Realising Genomics in Clinical Practice A case study

Realising Genomics in Clinical Practice: A case study in translation Alison Hall HELEX: Translation in Healthcare 25 June 2015

Realising Genomics in Clinical Practice About us The PHG Foundation is a pioneering independent multidisciplinary UK think-tank with a special focus on genomics and other emerging health technologies that can provide more accurate and effective personalised medicine • Active since 1997 • Located in Cambridge UK, Member of Cambridge University Health Partners and Cambridge Institute of Public Health • Funded by philanthropy, grants, and fees for commissioned work

Our mission Making science work for health Harnessing genomic and bioscience research to deliver improved and affordable healthcare We provide knowledge, evidence, tools and opportunities for policymakers to deliver rational and responsible changes in health policy and practice. We focus on: • The personalisation of health • Across the whole of life • Including ethical, legal, and social dimensions

Our healthcare manifesto Personalised healthcare/disease prevention • Transforming health systems • Making the best use of data • Putting individuals at the centre of their own healthcare

Transforming health systems Realising Genomics: Aim and outputs Aim: Identify and address the broad range of ethical, legal, social and practical issues arising from the clinical implementation of next generation sequencing or whole genome sequencing technologies Outputs: • Substantive recommendations and guidelines • PHGF report, peer reviewed papers, briefings

Realising Genomics Facilitating implementation • American College of Medical Genetics and Genomics • Managing incidental and pertinent findings (PHGF) • UK 100, 000 Genomes Project Sequencing of patients with rare diseases, cancers, infectious disease

Realising Genomics Project Timeline Evidence, Gene packages/ experts Steering Research/ Steering Patient and reopen group clinical ELSI group meeting workshop interface pathways sequencing contact Launch event Work on Project Commences Jan 2013 April 2013 July 2013 Dec 2013 Outline and aims agreed Feb 2014 July 2014 December Jan 2014 2015 Strategic recommendations Iterative content WS 1 WS 2 WS 3 Briefing Wider dissemination Report publication

Realising Genomics Schedule of Workshops Workshop 1: Empirical research on use of WGS/ES in clinical practice Workshop 2: Research/clinical interface Workshop 3: Iterating the patient pathway Workshop 4: Gene packages and open sequencing Workshop 5: Evidence base, expert committees and recontact

Realising Genomics Workshop 1: Empirical Ethics - July 2013 • Empirical research into clinical implementation Findings: – Scale, conceptual clarity, operational issues • The context (i. e. research or clinical use guides the ethical and legal principles that apply)

Realising Genomics Workshop 2: Research/clinical interface - Dec 2013 • Findings: – Need for transparency, evolving obligations of professionals and changing regulatory context

Realising Genomics Workshop 3: Iterating the patient pathway Feb 2014 • Genomic sequencing and patient pathways Findings: – Targeted sequencing minimises ELSI – Criteria for using open sequencing need to be formulated – Interpretation and validation • Shared evidence base • Centralisation and expert committees – Operationalising reanalysis/recontact

Realising Genomics Workshop 4: Gene packages and open sequencing - July 2014 Findings: – Mechanisms for constructing gene lists – Justifications for open sequencing Workshop 5: Evidence base, consent, expert committees and reanalysis/recontact – July 2014 Findings: – Creating an NHS Database – Infrastructure for interpreting VUS/IFs – Recommendations for reanalysis/recontact

Realising Genomics Identify and prioritise key issues Workshop 5 Evidence base, expert committees and recontact Workshop 4 Gene packages and open sequencing Workshop 1 Empirical Ethics Building recommendations and ongoing advocacy Workshop 2 Genomics and the Research and Clinical Interface Workshop 3 Iterating patient pathways

Realising Genomics: The purpose and scope of the Report 1. Inform the ethical implementation of NGS technologies through recommendations - ‘Needs’ and ‘shoulds’ 2. Report on workshop outcomes (as a secondary purpose) - Workshop briefing notes appended 3. Aimed at a general audience including policy makers, clinicians, and lab scientists - Includes glossary and scientific appendix http: //www. phgfoundation. org/reports/16447/

