Edwards R, Gray LA, Stout

L, Owen S, Hollingworth W, Ghdoke B, Annesley-Williams DJ, Ralston SH, Jarvik JG. A randomized

trial of vertebroplasty for osteoporotic spinal fractures. N Eng J Med 2009; 361: 569-579.

Kessler D, Kaur S, Wiles N, King M, Weich S, Lewis G, Sharp DJ, Araya R, Hollinghurst S, Peters TJ.

Therapist-delivered Internet psychotherapy for depression: a randomised controlled trial in primary

care. Lancet 2009; 374: 594-595.

Kessler D, Lewis G, Kaur S, Wiles N, King M, Weich S, Sharp DJ, Araya R, Hollinghurst S, Peters TJ.

Therapist-delivered internet psychotherapy for depression in primary care: a randomised controlled

trial. The Lancet 2009; 374: 628-34. DOI: 10.1016/S0140-6736(09)61257-5.

Lancaster GA, Campbell MJ, Eldridge, S, Farrin A, Marchant MA, Muller S, Perera R, Peters T J,

Prevost AT, Rait G. Trials in primary care: statistical issues in the design, conduct and evaluation of

complex interventions. Statistical Methods Medical Research 2010; 19: 349-377.

Lane JA, Murray L, Harvey I, Donovan JL, Nair P, Harvey RF Clinical trial: Helicobacter pylori

eradication is associated with increased body mass index in a randomised controlled trial. Aliment

Pharmacol Ther 2011; 33: 922-929.

Lane JA, Hamdy FC, Martin RM, Turner EL, Neal DE, Donovan JL. Latest results from the UK trials

evaluating prostate cancer screening and treatment: the CAP and ProtecT studies. E J Cancer 2010;

46 (17): 3095-30101.

Lawlor DA, Jago R, Noble SM, Chittleborough CR, Campbell R, Mytton J, Howel LD, Peters TJ, Kipping

RR. The Active for Life Year 5 (AFLY5) school based cluster randomised controlled trial: study

protocol for a randomized controlled trial. Trials 2011; 12: 181.


38

Lewis G, Mulligan J, Wiles N, Cowen P, Craddock N, Ikeda M, Grozeva D, Mason V, Nutt D, Sharp D,

Tallon D, Thomas L, O'Donovan MC, Peters TJ. The 5HT transporter polymorphism and response to

antidepressants: randomised controlled trial. Br J Psychiatr 2011; 198: 464-71.

Lu G, Ades AE. Modeling between-trial variance structure in mixed treatment comparisons.

Biostatistics 2009; 10: 792-805.

Lu G, Welton NJ, Higgins JPT, White IR, Ades AE. Linear inference for mixed treatment comparison

meta-analysis: a two-stage approach. Research Synthesis Methods 2011 (In press).

Madan J, Stevenson M, Cooper K, Ades AE, Whyte S, Akehurst R. Consistency between direct and

indirect trial evidence: Is direct evidence always more reliable? Value in Health 2011; 14: 953-960.

Madan J, Welton NJ, Ades AE. An overview of models used in economic analyses of biologic

therapies for arthritis: from current diversity to future consensus. Rheumatology 2011; 50: iv10-iv18.

Malpass A, Wallond J, Carel H, Kessler D, Ridd M, Shaw A, Sharp D. Transforming the perceptual

situation: A meta-ethnography of qualitative work reporting patients’ experiences of mindfulness

based approaches. Mindfulness (in press).

McIntosh B, Cameron C, Singh SR, Yu C, Ahuja T, Welton NJ, Dahl M. Second-line therapy in patients

with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and

mixed-treatment comparison meta-analysis. Open Medicine 2011; 5: e35.

McNair AG, Blazeby JM. Health-related quality-of-life assessment in GI cancer randomized trials:

improving the impact on clinical practice. Expert Rev Pharmacoecon Outcomes Res 2009; 9(6): 559-

67.

Mills N, Donovan JL, Wade J, Hamdy FC, Neal DE, Lane JA. Exploring treatment preferences

facilitated recruitment to randomised controlled trials: a qualitative study. J Clinical Epidemiology

2011; 64: 1127-1136.

Minasian C, Wallis C, Metcalfe C, Bush A. Comparison of inhaled mannitol, daily rhDNase, and a

combination of both in children with cystic fibrosis: a randomised trial. Thorax 2010; 65: 51-56.

Moreno SG, Sutton AJ, Ades AE, Cooper NJ, Abrams KR. Adjusting for publication biases across

similar interventions performed well when compared to gold standard data. Journal of Clinical

Epidemiology 2011 (In press).

Moreno SG, Sutton AJ, Ades AE, Stanley TD, Abrams KR, Peters JL, Cooper NJ. Assessment of

regression-based methods to adjust for publication bias through a comprehensive simulation study.

BMC Medical Research Methodology 2009; 9: 2 doi:10.1186/1471-2288-9-2.

Moreno SG, Sutton AJ, Turner EH, Abrams KR, Cooper NJ, Palmer TM, Ades AE. Novel methods to

deal with publication bias: global application to anti-depressant trials where a gold standard exists.

BMJ 2009; 339: b2981.




39

Noble S, Donovan J, Turner EL, Metcalfe C, Lane JA , Rowlands M, Neal D, Hamdy F, Ben-Shlomo Y,

Martin RM. Feasibility and cost of obtaining informed consent for essential review of medical

records in large-scale public health research. J Health Research and Policy 2009; 14(2): 77—81.

Oñate-Ocaña LF, Velázquez-Monroy N, Vázquez L, Espinosa-Mireles-de-Villafranca P, Núñez-Rosas E,

Ovando-Lezama M, Vilar-Compte D, García-Hubard G, Carrillo JF, Blazeby JM, Aiello-Crocifoglio V.

Clinical validation of the EORTC QLQ-OG25 questionnaire for the evaluation of health-related quality

of life in Mexican patients with esophagogastric cancers. Psychooncology 2011; May 2. doi:

10.1002/pon.1974.

Parameswaran R, Blazeby JM, Hughes R, Mitchell K, Berrisford RG, Wajed SA. Health-related quality

of life after minimally invasive oesophagectomy. Br J Surg 2010; 97(4): 525-31.

Price MJ, Welton NJ, Ades AE. Parameterisation of treatment effects for meta-analysis in multi-state Markov models. Statistics in Medicine 2011; 30: 140-51.

