Improving Quality of Trials through the MRC Network of Hubs for Trials Methodology Research

Professor Lucinda (Cindy) Billingham

Professor of Biostatistics

Director, MRC Midland Hub for Trials Methodology ResearchBiostatistics Lead, Cancer Research UK Clinical Trials Unit

University of Birmingham

NIHR Statistical Meeting, LondonFebruary 13th 2012

Agenda

• Explain structure, objectives and activity of:– Network of MRC Hubs for Trials Methodology

Research (HTMR)– MRC Midland Hub for Trials Methodology

Research (MHTMR) • Examples of Methodology Research

– Query from clinical research community: crossing survival curves

– MRC initiated topic: stratified medicine– Working with a CTU: rare diseases

Why Do We Need Funding for Trials Methodology Research?

Clinical Trials UnitsDesign, conduct and analyse trials

Evidence synthesis from trials

Identify methodological problem

Methodology review – identify a solution

Methodology research and development

Not Directly Funded

MRC / NIHR Initiative

HTMR Network

www.methodologyhubs.mrc.ac.uk

All-Ireland Hub led by Professor Mike Clarke

Dr Adrian Mander

1. Promoting high quality collaborative methodological research, both between Hubs and with other groups, nationally and internationally

2. Providing methodological advice to the clinical trials community

3. Encouraging the implementation of the most effective and appropriate methodological practice, for example by providing education and training

4. Working with stakeholders, in particular to agree on shared priorities for research and guidance

Network Objectives

What Do the Hubs Do?

Research ProgrammeDevelop existing expertise

Develop new research themes identified by trials communityCollaborative, practical use to the trials community

Training ProgrammeTrain the experts of the future

Provide training for current practitioners

Advice, Support and Dissemination FunctionAdvice facility for trial practitioners

Make knowledge accessible to the trials community

Provide core of expertise in trials methodologyMake UK a leader in trials methodology

Hubs will become self sufficient

Structure of the Midland Hub (MHTMR)

University of BirminghamCollege of Medical

and Dental Sciences

School of Cancer Sciences

Cancer Research UK Clinical Trials Unit

Billingham, Johnson,

Wheatley (Stocken)

Birmingham Clinical

Trials Unit

Ives

School of Health and Population Sciences

Primary CareClinical

Sciences Unit

Calvert, Wilson (Draper)

Public Health, Epidemiology and Biostatistics Unit

Lilford, Deeks, Zeegers

Riley (Girling)

Health Economics

Unit

Coast(Al-Janabi,

Barton)

Director: Prof Lucinda BillinghamDeputy Director: Dr Richard Riley

MHTMR Hub Resources

Director (60%) Day-to-day management; support and mentorship to RFs and PhD students; ensure successful delivery Hub programme; networking

10 Hub Investigators Supervision and development of research projects and contributions to training and advisory service

3 Research Fellows Methodological research projectsProject grant applications Provision and coordination of advice facilityTraining and support to PhD students

1 Senior Administrator

Support Director, Investigators, Research FellowsSupport training programme and PhD studentsOrganise Hub meetings and events

5 PhD Students Methodological development

Plus other affiliated RFs and PhD students

Clinical Trial Pathway for Research

Phase I, II, III

Add-on translational

studies

Network: Working Groups

• Trial recruitment group• Outcomes group• Evidence synthesis group• Trial conduct group• Adaptive design group• (Stratified medicine group)

HTMR Network Funds for Small Projects

• Proposals for methodological research and workshops in all areas relating to trials– Organising a research workshop– Organising training/educational workshops– Knowledge exchange visits for pilot/feasibility work– Systematic review of methodology– Methodological guidelines development

• Short-term <12 months, max £50k• Lead applicant based at one of the Hubs, involve

researchers from at least 2 of the Hubs, additional investigators from outside Hub encouraged

• 4 times per year: next is March 26th 2012• Application on http://www.methodologyhubs.mrc.ac.uk/