Realising Genomics: 25 Recommendations • Targeting • Core gene lists • Consent • Building an evidence base and data-sharing • Ensuring consistent practice – Interpreting and disclosing variants of unknown significance (VUS) and incidental findings (IFs) – Reanalysis and recontact • Wider infrastructure

Realising Genomics: Targeting TARGET • NHS should adopt targeted analysis using gene lists (1) DON’T LOOK • Bioinformatics search strategies should minimise incidental findings (IFs) (5) USE WES/WGS as 2 nd LINE TEST (unless justification for 1 st line) • Develop criteria for use as a 2 nd (and 1 st) line test (6)

Realising Genomics: Utilise Core Gene Lists GENE LISTS • Core/standardised genes based on phenotype (3) CONSISTENT STANDARDS • Clear, standard referral criteria (2) • Multidisciplinary expert groups should apply standardised eligibility criteria to select genes. Also responsible for curation/updating (4)

Realising Genomics: Consent WHAT NEEDS TO BE INCLUDED IN CONSENT? Targeted/open sequencing and analysis IFs and VUS • Generation and significance of IFs and VUS • Implications – further investigation of IFs and VUS (7) implications for relatives (8) • Patient views on receiving IFs (9) REANALYSIS AND RECONTACT • Reanalysis/recontact (7). • Opportunity to opt-out of recontact (10) DATA SHARING • When and how data will be shared (11, 15)

Realising Genomics: Building an evidence base and data-sharing EVIDENCE BASE (build on existing systems (14) flexible and dynamic (21)) • Secure, comprehensive accessible NHS database (12) • Mandated deposition of data (13) DATA SHARING • Provision for wider data sharing outside NHS (via consent) (15) • Mechanism to facilitate VUS interpretation (16)

Making the best use of data Why is this a complex and difficult area? • In the UK, the legality of data sharing depends upon – – The purpose of sharing (direct care or secondary uses) – Whether it is identifiable data – The safeguards put in place (e. g. managed or role based access) • BUT the interface between clinical care and research is permeable and fluid • Some genomic data may not be capable of being anonymised • Pseudonymised data has uncertain legal status

Personal Genome Project (UK) Aim: to generate ‘freely available scientific resources that bring together genomic, environmental and human trait data” • generate publicly accessible resources • high threshold for participation • BUT acknowledgement that privacy, confidentiality and anonymity are “impossible to guarantee” • examples of hypothetical harms in PIS include non-paternity; potential for discrimination; criminal liability • participants have password protected access to their data but not for medical purposes

Making the best use of data What are the possible solutions? AIM – COMPREHENSIVE; FACILITATE NOT DETER SHARING; ROBUST; LEGALLY COMPLIANT; TRUSTWORTHY; SCALABLE • Be transparent about how data will be shared and systematic about seeking consent as routine • Secure, comprehensive, accessible NHS database – Options could include building on existing infrastructure e. g. 100, 000 Genomes Project data repository – Building on existing processes e. g. Consortium based sharing developed through Decipher

Making the best use of data What are the possible solutions? • Work with stakeholders to achieve greater understanding • Work towards harmonised standards • Develop technological tools to enable sharing without compromising identification – Global Alliance – Matchmaker exchange – BRCA challenge

Realising Genomics: Ensuring consistent, evidence based practice DON’T ACTIVELY LOOK FOR IFs • Bioinformatics search strategies should minimise incidental findings (IFs) (5) INTERPRETING AND DISCLOSING IFs and VUS • Mechanism to facilitate VUS interpretation (16) • Standards for (a) labs to report to clinicians (b) clinicians to report to patients (17) REANALYSIS AND RECONTACT • Systematic approaches to reanalysis/recontact (18)

Realising Genomics Should we actively look for secondary findings? IN PUBLICLY FUNDED HEALTH CARE SETTINGS • The balance of benefits and harms is not yet clear in ‘asymptomatic’ populations without family history in clinical settings • ‘Staff capacity and budgets are already stretched to cope with existing demands’ • ‘Demand for follow-on testing and management could overwhelm health services’ • PRIORITISING THOSE WHO HAVE PRE-EXISTING PROBLEMS MAY NOT BE EQUITABLE

Should we actively look for secondary findings? What do professionals and publics want? Evidence from a research setting.