Rees K, Shaw A, Bennert K, Emmett C, Montgomery A. Healthcare professionals’ views on two

computer-based decision aids for women choosing mode of delivery after previous caesarean

section: a qualitative study. British Journal of Obstetrics and Gynaecology 2009; 116: 906–914.

Rutegård M, Hughes R, Lagergren P, Blazeby JM. Determinants of global quality of life before and

after major cancer surgery: an exploratory study. Qual Life Res 2009; 18(9): 1131-6. Epub 2009.

Salanti G, Ades AE, Ioannidis JPA. Graphical methods and numerical summaries for presenting

results from multiple-treatments meta-analysis: an overview and tutorial. Journal of Clinical

Epidemiology 2011; 64: 163-171.

Salanti G, Dias S, Welton NJ, Ades AE, Golfinopoulos V, Kyrgiou M, Mauri D, Ioannidis J. Evaluating

novel agent effects in multiple treatments meta-regression. Statistics in Medicine 2010; 29: 2369-

2383.

Sampson UK, Metcalfe C, Pfeffer MA, Solomon SD, Zou KH. Composite outcomes: Weighting

component events according to severity assisted interpretation but reduced statistical power. J Clin

Epidemiol 2010; 63: 1156-8.

Sharp D, Chew-Graham C, Tylee A, Lewis G, Howard L, Anderson I, Abel K, Turner K, Hollinghurst S,

Tallon D, McCarthy A, Peters T. A pragmatic randomised controlled trial to compare antidepressants

with a community-based psychosocial intervention for the treatment of women with postnatal

depression: the RESPOND trial. Health Technology Assessment 2010; 14(43).

Stallard P, Montgomery AA, Araya R, Anderson R, Lewis G, Sayal K, Buck R, Millings A, Taylor JA.

Protocol for a randomised controlled trial of a school based cognitive behaviour therapy (CBT)

intervention to prevent depression in high risk adolescents (PROMISE). Trials. 2010; 11: 114.

Tallon D, Mulligan J, Wiles N, Thomas LJ, Peters TJ, Elgie R, Sharp DJ, Lewis G. Involving patients with

depression in primary care research: a survey of patients’ attitudes to participation. British Journal of

General Practice 2011; DOI: 10.3399/bjgp11X567036.

Toerien M, Brookes ST, Metcalfe C, de Salis I, Tomlin Z, Peters TJ, Sterne J, Donovan JL. A review of

reporting of participant recruitment and retention in RCTs in six major journals. Trials 2009; 10: 52.








40

Van den Bruel A, Gailly J, Devriese S, Welton NJ, Shortt AJ, Vrijens F. Comparing ophthalmic

viscoelastic devices on endothelial cell loss during cataract surgery: a meta-analysis using mixed

treatment comparisons. British Journal of Ophthalmology 2011; 95: 5-10.

Wade J, Donovan JL, JA Lane, Neal DE, Hamdy FC. It’s not only what you say, it’s also how you say it:

opening the ‘black box’ of recruitment to randomised controlled trials. Soc Soc Med 2009; 68: 2018-

2028.

Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S. Glucosamine,

chondroitin or placebo for osteoarthritis of the hip or knee: network meta-analysis. BMJ 2010; 341:

c4675.

Welton NJ, Ades AE, Carlin JB, Sterne JAC. Models for potentially biased evidence in meta-analysis

using empirically based priors. JRSS A: Statistics in Society 2009; 172(1): 119-136.

Welton NJ, Caldwell DM, Adamopoulos E, Vedhara K. Mixed Treatment Comparison Meta-Analysis of

Complex Interventions: Psychological Interventions in Coronary Heart Disease. American Journal of

Epidemiology 2009; 169(9): 1158-1165.

Welton NJ, Willis S, Ades AE. Synthesis of Survival and Disease Progression Outcomes for Health

Technology Assessment of Cancer Therapies. Research Synthesis Methods 2010; 1: 239-257.

Whistance RN, Blazeby JM. Systematic review: quality of life after treatment for upper

gastrointestinal cancer (Review). Curr Opin Support Palliat Care 2011; 5(1): 37-46.

Whistance RN, Blencowe NS, Blazeby JM. The need for standardised outcome reporting in

colorectal surgery. Gut 2011; Jul 8 (letter).

Whistance RN, Gilbert R, Fayers P, Longman RJ, Pullyblank A, Thomas M, Blazeby JM. Assessment of

body image in patients undergoing surgery for colorectal cancer. Int J Colorectal Dis 2010 25(3):369-

74.

Wiles NJ, Mulligan J, Peters TJ, et al. Severity of depression and response to antidepressants: the

GENPOD randomised controlled trial Br J Psychiatr 2011 (In press)

Williamson PR, Altman DG, Blazeby JM, Clarke M. Driving up the quality and relevance of research-

based knowledge through the identification and use of core outcomes: the COMET Initiative. Journal

of Health Services Research and policy 2011 (In press).

Wylde V, Gooberman-Hill R, Horwood J, Beswick A, Noble S, Brookes S, Smith AJ, Pyke M, Dieppe P,

Blom AW. The effect of local anaesthetic wound infiltration on chronic pain after lower limb joint

replacement: a protocol for a double-blind randomised controlled trial. BMC Musculoskelet Disord

2011; 12: 53.








41

Submitted

Blencowe N, Strong S, McNair A, Davis C, Brookes ST, Blazeby JM. Standards of outcome reporting

in surgical oncology: a case study in esophageal cancer" Submitted to Journal of the National Cancer

Institute

Caldwell DM, Welton NJ, Dias S, Adea AE. Selecting the best scale for measuring treatment effect in

network meta-analysis: a case study in childhood nocturnal enuresis. Submitted to Research

Synthesis Methods.

Chen Y-F, Madan J, Welton NJ, Aveyard P, Bauld L, Wang Dechao, Munafo MR. Computer and other

electronic aids for smoking cessation (08/60/01). Submitted to Health Technology Assessment.

Dias S, Ades AE, Sutton AJ, Welton NJ. A generalised linear modelling framework for pairwise and

network meta-analysis of randomised controlled trials. Submitted to Medical Decision Making.

Dias S, Sutton AJ, Welton NJ, Ades AE. Embedding evidence synthesis in probabilistic cost-

effectiveness analysis: software choices. Submitted to Medical Decision Making.

Dias S, Welton NJ, Sutton AJ, Ades AE. Evidence synthesis in the baseline natural history model.

Submitted to Medical Decision Making.

Dias S, Welton NJ, Sutton AJ, Caldwell DM, Lu G, Ades AE. Inconsistency in networks of evidence

based on randomised controlled trials. Submitted to Medical Decision Making.