• Core Outcome Measures in Effectiveness Trials (COMET)• Database of Resource-Use Data Collection Instruments for

Trial-based Health Economic Evaluations (DIRUM)• Methodology for Trials of Radiotherapy Interventions• CONSORT Extension on Quality of Life Reporting

Standards• Research Exchange Visits for Improving Multi-Arm, Multi-

Stage Clinical Trials• Trial Monitoring – Towards Best Practice • Central Statistical Monitoring• IPD Meta-analysis• Guidelines for Reporting Biases

HTMR Funded Collaborative Methodological Research

MHTMR: Research Themes

1) QoL evaluation for clinical and health economic assessment

Outcome measures; evaluating costsPhD: Capability as an outcome measure (Tom Keeley; Coast, Al-Janabi)

2) Discovery and evaluation of diagnostic, prognostic and predictive biomarkers

Stratified medicine; statistical modelling; analysis of multiple serial biomarkers; design and analysis of proteomic studiesPhD (MHTMR): Stratified medicine: methods for evaluating predictive biomarkers (Kinga Malottki; Billingham, Deeks, Riley)PhD: Use of flexible parametric modelling in prognosis research (Kym Snell; Riley, Stocken, Billingham)

3) Methods to obtain reliable conclusions and involve users

Phase I/II trials; complex interventions (specifically radiotherapy); rare diseases/ paediatrics; complex time-to-event data ; trial conductPhD: Electronic participant information sheets (Helen Kirkby; Wilson, Draper, Calvert)

4) Bayesian methods in trials PhD: Bayesian methods for design and analysis of clinical trials (Danielle Burke; Billingham, Girling)

5) E-trials

6) Systematic reviews for clinical and health economic evaluation

Systematic review of biomarkers, decision modellingPhD: evidence synthesis for risk prediction (Ikhlaaq Ahmed; Deeks, Riley) PhD (Maths): meta-analysis of prognostic factors (Ghada; Deeks,Riley)PhD (NIHR): allocation of cancer resources to maximise health benefits (Lazaros Andronis; Billingham, Barton)

7) Education in trial methodology

Training Schemes Provided by Hubs

5 PhD Studentships

MSc courses

MSc dissertation projects

Experts of the futureCurrent practitioners

CPD Courses • Best practice

• New methodology

Via existing mechanisms Regular seminarsOne-off symposia

Annual one-day meeting

Network: • Workshops• Annual Meeting • Sponsored speakers/events at major

meetings• UK Clinical Trials Methodology Conference

Example: Nov 17th 2011QoL Assessment in Cancer Research

(MHTMR/CRCTU/ECMC at UoB)

Workshops Hosted by Network

• Using Existing Data in Trial Design• Biologic Therapies in Inflammatory Joint Diseases- Models for Decis

ion Making• Routinely collected medical data - Use in clinical trials• The use of ICECAP measures in clinical trials and economic evaluat

ion• Handling Missing Outcome Data• Accrual and Recruitment in Paediatric Trials• Complex Interventions• Ordinal Outcome Data• Core Outcome Measures for Effectiveness Trials (COMET)• Recruitment in Surgical Trials• Diagnostic Evaluation in Stratified Medicine - joint workshop with Effi

cacy and Mechanism Evaluation program (EME)

Advice Function

HTMR Network

Regional Hub

Hub with relevant

specialist expertise

CTU: design, conduct and analysis of

trials

RDS: designing research studies

Specialist expertise external to HTMR Network

In-house research

Systematic Reviewers

Pharmaceutical Industry

In-house research

MAST

Methodology Advisory Service for Trials (MAST)

• Advice provided by individual Hubs through Network

• ‘Non-standard’ methodological problems– E.g. Adaptive trial designs, incorporating qualitative

research, analysis with missing data

• For statisticians and trialists working within the registered Clinical Trials Units and Research Design Services in the UK