Should we actively look for secondary findings? • Project aiming to sequence 100, 000 genomes from around 40, 000 NHS patients with rare diseases, cancers and infectious disease • A ‘hybrid’ transformational project straddling clinical care and research • Participants will be offered to OPT IN to feedback of: – Secondary findings ‘additional looked for findings of healthcare importance’ – E. g. HNPCC, FAP, hereditary breast and ovarian cancers, multiple endocrine neoplasia types 1 and 2 – Carrier status – autosomal recessive – e. g. SCA, CF, thalassemias – X-linked disorders – e. g. DMD, haemophilia

Should we actively look for secondary findings? What are the possible solutions? Genomics England Clinical Interpretation Partnerships (Ge. CIPs) • Multidisciplinary collaborations across disease specific and cross cutting domains • Will supply annotation and interpretation of sequence data • Opportunities for research and drug development • Findings will be validated by referring centres before feeding back to physicians and patients • Work streams: Practical Ethics and Evaluation and Implementation sub-domains

UK Biobank The contribution of genetics and lifestyle to health • 500, 000 people aged between 40 -69 recruited between 2006 -2010 • Aim to offer 100, 000 MRI imaging (brain, heart, carotid artery, bone density) – Return of results – Potentially serious (lifespan or impact on bodily functions or quality of life) regardless of actionability. • Genotyping using Affymetrix array (820, 967 SNP and indel markers) • Genomic results available to researchers Q 3/4 2015 • Increasing clarity about ‘normal’ population

Realising Genomics: Wider infrastructure SUPPORTED BY • ELSI research (19) • Health economics research (20) • Educational resources (22) • Evaluation (24) • Commissioning (25) All these are needed to build public trust and confidence (22).

Realising Genomics: How to traverse the translational gap? 1. Within a state funded health system access to genomic sequencing should be – Targeted (conditions where genomic sequencing offers clinical utility, gene lists, pertinent rather than secondary findings); Standardised (‘what’ - scope of testing depends on clinical utility; ‘how’ - communications between lab/clinician/patient) Transparent (robust processes (UKGTN); patient facing consent) Cost-effective – will only be adopted if perform as well or better than existing tests

Realising Genomics: Building an evidence base 2. However other models offer useful insights and help build the infrastructure and evidence base for implementation 100, 000 Genomes Project • Will catalyse infrastructure, capacity building (education) and downstream management (pertinent and secondary findings), and wider investment Personal Genome Project • Publicly accessibility will boost research and help to assess wider risks to participants (re-identification and discrimination) UK Biobank • Build longitudinal evidence base, interactions between gene/environment interaction

Realising Genomics: Translation in transition 3. What other drivers are emerging? • Generating value from health data 100, 000 Genomes Project • GENE consortium (Genomics Expert Network for Enterprises) • Access up to 5000 WGS and corresponding health information • Membership fee for storage, security and analytic services Direct-to consumer companies • $10 M Genentech in 23 andme – aggregated data from 600, 000 customers

Realising Genomics: Some conclusions 4. BUT the situation is dynamic and evolving • Multiple stakeholders, drivers and barriers Health services use • Increasing potential for direct-to-consumer access Research • Need for clarity about context, purpose, benefits, harms and uncertainties • Work towards fair and transparent systems that provide equity of access • Avoid exaggeration Personal direct-to-consumer • Enforceable legal sanctions • Beyond genomics to other ‘omics’

Realising Genomics: Acknowledgements PHGF staff Realising Genomics Report is available at • Corinna Alberg www. phgfoundation. org • Tom Finnegan • Nina Hallowell Contact: alison. hall@phgfoundation. org • Hilary Burton • Mark Kroese • Leila Luheshi • Sobia Raza • Jane Lane • Communications team Associates • Jo Whittaker • Caroline Wright External steering group Workshop delegates