Franchini, AJ, Dias S, Ades A E, Jansen JP, Welton, NJ. Accounting for correlation in mixed treatment

comparisons with multi-arm trials. Submitted to Research Synthesis Methods.

Guyot P, Welton NJ, Ades AE. Reconstructing the Kaplan-Meier data from published survival curves.

Submitted to BMC Medical Research Methodology.

Hampson LV, Metcalfe C. Incorporating prognostic factors into causal estimators: a comparison of

methods for RCTs with a time to event outcome. Submitted to Statistics in Medicine.

Hollingworth W, McKell-Redwood D, Hampson L, Metcalfe C. Cost utility analysis conducted

alongside RCTs: Are economic endpoints considered in sample size calculations and does it matter?

Submitted to Clinical Trials.

Savovic J, Jones HE, Altman DG, Harris RJ, Juni P, Pildal J, Als-Nielson B, Balk EM, Gluud C, Gluud LL,

Ioannidis JPA, Schulz KF, Beynon R, Welton NJ, Wood L, Moher D, Deeks JJ, Sterne JAC. Influence of

study design characteristics on intervention effect estimates from randomised controlled trials:

combined analysis of meta-epidemiological studies (BRANDO study) (06/91/10). Submitted to Health

Technology Assessment.

Savovic J, Jones HE, Altman DG, Harris RJ, Jűni P, Pildal J, Als-Nielsen B, Balk EM, Gluud C, Gluud LL, Ioannidis JPA, Schulz KF, Beynon R, Welton NJ, Wood L, Moher D, Deeks JJ, Sterne JAC. Influence of study design characteristics on intervention effect estimates from randomized controlled trials: combined analysis of meta-epidemiological studies. Submitted to JAMA.


42

5. Presentations


Donovan JL, Adamson J, Mills N, Wade J, Paramasivan S, Lane JA, Blazeby J. Intervention to improve recruitment to randomised controlled trials and trial conduct. Poster presentation at Society for Clinical Trials, Baltimore USA, May 2010.

Donovan JL, Mills N. Uncertainty and patient treatment preferences: preventing or facilitating trial recruitment? Invited speakers at “Randomised controlled trials in surgery – How can we do more?” Royal College of Surgeons of England, Sept 2011.

Donovan JL. Invited Keynote Lecture in NCRI Consumer Session, NCRI annual conference. 'Involving consumers in research: the Protect RCT'. Liverpool, Nov 2010.

Donovan JL. Invited lecture and workshop Health Services Research Unit, University of Aberdeen. Talk entitled 'Integrating qualitative research within RCTs' May 2010.

Donovan JL. Invited Lecture. The role of qualitative research methods in improving recruitment to RCTs, University of Liverpool, Feb 2009.

Donovan JL. Invited seminar 'The contribution of qualitative research methods to RCTs'. National School of Primary Care, Manchester, Nov 2010.

Donovan JL. Keynote lecture: Involving participants in the design and conduct of RCTs.

Comprehensive Biomedical Research Centre, King's College London, June 2010.

Donovan JL. Strategies for enhanced recruitment to RCTs: the integration of qualitative research. Presentation at NCRI National Colorectal Trials meeting, London March 2010.

Mills N, Donovan JL, Wade J, Hamdy FC, Neal DE, Lane JA. Exploring treatment preferences facilitates recruitment to randomised controlled trials: a qualitative study. Poster presentation at Society for Clinical Trials, Baltimore USA, May 2010 and NCRI Conference, Liverpool, Nov 2010.

Mills N, Donovan JL, Wade J, Lane JA, Neal DE, Hamdy FC. Addressing patient treatment preferences at trial recruitment. Poster presentation at MRC Clinical Trials Methodology Conference, Bristol, October 2011.

Paramasivan S, Donovan JL, Huddart R, Hall E, Birtle A, Lewis R, Jones E. Key issues in recruitment to randomised controlled trials with disparate treatment arms: lessons from the SPARE trial. Poster presentation at NCRI Conference, Liverpool, Nov 2010.

Tomlin Z, Donovan JL, de Salis I, Toerien M. Nurses involved in recruitment to RCTs: trials and tribulations. Poster presentation at NCRI Conference, Liverpool , Nov 2010.


43

2. Evidence synthesis and Expected Value of Information for prioritisation of RCTs

Dias S, Welton NJ, Marinho VCC, Salanti G, Ades AE. Estimation and adjustment of Bias in randomised evidence using Mixed Treatment Comparison Meta-analysis. 30th International Conference for Clinical Biostatistics. 23-27 August, 2009. Prague, Czech Republic.

Guyot PG, Ades AE, Ouwens MJNM, Welton NJ. Recontructing Kaplan-Meier data from published survival curves. Methods in Meta-Analysis 21st June 2011, Royal Statistical Society, London.

Madan J, Ades AE. Is direct evidence more’valid’ than indirect? A case study involving neutropenia prophylaxis. Methods in Meta-Analysis Meeting, RSS, London. 21st June 2011.

Madan J, Welton NJ Using Bayesian methods to synthesise evidence on the efficacy of electronic aids to smoking cessation. 32nd Annual Meeting of the Society for Medical Decision Making (October 24-27, 2010), Toronto, Canada.

Price MJ, Welton NJ, Ades AE. Model averaging in the presence of structural uncertainty about treatment effects: impact on treatment decision and expected value of information. 31st Annual Meeting of the Society for Medical Decision Making (October 18 - 21, 2009), Hollywood.

Welton NJ et al. Models for potentially biased evidence in meta-analysis using empirically based priors. Society for Research Synthesis Methodology. 5th Annual Meeting, 5-7th July 2010, Cartegena, Spain.

Welton NJ, Ades AE, Carlin JB, Altman D, Sterne JAC, Harris R. Models for potentially biased evidence in meta-analysis using empirically based priors. Avon Local Group of the Royal Statistical Society 25th May 2010.

Welton NJ, Ades AE. Prioritising further research when there are multiple competing health technologies. HTAi 2010 Maximising the Value of HTA, 7th Annual Meeting, 6th - 9th June 2010, Dublin, Ireland. (oral presentation)

Welton NJ, Willis SR, Ades AE. Synthesis of survival and disease progression outcomes for health technology assessment of cancer therapies. Methods in Meta-Analysis Meeting, RSS, London. 26th November 2009

Welton NJ, Willis SR, Ades AE. Synthesis of survival and disease progression outcomes for health technology assessment of cancer therapies. Health Economics and Decision Science Seminar, ScHARR, Sheffield. 19th November 2009

Welton NJ. Value of Information analysis in the prioritisation and design of RCTs. HUBs for Trial Methodology Research Network workshop: Using Existing Data to Inform Clinical Trial Design. Goodenough College, London. 16th March 2010.