• Fill out the MAST Query Form and email to enquiries@methodologyhubs.mrc.ac.uk and the query will be directed to the appropriate Hub

Example of Methodological Issue in the Clinical Research Community

Gefitinib Gem/CisNEvent

159153 (96.2%)

150142 (94.6%)

HR (95%CI) = 0.813 (0.641 to 1.031), P=0.044

Median PFS 4 month PFS (%)6 month PFS (%)1 year PFS (%)2 year PFS (%)

6.1 m60.350.220.34.2

6.6 m78.658.85.00.7

First-SIGNAL (Jin Soo Lee et al): PFS in never smoking adeno NSCLC

‘PFS was better in gefitinib arm’

Methodology Review: Aims

• To identify the different methods that have been proposed for crossing survival curves

• To determine if these methods are available using standard software and if not consider developing code

• To investigate how they operate under different circumstances

• To make recommendations regarding best practice

Example of MRC initiated topic: ‘Stratified Medicine’

• Recent term: 15 hits on PubMed• Association for the British Pharmaceutical Industry

(ABPI) white paper 2009– ‘the ability to classify individuals into subpopulations that differ in

their susceptibility to a particular disease or their response to a specific treatment’

• Trusheim et al (Nature Reviews Drug Discovery 2007)– ‘In stratified medicine, a patient can be found to be similar to a

cohort that has historically exhibited a differential therapeutic response using a biomarker that has been correlated to a differential response’

• Other terms– Diagnostic biomarkers, prognostic biomarkers, predictive

biomarkers (e.g. Cancer Research UK)– ‘Patient Segmenting’– Biomarker classifiers

Biomarker Classifiers for Stratified MedicineB

iom

arke

rs Classifier+

Classifier-

Mathematical Function (weights, cut-points)

DNA, RNA, proteins

…Predict to benefit

Predict to NOT benefit

Classifier needs to be: quick, cheap, reliable, reproducible, high sensitivity and specificity

Example: HER2 status for herceptin treatment in breast cancer

Trial Designs Assessing Application of Biomarkers in Clinical Practice

Discovery

Development

Validation

Application

Change Clinical Practice

Randomised Clinical Trial1) Stratified Trial Design

a) Stratified Assessment Designb) Targeted Trial Design c) Treatment-Marker Interaction Design

2) Marker-Based Strategy Design

• Sargent DJ et al JCO 2005; 2020-2027• Simon R Clin Cancer Research 2008; 5984-5992

(plus many more!)• Freidlin et al JNCI 2010; 152-160

Research Hypothesis: there is a validated biomarker classifier that

accurately identifies patients who are highly likely to gain survival time from a

marker-based treatment (M-Trt)

Measure Biomarkers

Classifier + Classifier -

RANDOMISE

M-Trt Control ControlM-Trt

RANDOMISE

Stratified Trial Design

Marker-Based Strategy Design RANDOMISE

Marker-based treatment strategy Standard Care

Classifier+ Classifier-

Standard Care

Measure Biomarkers

M-Trt

Stratified Medicine: Evidence of the Need for Information Provision on Methodology

• 2nd Late Phase Trials Forum, London, June 2008• International Lung Cancer Conference Liverpool, July 2008• NCRI Cancer Conference, Birmingham, October 2008• First International Workshop on Thoracic Oncology, Turin, April 2009• CRUK/ECMC Biomarker Roadmap Meeting, Leeds, April 2009• 3rd Late Phase Clinical Trials Forum (multimodality setting), London, June

2009• World Conference on Lung Cancer, San Francisco, July 2009• International Society for Clinical Biostatistics, Prague, August 2009• Critical Issues in Lung Cancer Research: The Swedish Approach and the

International Standards, Stockholm, February 2010• European Congress: Perspectives in Lung Cancer, Amsterdam, March 2010• National Lung Cancer Partnership 2010 Annual Meeting, Chicago, June 2010

