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

1. 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 Research Biostatistics Lead, Cancer Research UK Clinical Trials Unit University of Birmingham NIHR Statistical Meeting, London February 13th 2012

2. 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

3. Why Do We Need Funding for Trials Methodology Research? Clinical Trials Units Design, conduct and analyse trials Evidence synthesis from trials Identify methodological problem Methodology review – identify a solution Not Directly Funded Methodology research and development

4. MRC / NIHR Initiative

5. HTMR Network All-Ireland Hub led by Professor Mike Clarke Dr Adrian Mander www.methodologyhubs.mrc.ac.uk

6. Network Objectives 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

7. What Do the Hubs Do? Research Programme Develop existing expertise Develop new research themes identified by trials community Collaborative, practical use to the trials community Training Programme Train the experts of the future Provide training for current practitioners Advice, Support and Dissemination Function Advice facility for trial practitioners Make knowledge accessible to the trials community Provide core of expertise in trials methodology Make UK a leader in trials methodology Hubs will become self sufficient

8. Structure of the Midland Hub (MHTMR) Director: Prof Lucinda Billingham Deputy Director: Dr Richard Riley

9. MHTMR Hub Resources Plus other affiliated RFs and PhD students

10. Clinical Trial Pathway for Research Phase I, II, III Add-on translational studies

11. Network: Working Groups • Trial recruitment group • Outcomes group • Evidence synthesis group • Trial conduct group • Adaptive design group • (Stratified medicine group)

12. 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/

13. HTMR Funded Collaborative Methodological Research • 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

14. MHTMR: Research Themes

15. Training Schemes Provided by Hubs Current practitioners Experts of the future • CPD Courses • Best practice • New methodology • Via existing mechanisms • Regular seminars • One-off symposia • Annual one-day meeting 5 PhD Studentships MSc courses MSc dissertation projects Example: Nov 17th 2011 QoL Assessment in Cancer Research (MHTMR/CRCTU/ECMC at UoB) • Network: • Workshops • Annual Meeting • Sponsored speakers/events at major meetings • UK Clinical Trials Methodology Conference

16. Workshops Hosted by Network • Using Existing Data in Trial Design • Biologic Therapies in Inflammatory Joint Diseases- Models for Decision Making • Routinely collected medical data - Use in clinical trials • The use of ICECAP measures in clinical trials and economic evaluation • 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 Efficacy and Mechanism Evaluation program (EME)

17. Advice Function In-house research In-house research CTU: design, conduct and analysis of trials RDS: designing research studies HTMR Network MAST Pharmaceutical Industry Regional Hub Systematic Reviewers Hub with relevant specialist expertise Specialist expertise external to HTMR Network

18. 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

19. Example of Methodological Issue in the Clinical Research Community First-SIGNAL (Jin Soo Lee et al): PFS in never smoking adeno NSCLC ‘PFS was better in gefitinib arm’

20. 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

21. 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

22. Biomarker Classifiers for Stratified Medicine Predict to benefit Classifier+ Mathematical Function (weights, cut-points) Biomarkers Classifier- … Predict to NOT benefit Classifier needs to be: quick, cheap, reliable, reproducible, high sensitivity and specificity DNA, RNA, proteins Example: HER2 status for herceptin treatment in breast cancer

23. Trial Designs Assessing Application of Biomarkers in Clinical Practice Discovery 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) Randomised Clinical Trial 1) Stratified Trial Design a) Stratified Assessment Design b) Targeted Trial Design c) Treatment-Marker Interaction Design 2) Marker-Based Strategy Design Development Validation Application • 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 Change Clinical Practice

24. Stratified Trial Design Measure Biomarkers Classifier + Classifier - RANDOMISE RANDOMISE M-Trt Control M-Trt Control Marker-Based Strategy Design RANDOMISE Marker-based treatment strategy Standard Care Measure Biomarkers Classifier+ Classifier- M-Trt Standard Care

25. Stratified Medicine: Evidence of the Need for Information Provision on Methodology Trial Designs to Assess Biomarkers in Clinical Practice • 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 Research activity for publication How sensitivity and specificity of a biomarker affects statistical power Review the evidence behind the stratified medicine decisions

26. Example of MHTMR Working with CTUs:Trials in Rare Diseases Phase III trials in rare diseases will never be large enough to determine best practice with adequate certainty 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 Trials in rare diseases are not a worthwhile investment due to high cost-utility

27. 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 )

28. Example: Bayesian Analysis of Trial Data with No Prior Information - Data: HR=0.8, d=50 Posterior probability distribution for True HR P(HR<1)=0.78

29. What about Incorporating Prior Information? • 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 • 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 Application to merkel cell carcinoma: Lucinda Billingham, KingaMalottki, Mark Pritchard, Jerry Marsden, Neil Steven

30. 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

31. 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

32. 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

33. 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