44


Lane JA ‘A systematic review of on-site monitoring and a peer review intervention for monitoring and evaluating sites’. HTMR conference. Birmingham. January 2011 (oral presentation).

Lane JA ‘BRTC, the MRC Hubs for Methodology Research and the UK Trial Managers Network’. South West Research Managers Forum. Exeter. October 2010 (oral presentation).

Lane JA ‘Methods for Monitoring Clinical Trial Sites, including a Peer Review Process’. Welsh Clinical Trials Units invited seminar. Cardiff, July 2010 (oral presentation).

Lane JA 'Engaging with the MRC Hubs for Trial Methodological Research-ConDuCT Hub’. CRC Cymru Annual conference. Cardiff. June 2009 (oral presentation).

Lane JA, ‘Peer review intervention for monitoring and evaluating sites that improved randomized controlled trial conduct and performance’. 32nd Meeting of the Society of Clinical Trials. Vancouver. May 2011 (oral presentation).

Lane JA, Down L, Wade J, Neal DE, Hamdy FC, Donovan JL ‘Factors influencing questionnaire response rates in trials’. 31st Meeting of the Society of Clinical Trials. Baltimore. May 2010 (poster).

Lane JA, Down L, Wade J, Neal DE, Hamdy FC, Donovan JL ‘Understanding factors influencing questionnaire response rates to maximise retention in a long term complex intervention trial’. MRC Clinical Trials Methodology Conference. Bristol. October 2011 (poster).

Lane JA, Metcalfe C, Moody H, Horwood J, Avery KNL, Gillatt D, Holly JMP, Macefield RC, Donovan JL, ‘ProDiet: The feasibility of a randomised controlled trial of dietary interventions for men at high risk of prostate cancer’. National Cancer Research Institute Conference. Liverpool. November 2010 (poster).

Macefield RC, Metcalfe C, Avery KNL, Gillatt D, Hamdy FC, Neal DE, Donovan JL, Lane JA ‘Investigating and measuring adherence to a dietary intervention in a feasibility trial for prostate cancer prevention’. National Cancer Research Institute Annual Conference. Liverpool. November 2011. (poster)


Hampson L. Comparison of causal estimators for survival data. Royal Statistical Society Primary Health Care Study Group, London, 2010.

Hampson L. Efficient group sequential tests for survival data, International Society for Clinical Biostatistics Conference, Montpellier, France, 2010.

Hampson L. Group Sequential and Adaptive designs for delayed responses. London, 2011.

Hampson L. Incorporating baseline covariates into causal estimators for survival data: a comparison of methods. International Society for Clinical Biostatistics Conference, Ottawa, Canada, 2011.


45

Hampson L. Incorporating baseline covariates into causal estimators in survival data. Causal discussion group, London School of Hygiene and Tropical Medicine, 2011.

Metcalfe C. Holding on to power; why confidence intervals are not (usually) the best basis for sample size calculations. MRC Clinical Trials Methodology Conference, Bristol, October 2011.


Hollinghurst S ‘Cost-effectiveness of therapist-delivered online cognitive behavioural therapy for depression: a randomised controlled trial’ SW Society of Academic Primary Care. Oxford. March 2010 (Oral presentation)

Hollingworth W ‘Introduction to economic evaluation of end of life care. MORECare - Methods for evaluating service delivery models for end of life care (EoLC): development of best practice guidance’ Expert think tank - Economic evaluation. Manchester. May 2011 (Oral presentation)

Hollingworth W ‘Distress Thermometer Intervention Trial’ Avon, Somerset, Wiltshire Cancer Research Network meeting Bristol. November 2009 (Oral presentation)

Hollingworth W, McKell-Redwood D, Hampson L, Metcalfe C ‘Clinical versus economic interpretations of RCT results - Mixed messages?’ Society for Social Medicine Conference. Warwick. September 2011 (Oral presentation)

Hollingworth W, McKell-Redwood D, Hampson L, Metcalfe C ‘Cost utility analysis alongside RCTs: Is efficiency considered in sample size calculations and does it matter?’ Clinical Trials Methodology Conference. Bristol. October 2011 (Poster presentation)

Noble S, Hollingworth W, Tilling K ‘Missing data in trial based cost-effectiveness analysis: The current state of play’ Health Economics Study Group Conference. London. January 2010 (Oral presentation)

Noble SM, Marques E, Johnson E, Blom A (on behalf of the APEX trial )‘The use of participant response use logs in reducing the amount of missing data in resource use questionnaires’ IHEA. Toronto. July 2011 (Short oral and poster presentation)

Noble SM, Hollingworth W, Thorn J, McKell-Redwood D ‘Publication and interpretation of economic evaluation results’ MRC trials methodology hubs meeting. Birmingham. January 2011 (Oral presentation)

Noble SM, Marques E, Johnson E, Blom A (on behalf of the APEX trial) ‘The use of participant response use logs in reducing the amount of missing data in resource use questionnaires’ Clinical Trials Methodology Conference. Bristol. October 2011 (Poster presentation)

Thorn J, Hollingworth W and Noble SM ‘Timely and complete publication of economic evaluations alongside randomised controlled trials’ SW Health Economists meeting. Exeter. May 2011 (Oral presentation)

Thorn J, Hollingworth W, Noble SM ‘Timely and complete publication of economic evaluations alongside randomised controlled trials’ Society for Social Medicine Conference. Warwick. September 2011 (Oral presentation)


46


Blazeby J, Boulind C. Methodological issues of blinding in trials of complex interventions NCRI complementary therapies group, London, July 2010.

Blazeby J, McNair AGK. Core outcomes and core disclosure in cancer surgery. COMET, Liverpool January 2010.

Blazeby J. Core outcomes sets to improve trial conduct. NCRI consumer liaison group meeting, Leeds, September 2010.

Blazeby J. Measuring, results and implications of assessing QOL in clinical trials of gastric cancer. European Gastric Cancer Meeting, Madrid, March 2010.

Blencowe NS, Davis CR, McNair AGK, Allum W, Blazeby JM. Short-term clinical outcomes following oesophagectomy: the need for standardised reporting systems in the literature, ASGBI, April 2010.