Trial Designs to Assess Biomarkers in Clinical Practice

Research activity for publicationHow sensitivity and specificity of a biomarker affects statistical powerReview the evidence behind the stratified medicine decisions

Example of MHTMR Working with CTUs:Trials in Rare Diseases

Randomised Phase III trials are the optimal

method for establishing best patient care

Patients with rare diseases have the same right to evidence based treatment as those with

common diseases

Phase III trials in rare diseases will never be

large enough to determine best practice with adequate certainty

Trials in rare diseases are not a worthwhile

investment due to high cost-utility

Lilford’s ProposalLilford R, Thornton JG, Braunholtz D Clinical trials and rare diseases: a way out of a conundrum BMJ

1995

• Ethics of small clinical trials– Small well designed study better than no study– Contribute to a pool of knowledge

• Proposes an alternative view to clinical trials:– Carry out a trial NOT to gain a definitive

answer but to change the level of uncertainty• Bayesian perspective is useful in these

circumstances

• Make use of all knowledge, results from non-randomised studies should not be discarded

p ( treatment effect lies in a particular range | data, prior )

p-value = p ( data | no treatment effect )

Example: Bayesian Analysis of Trial Data with No Prior Information - Data: HR=0.8, d=50

P(HR<1)=0.78

Posterior probability distribution for True HR

What about Incorporating Prior Information?

• Aim: Combine all current evidence into a single prior probability distribution for the treatment effect

• Systematic review of literature and identify relevant studies• Obtain HR from each study (actually log HR)• Weight the different studies according to:

– Pertinence: how close is the information to that we wish to obtain– Validity: quality of the study– Precision: depends on number of events

• Combine the log HR and weights

• Tan S-B, Dear KBG, Bruzzi, P, Machin D Strategy for randomised clinical trials in rare cancers BMJ 2003– Propose methodology for representing existing evidence as prior

distribution• Tan S-B, Wee J, Wong H-B, Machin D Can external and subjective

information ever be used to reduce the size of randomised controlled trials? Contemporary Clinical Trials 2008– Illustrate the methodology on nasopharyngeal carcinoma example

Application to merkel cell carcinoma: Lucinda Billingham, Kinga Malottki, Mark Pritchard, Jerry Marsden, Neil Steven

Rare Diseases: Summary

• Small trial, ideally randomised, is better than no trial• Existing evidence is important in this setting• Bayesian approach enables:

– small trials to be regarded as reducing the uncertainty in estimation of a treatment effect

– probability statements about treatment effects which may be more useful in small studies

– ‘cumulative learning’ which facilitates adaptive trial designs

– inclusion of prior information which maximises the utility of the evidence • Inclusion of prior is controversial - evidence

synthesis needs to provide a believable prior

MHTMR Working with CTUs

• International Rare Cancers Initiative – National Cancer Research Institute (NCRI), – Cancer Research UK– National Cancer Institute (NCI in USA)– European Organisation in Research of Treatment for

Cancer (EORTC)• 8 rare cancers selected for trials• Aim: develop first phase III trial ever in penile cancer

– Institute for Cancer Research CTU, Sutton Statistician: Dr Emma Hall

– MHTMR: Methodology Advisors– Potential Collaboration: M.D. Anderson Cancer

Centre Statisticians - Professor Peter Thall

Hub Network: Stakeholder Meetings

•Arthritis Research UK •British Heart Foundation•Cancer Research UK•Health Technology Assessment Programme•Medicines and Healthcare products Regulatory Agency•NIHR Comprehensive Clinical Research Network•Wellcome Trust•Association of the British Pharmaceutical Industry•Cochrane Collaboration•Statisticians in the Pharmaceutical Industry•Registered clinical trials units•National Institute for Health and Clinical Excellence•National Ethics Research Service

How can the Hub Network support the NIHR Statisticians?

L.J.Billingham@bham.ac.uk

Senior Administrator for Hub and PA to Director: Karen Biddle, K.Biddle@bham.ac.uk

www.bham.ac.uk/mhtmr