1. Coming Soon – the MRC Framework for the Development, Design and Analysis of Stratified Medicine Research Dr David Crosby MRC Programme Manager for Methodology and Experimental Medicine UK Pharmacogenetics & Stratified Medicine Network Annual Open Meeting, 17 th March 2016

2. 13 internationally competitive stratified medicine discovery engines Build on NIHR and DA clinical research funding Total investment c. £60m 3 charity co-funders (CRUK, ARUK, BHF) 32 academic and 51 commercial partners MRC Stratified Medicine Consortia COPDMAP RAMAP-I MASTERMIND GAUCHERITE STOP-HCV MATURA-I UKPBC STRATA PSORT MASTERPLANS RASP-UK AIM HY S-CORT Auto-Immune Respiratory Cancer Infections Mental Health Cardiovascular Diabetes Congenital RAMAP-II MATURA-II

3. Challenges Need for development of clinical descriptors in line with biomarker studies for both disease classification and drug response. If descriptors are weak, starting group definitions will be weak, making biomarker discovery more difficult Use of adaptive screens to identify and prioritize drivers of variability The development, in collaboration with clinical colleagues, of estimates of the diagnostic power required from a test used to direct therapy choice, if it is to impact clinical decision making. Such estimates can help in study design. How the different data types collected will be stored, integrated and shared both within the consortium and more widely Modelling capacity able to both identify statistically significant biomarkers and develop systems biomedicine models of disease mechanism

4. Why Methodology for Stratified Medicine? A cautionary note on data gathering and (over)interpretation: “And in his brain, which is as dry as the remainder biscuit after a voyage, he hath strange places crammed with observation, the which he vents in mangled forms.” 1 1 As You Like It, Act 2, Scene 7

5. Why Methodology for Stratified Medicine? Lack of clarity and consensus in the Stratified Medicine community on methodology and experimental design Lack of consideration of mechanistic plausibility Lack of reproducibility and clinical predictiveness Sporadic guidance in niche areas, but no existing unifying framework

6. The Process International expert steering group: Consortia, industry, diagnostics, statistics, informatics Workshop 40 invited participants Consortia, industry, diagnostics, statistics, informatics…. Epidemiology, behavioural research, regulators, systems biology Plenary presentations, thematically structured discussion

7. The Objective The Framework will cover methodological issues in: the discovery and verification of stratifying biomarkers the definition of strata by integration of marker information the diagnostic methodologies to facilitate this methods for deriving mechanistic insight from these markers/strata informing trials able to test new stratifying hypotheses. (not trial design or health economics) The purpose of the MRC Methodology for Stratified Medicine workshop was to inform the development of an MRC Framework for Development, Design and Analysis of Stratified Medicine Research (the Framework). The Framework publication is intended to provide guidance to investigators on current best practice in methodological design of stratified medicine research.

8. The Framework Mission

9. The Framework Structure 1.Framing the question/defining the population Team composition, defining phenotypically complex study populations, selecting and defining outcomes, mechanism 2.Designing Stratum Discovery Studies; selecting variables, defining response and powering Selecting variables to measure, effect and sample size, planning for verification 3.Assay Design; managing complexity and noise Sources of variability – pre-analytic/technical/operator, collecting meta data to look for drift/artefact 4.Defining Strata; data integration, linkage to existing knowledge, linkage to outcome Defining strata by multiple markers, dealing with high-dimensional data, clear and adaptable analysis plans 5.Stratum Verification Design to break association, dealing with inflated effect sizes from discovery work, data set selection 6.Progression Towards Clinical Utility Characteristics of stratifiers that “make it”, relevance of the research question to the clinic, requirements of trials and clinical assay development

10. Next steps First draft Consultation with workshop attendees Steering group redraft Online publication for full guidance Framework Journal publication for summary paper Dissemination and communications