Blencowe NS, Davis CR, McNair AGK, Blazeby JM. Reporting outcomes of oesophageal cancer surgery: standards for future practice. AUGIS, Belfast, September 2010.

Blencowe NS, Macefield R, Jacobs M, Korfage I, Nicklin J, Brookes ST, Sprangers MA, Blazeby JM. HRQL data reporting following curative treatment of oesophageal cancer: a systematic review. AUGIS, Belfast, Sept 2011.

Blencowe NS, Strong S, McNair AGK, Allum W, Blazeby JM. Reporting complications following

oesophagectomy: a systematic review. ASGBI, May 2011.

Blencowe NS, Strong S, McNair AGK, Blazeby JM. Reporting outcomes of oesophageal cancer

surgery: standards for future practice. NIHR Trainees Conference, November 2010.

Blencowe NS, Strong S, McNair AGK, Blazeby JM. Short-term clinical outcomes following

oesophagectomy: the need for standardised reporting systems in the literature. Severn Audit and

Research meeting, Bristol, October 2010.

Eveleigh MO, Blencowe NS, Mills N, Blazeby JM. Understanding the complexity of surgical

procedures in RCTs: a pilot study to test the application of the MRC framework for evaluating

complex healthcare interventions in the operating theatre. MRC HTMR Clinical Trials Methodology

Conference, October 2011.

Forsythe RO, Whistance RN, McNair AGK, Avery K, Brookes ST, Blazeby JM. Results of the

systematic review of clinical outcomes of colorectal cancer surgery. Core Sets in Colorectal Cancer

steering committee meeting, Bristol, September 2011.

Macefield R, Jacobs M, Blencowe NS, Korfage I, Nicklin J, Brookes ST, Sprangers MA, Blazeby JM. The case for a core outcome set: outcome reporting bias in oesophageal cancer studies. International Society of Quality of Life Research 18th Annual meeting, Denver CO, October 2011.


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Macefield R, Jacobs M, Blencowe NS, Korfage I, Nicklin J, Brookes ST, Sprangers MA, Blazeby JM. Identifying core HRQL domains: a case study in oesophageal cancer. International Society of Quality of Life Research 18th Annual meeting, Denver CO, October 2011.

Macefield R, Jacobs M, Blencowe NS, Korfage I, Nicklin J, Brookes ST, Sprangers MA, Blazeby JM. The case for a core outcome set: outcome reporting bias in oesophageal cancer studies. MRC HTMR Clinical Trials Methodology Conference, Bristol, October 2011.

Macefield R. Integrating health-related quality of life and clinical data to inform decision making: a systematic review of reporting in randomised controlled trials in gastrointestinal cancer. International Society of Quality of Life Research 17th Annual meeting, London, October 2010.

Macefield RC, McNair AGK, Blencowe NS, Brookes ST, Blazeby JM. Incorporating patient reported outcomes (PROs) in gastro-intestinal (GI) cancer randomised controlled trials (RCTs): the need for adequate rationale and integrated reporting. MRC HTMR Clinical Trials Methodology Conference, Bristol, October 2011.

Potter S, Brigic A, Harcourt D, Cawthorn SJ, Donovan J, Blazeby JM. A Systematic Review of Methods for Cosmetic Outcome of Breast Reconstruction. BAPRAS Summer Meeting, Sheffield, June/July 2010.

Potter S, Mills N, Cawthorn S, Blazeby JM. Will women considering breast reconstruction enter a randomised trial? Southwest Surgeons Meeting, Bristol Zoo Gardens, October 2010.

Potter S, Thomson SJ, Greenwood RJ, Winters ZE. A comparison of quality of life assessment tools in breast reconstruction: Are we asking the right questions? AGSBI International Surgical Congress (published abstract in BJS), Bournemouth, May 2008.

Rees, J. Patient reported outcomes after hepatic resection of colorectal cancer metastases. Poster presentation NIHR Trainees Meeting, Leeds, Sept 2011.

Rees, J. Patient reported outcomes after hepatic resection of colorectal cancer metastases. Severn and Peninsula Deanery Audit and Research Meeting, Bristol, Oct 2011.

Rees, J. The role of patient reported outcomes during the surgical consultation. Severn and Peninsula Deanery Academic Showcase Event, Bristol, Oct 2011.

S Strong, S Brookes, J Donovan, W Hollingworth, T Crosby, M Griffin, JM Blazeby. The feasibility of conducting a randomised trial of surgical and non-surgical treatment for oesophageal squamous cell cancer: definitive chemoradiotherapy versus chemotherapy and surgery. Poster presentation, AUGIS, Belfast, 2011.

Strong S, Blencowe N, McNair A, Blazeby J. The need for standardised outcome reporting in surgical oncology: a systematic review. Podium presentation at South West Surgeons Meeting, Bristol, Oct 2010.

Strong S, Blencowe N, McNair A, Blazeby J. Reporting complications following oesophagectomy: a systematic review. poster presentation, ASGBI, Bournemouth, 2011

Strong S, Blencowe N, McNair A, Blazeby J. The need for standardised outcome reporting in surgical oncology: a systematic review. Oral presentation at the Royal Society of Medicine, London, 2010.


48

Strong S, Blencowe NS, McNair AGK, Blazeby JM. Reporting outcomes of oesophageal cancer surgery: standards for future practice. Oral presentation at Royal Society of Medicine Surgical Section, November 2010.

Strong S, Blencowe NS, McNair AGK, Blazeby JM. Short-term clinical outcomes following oesophagectomy: the need for standardised reporting systems in the literature. Oral presentation at the South West Surgical Society meeting, November 2010.

Strong S, Brookes S, Donovan J, Hollingworth W, Crosby T, Griffin M, Blazeby JM. The feasibility of conducting a randomised trial of surgical and non-surgical treatment for oesophageal squamous cell cancer: definitive chemoradiotherapy versus chemotherapy and surgery. Podium presentation at the European Society of Oesophagology, Newcastle, Nov 2011.

Strong S, Brookes S, Donovan J, Hollingworth W, Crosby T, Griffin M, Blazeby JM. The feasibility of conducting a randomised trial of surgical and non-surgical treatment for oesophageal squamous cell cancer: definitive chemoradiotherapy versus chemotherapy and surgery. Podium presentation Severn Deanery Research and Audit Day, Bristol, Oct 2011.

Whistance RN, Forsythe RO, McNair AGK, Avery K, Brookes ST, Blazeby JM. The need for a core outcome set in colorectal cancer: a systematic review. COMET meeting, Bristol, July 2011.

Whistance RN, Forsythe RO, McNair AGK, Avery K, Brookes ST, Blazeby JM. Development of a core outcome set in colorectal cancer. Core Sets in Colorectal Cancer steering committee meeting, Bristol, September 2011.

Whistance RN, Forsythe RO, McNair AGK, Avery K, Brookes ST, Blazeby JM. Heterogeneity of reporting of death after surgery for colorectal cancer: a systematic review of outcomes. Severn Deanery School of Surgery Research and Audit Day, Bristol, October 2011.

Whistance RN, McNair AGK, Avery K, Brookes ST, Blazeby JM. Core Outcome Measures for Effectiveness Trials, the COMET initiative with an example in colorectal cancer. NRCI consumer liaison group meeting, Leeds, September 2010.

Whistance RN, McNair AGK, Avery K, Brookes ST, Blazeby JM. Development of core sets in colorectal cancer. University of Bristol Postgraduate symposium, Bristol, December 2010.

Whistance RN, McNair AGK, Avery K, Brookes ST, Blazeby JM. The development of a core outcome set in colorectal cancer. EORTC quality of life group meeting, Brussels, March 2011.


49

6. Research Grants

Research grants (a) funded; (b) in progress; and (c) not funded; are listed below by ConDuCT hub

theme. Where a grant is a collaboration across themes, the grant is listed under just one theme. All

ConDuCT hub members are indicated in bold.

Research grants funded


Crawley E, Montgomery A, Mills N, Sterne J, Hollingworth W, Gibson A, Finch F, Parker P, Donovan

J. Feasibility of RCT of interventions for CFS/ME. Awarded by Linbury and Ashden Trusts (£61,531)

for Hub qualitative work. Collaboration across Departments within the University of Bristol and

Lightning Process team; using standard and innovative methods of interviewing, observation and

audio recording of recruitment appointments. Further funding has been secured to extend the

feasibility study and fund the full trial 01/09/2010 - 27/7/2012.

Donovan JL and Mills N are involved with qualitative research within the ProtecT study (Prostate

cancer testing and treatment study) focussing on: a. The development of a complex intervention to

improve rates of randomisation and improve informed consent; b. Information provision and

recruiter techniques to maximise informed consent; c. Exploring treatment preferences at

recruitment to RCTs; d. Towards the development of a framework for eliciting preferences at trial

recruitment; e. EPIC – development of a rating scale for measure effectiveness of information

provision during informed consent consultations for trial recruitment.

Donovan JL. Recruitment process study within SPARE bladder cancer RCT. Awarded by CR UK,

£50,000 for Hub qualitative work. Collaboration with ICR; qualitative research to understand

recruitment difficulties, followed by implementation of Hub-designed intervention to improve

recruitment. 1/4/09 - 31/3/10.

Heawood A, Barnes R, Malpass A, Kessler D. Negotiating a ‘therapeutic alliance’ during online CBT:

an analysis of patient-therapist interactions. Awarded by The BUPA Foundation, £71,000.

Collaboration with Peninsula Medical School; linked to a trial of online CBT for depression; using the

innovative methods of Conversation Analysis. 31/07/2011-15/11/2012.

Heawood is a co-applicant on the SCOOP trial funded by the MRC and ARC. This is a multi-centre

trial evaluating the effectiveness and cost-effectiveness of a screening programme for prevention of

fractures in elderly women. The trial is led by UEA at Norwich, with a nested qualitative study led by

Heawood. The qualitative study is evaluating women’s experiences of screening and the

acceptability of the intervention.


50

Martin RM, Donovan JL, Hamdy F, Neal DE, Ben-Shlomo Y, Brindle P, Metcalfe C, Sterne JAC, Evans

S, Lane JA, Noble S, Oliver S, Wolstenholme J. Evaluating population-based screening for localised

prostate cancer in the United Kingdom: the CAP (Comparison Arm for ProtecT) study. Cancer

Research UK, £1,125,000. 2010-2012.


Ades AE (PI), Brazier JE, Churchill R, Lu G, Welton NJ. Widening the spectrum of health outcomes

used in health technology assessment: integrated synthesis and mapping to QALYs. MRC

Methodology Research Grant. G0901488 £232,052. 1st Jan 2010 – 31st Dec 2012

Ades AE, Dias S, Welton NJ. NICE Clinical Guidelines Technical Support Unit. £313,872. NICE.

Duration: 3 years. Start date: 1st March 2001

Ades AE, Welton NJ. Analysis and synthesis of time-to-event data from cancer trials in the

assessment of cost-effectiveness. MRC G1001338. £145,106 MRC contribution. Start date 1st

December 2010 for 30 months.

Blazeby JM (PI), Welton NJ (co-app). NIHR Research Methods Fellowship and Internship. NHS

National Institute for Health Research (NIHR).

Chetter I (PI), Cullum N, Claxton K, Torgerson D, Welton N, Adamson J, Ball J, Dumville J, Ashby R,

Henderson E, Soares M, Porcher C, Oswald A. Surgical wounds healing by secondary intention:

characterising and quantifying the problem and identifying effective treatments. NIHR Programme

Grant Ref: RP-PG-0609-10171. £13,820 for my time. 1st June 2011 – 31st May 2015.

Madan J, Silman A, Ades AE, Welton NJ, Barton P. Biologic therapies for rheumatoid and psoriatic

arthritis: consensus models for decision-making. £8,566 workshop funding equally supported by

Arthritis Research UK and the MRC HTMR network. September 2011 – March 2012.

Munafo MR (PI), Aveyard P, Bauld L, Welton NJ, Wang Dechao, Chen Y-F. Computer and other

electronic aids for smoking cessation. NHS R&D HTA Programme. HTA Priority Area 08/60/01

£91,015. 1st April 2009 – 31st March 2010

Penny Bee (PI) et al. Community-based interventions for maintaining or improving quality of life in

children and adolescents of parents with serious mental illness: An evidence synthesis. HTA. Welton

listed as a collaborator for the EVI analysis.

Rowan KM, Harrison DA, Palmer SJ, Ades AE, Welton NJ, Singer M, Sewell WAC, Ramsay G, Beale R.

An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled

trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock) NHS R&D HTA

Programme. HTA Priority Area 08/70/01. £126,799. 1st May 2009 – 30th April 2010


51

Welton NJ (PI), Silman A, Ades AE, Blazeby J. Workshop: Biologic Therapies in Inflammatory Joint

Diseases: Models for Decision Making, 1st September 2010. 50% funding from: MRC Network of Hubs

for Trials Methodology Research and 50% funding from Arthritis Research UK. £7532 total.

Welton NJ. Expected Value of Information and Synthesis Methods for Research Prioritisation and

Study Design. MRC Methodology Research Fellowship. G0802413 £495,521. 5th May 2009 – 4th May

2013.


Lane JA, Metcalfe C, Martin R, Donovan, J, Holly J, Neal DE, Hamdy FC. The feasibility of a

randomised controlled trial of dietary interventions for men at high risk of prostate cancer: the

ProDiet study. 2009-2011, CRUK (£40K).

Tudur-Smith C, Williamson P, Gamble C, Booth G, Landray M, Knott C, Meredith S, Bakobaki J, Lane

A. Clinical trial monitoring – towards establishing best practice? HTMR network funding, 2011-2012

(£15,712).


Andrews R, Hollinghurst S, Cooper A, Dayan C, Sharp D, Peters T, Montgomery A. ACTID Follow up:

A 3 year follow up of patients who took part in the Early ACTID study. NIHR Research for Patient

Benefit Programme, £244,395. 2011-2014.

Eddleston MP, Konradsen F, Dawson A, Gunnell D, Metcalfe C, Hawton K, et al. A community trial to

determine whether ‘Safe Storage’ reduces pesticide self-poisoning in rural Asia. Wellcome Trust

£786,251. 2010-2015.

Lawlor DA , Kipping RR, Jago R, Campbell R, Chittleborough C, Mytton J, Peters T, Noble S. ‘Active For

Life Year 5: A cluster randomised controlled trial of a primary school-based intervention to increase

levels of physical activity, decrease sedentary behaviour and improve diet’ NIHR Public Health

Research Programme (09/3005/04), 2011-2015 (£1,464,457)

Metcalfe C, Blazeby J, Donovan J, Noble S, Barham P, Hollowood A, Falk S, Berrisford R, Sanders G.

The ROMIO trial - Randomised Oesophagectomy: Minimally Invasive or Open, a feasibility study.

Funded by HTA (£416,881) contracting at present

Montgomery A. NIHR Research Methods Fellowship. NIHR. 2009-2012.


52


Audrey S, Brookes S, Campbell R, Cooper A, Hollingworth W, et al. Employer schemes to encourage

walking to work: feasibility study. NIHR PHR. £251,671 over 24 months.

Beaver K, Hollingworth W, et al. ENDCAT: Endometrial Cancer Telephone follow-up trial. 2011. NIHR

RfPB. £36,538 over 36 months.

Blom A, Beswick A, Gooberman-Hill R, Pyke M, Brookes S, Sackley C, Dieppe P, Learmonth I, Noble S,

Evans S, Wylde V, Haynes R. Improving patients' experience and outcome of total joint replacement

2008-2013 NIHR £1.977 million.

Campbell R, Metcalfe C, Noble S, Moore L, Butler C, Michie S, Endericks T. ‘Cluster randomised

controlled trial to test the effectiveness of an educational intervention to promote hand washing in

reducing absenteeism in primary schools’ NIHR Research for Patient Benefit Programme, 2009-2011

(£242,230)

Coast J et al (Midlands Hub) with W Hollingworth. ‘The use of ICECAP measures in clinical trials and

economic evaluation’ MRC Network of Hubs for Trials Methodology Research (£14,700)

Hay A, Hollinghurst S, Sterne J, Spears M. IOSAC steroids for cough. NIHR SPCR (£1.2m), 2012 to

2015

Hollinghurst S. ‘Changing eating behaviours to treat childhood obesity in the community using

Mandolean: the ComMando (Community Mandolean) randomised trial’ NIHR HTA (£2.1m)

Hughes D, (North West Hub), W Hollingworth, S Noble, J Thorn. ‘Development of a central

repository of resource-use data collection instruments for trial-based health economic evaluations’

MRC Network of Hubs for Trials Methodology Research (£32,523)


Adamson D, Byrne A, Blazeby JM et al. Palliative radiotherapy in addition to self-expanding metal

stent for improving outcomes of dysphagia and survival in advanced oesophageal cancer: ROCS

(Radiotherapy after Oesophageal Cancer Stenting) Study Funded by HTA (£1,817,000)

Blazeby J, Brookes S, Donovan J, Montgomery A, Hollingworth W, Griffin M, Crosby T. Oesophageal

squamous cell cancer: chemoradiotherapy versus chemotherapy and surgery - a feasibility study.

Funded by NIHR RfPB, £256,000, 2010-2012.

Blazeby J (PI), Donovan J, Reeves B, Rogers C, Welbourn R, Byrne J, Roderick P, Thompson J, Edmond

J, Wordsworth S. BYBAND - Gastric BYpass or adjustable gastric BANDing surgery to treat morbid

obesity: a multi-centre randomised funded by HTA (£2,874,696), 2011-2019.


53

Blazeby J, Donovan JL, Paramasivan S. Qualitative research to explore recruitment into a varicose

vein trial (CLASS). Awarded by the Exeter Trust, £6,000. In collaboration with Exeter and Aberdeen

Universities

Blazeby JM, Donovan J, Metcalfe C, Sharples L, et al £11,550 MRC Hubs Network funding 2011 to

2012 Randomised surgical trials: methods to improve recruitment and study design.

Calvert M, Blazeby J, Brundage M, Revicki D, Moher D. Quality of Life Reporting Standards:

Development of a CONSORT extension £49,450 MRC Hubs Network funding 2011 to 2012

Williamson P, Blazeby J, Altman D, Clarke M COMET (Core Outcome Measures in Effectiveness

Trials) £50K MRC Hubs Network funding 2011 to 2012

Research grants in progress


Donovan J (PI), co-applicants include Mills N. Collaboration with Clinical Trials Unit, University of

York. EQUATRE - Ethnographic Qualitative Investigation to Improve Trial Recruitment. In preparation

after rejection from MRC Methodology Programme.

Donovan J is co-applicant on FASHIon – UK feasibility study of a trial of arthroscopic surgery for hip

impingement procedure to improve grinding of hips feasibility study. Submitted grant proposal to

HTA.

Donovan J is co-applicant on Optima - chemotherapy and hormone treatment vs hormone

treatment only for women with luminal A breast cancer subtype (feasibility study). Submitted to

HTA.

Ekberg S, Heawood A and co-applicants. Using conversation analysis to unpack talk-based

interventions and evaluate retention and drop-out in trials of cognitive behavioural therapy for

patients with depression. In preparation for a NIHR and National School for Primary Care Research

Post-Doctoral Fellowship.

Heawood A (PI) and co-applicants. Evaluating online real-time interviewing as a qualitative method

for use within complex primary care-based trials. Collaboration with the University of Oxford; in

preparation for the National School for Primary Care Research.

Marks D and Crawley E (joint leads). Co-applicants include Mills N. Treatment of chronic disabling

fatigue in bone marrow transplant survivors. Proposal submitted to NIHR RfPB, Sept 2011.


54


Feder G, Hester M, Howarth E, MacMillan H, Stanley N, Welton NJ. What interventions improve

outcomes for children exposed to domestic abuse: a systematic review, evidence synthesis, and

research recommendations. In preparation for: NIHR HTA.

Lewis G, Dowrick C, Gilbody S, Peters T, Wiles N, Hollingwork W, Kendrick T, Robinson J, Malpass A,

Kessler D, Lamham P, Ades AE, Welton NJ, Churchill R, Araya R, Mulvenna S. What are the

indications for prescribing antidepressants that will lead to a clinical benefit? NIHR programme grant

provisionally accepted.

Macleod, Burt, Campbell, Montgomery, Turner, Horner, Hickman, Michie, Hellard, Womack, Eagle,

Morey, Bird, Coleman, Pye, Welton. The use of mobile telephone short message service to enhance

screening and control programmes for genital Chlamydia trachomatis: feasibility study. Submitted

to: NIHR HTA.

Sterne JAC, Casas JP, Caldwell D, Whiting P, Hingorani AD, Bodalia PN, Hollingworth W, Welton NJ.

Effectiveness and cost-effectiveness of new anticoagulants for venous thromboembolism and sroke

prevention in atrial fibrillation. Submitted to: NIHR HTA Clinical Evaluation and Trials board.


Lane A, Blazeby J, Metcalfe C, Noble S, Wade J. McDonald A, Tudur-Smth C, Hood K, Griffiths G

“Designing and evaluating site monitoring systems to improve the conduct of randomised trials”)

MRC MRP (£655,623) Grant under review.

Nuttall J, Robling M, Hood K, Lane A, et al. Maximising participant retention in trials and cohort

studies: development of an online theory driven toolkit. MRC MRP, Grant under review


Davies S, Kessler D, Lewis G. Montgomery A, Moore B, Noble S, Peters T, Wiles N, Mulligan J.

“Pregabalin Augmentation of SSRIs in Anxiety Disorders” NIHR HTA (£2,126,383)

Evans J, Montgomery A, Noble S, Turner K, Wiles N. “Anticipate II” NIHR HTA (£1,505,602)

Turner E, Martin R, Noble S, Donovan J, Metcalfe C, Lane A, Macleod J, Verne J, Oliver S, Van Staa T-

P, Neal D and Hamdy F . ‘Evaluating the potential of electronic data linkage for trial outcome

CAPture: The eCAP study’ NIHR HSR programme (£434,145)

Noble S, Donovan J, Metcalfe C. ‘Evaluating the potential of electronic data linkage for trial outcome

CAPture: The eCAP study’ NIHR HSR programme (£434,145)


55

Palmer S, Cramp F, Clark EM, Horwood J, Lewis R, Hollingworth W, Brooks S, Jenkinson T, Welton N.

The effects of a comprehensive physiotherapy intervention for adults with joint hypermobility.

Submitted to: NIHR HTA.


Efficace F with co-applicants Blazeby J, Fayers P, Pusic A. Investigating the evolution of reporting

quality of life/patient-reported outcomes over time in cancer clinical trials and the use of EORTC QLG

measures. EORTC Quality of Life Group 2011 Grant Application Under review at present

Williamson P with co-applicants Blazeby J, Clarke M, Altman D. Driving up the quality and relevance

of research-based knowledge through the identification and use of core outcomes: the COMET

Initiative. MRC Methodology Research Panel - Rejected 2011 but resubmitted and under review at

present G1002280

Research Grants Not Funded (Trial methodology grants only)


Donovan JL is co-applicant on OptiQual (OPTImising QUALitative research in RCTs) - a study to

evaluate the current contribution of qualitative research methods included in RCTs and lead

developments to optimise their use in future RCTs. Submitted to MRC methodology panel but

declined March 2010 (A very similar proposal has recently been funded).

Heawood A is co-applicant on FLAME (FLares and Antibiotics in the Managements of atopic Eczema).

Entails qualitative research within a trial of the management of atopic eczema. Declined by HTA at

outline stage.

Mills N, and Blazeby J co-applicants on the Dupuytren’s study - RCT of surgery for Dupytren’s

contracture of the fingers. Outline proposal submitted to NiHR HTA but declined.

Mills N is co-applicant PROMs in renal RCTs - Routine collection of PROMs in dialysis patients: a pilot

study. Entails qualitative research within a pilot trial of routinely collecting PROM data in dialysis

patients. Declined by NIHR HSR at outline stage.


56


Welton NJ (PI), Ades AE, Dias S, Churchill R, Salanti G, Sterne JAC, Sutton AJ, Furukawa, Barbui C,

Cipriani A. Multiple bias component models to explore heterogeneity in network meta-analysis of

RCTs. MRC Methodology Research Panel. Declined July 2010.


Pavitt S, Campbell M, Hewison J, Ardron D, Bosworth A, Tubeuf S, Hulme C, Twiddy M, Keenan AM,

Newman J, Inns K, Lane A, Collinson F. Quantifying and Evaluating the Impact of Patient Public

Involvement (PPI) on Recruitment and Retention in Clinical Trials. NIHR HSR/Involve commissioned

call, rejected 2010.


Brookes ST, Montgomery AA and others. Comparing methods for interim analysis using data from

BRTC portfolio trials. NIHR School for Primary Care research. Rejected early 2011.

Metcalfe C, Hollingworth W, Montgomery A, Wiles N, Hollinghurst S, Peters T. Elaborating the net

benefit regression framework for estimating cost effectiveness in randomised trials. MRC

Methodology Research Panel. Rejected at March 2011 meeting.

Metcalfe C, Peters T, Montgomery A. NIHR Research Methods Fellowship. Rejected at June 2011

meeting


‘Elaborating the net benefit regression framework for estimating cost-effectiveness in randomised

trials’. MRC MRP


Velikova G with co-applicants Brown J, Blazeby J, Hillmen P, Seymour M. Real-time Electronic Patient

Outcome ReporTing of adverse events in UK cancer trials (REPORT-UK). MRC Methodology Research

Panel - G1002314 Rejected 2011


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