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Transcript of Realising Genomics in Clinical Practice: A case study in translation Alison Hall HELEX: Translation...
Realising Genomics in Clinical Practice: A case study in translation
Alison HallHELEX: Translation in Healthcare 25 June 2015
Realising Genomics in Clinical Practice
About usThe 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 systemsRealising 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 ProjectSequencing of patients with rare diseases, cancers, infectious disease
Realising Genomics Project Timeline
Gene packages/
open sequencing
Reportpublication
December 2014
Wider dissemination
Strategic recommendations
Work on Project Commences
Jan 2013
ELSI workshop
April 2013
Iterative content
July 2013
Steering group
meeting
Outline and aims agreed
Dec 2013 Feb 2014 July 2014
Research/ clinical
interfacePatient
pathways
Evidence, experts and re-contact
WS1
Briefing
WS3
Briefing
WS2
Briefing
Steering group
meetingLaunch event
Jan 2015
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 Workshops
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 Workshops
Workshop 2: Research/clinical interface - Dec 2013•Findings:
– Need for transparency, evolving obligations of professionals and changing regulatory context
Realising Genomics Workshops
Workshop 3: Iterating the patient pathwayFeb 2014•Genomic sequencing and patient pathwaysFindings:
– 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 Workshops
Workshop 4: Gene packages and open sequencing - July 2014Findings:
– Mechanisms for constructing gene lists– Justifications for open sequencing
Workshop 5: Evidence base, consent, expert committees and reanalysis/recontact – July 2014Findings:
– Creating an NHS Database– Infrastructure for interpreting VUS/IFs– Recommendations for reanalysis/recontact
Realising Genomics
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 2nd LINE TEST (unless justification for 1st line)•Develop criteria for use as a 2nd (and 1st) 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 analysisIFs 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 dataWhy 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 dataWhat 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 dataWhat 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 GenomicsShould 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 (GeCIPs)•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 BiobankThe 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 Q3/4 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 data100,000 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 servicesDirect-to consumer companies•$10M Genentech in 23andme – aggregated data from 600,000 customers
Realising Genomics: Some conclusions
4. BUT the situation is dynamic and evolving•Multiple stakeholders, drivers and barriers •Increasing potential for direct-to-consumer access•Need for clarity about context, purpose, benefits, harms and uncertainties•Work towards fair and transparent systems that provide equity of access•Avoid exaggeration •Enforceable legal sanctions•Beyond genomics to other ‘omics’
Health services use
Personal direct-to-consumer
Research
Realising Genomics: Acknowledgements
PHGF staff •Corinna Alberg •Tom Finnegan•Nina Hallowell•Hilary Burton•Mark Kroese •Leila Luheshi•Sobia Raza •Jane Lane •Communications team Associates•Jo Whittaker •Caroline WrightExternal steering groupWorkshop delegates
Realising Genomics Report is available at www.phgfoundation.org
Contact: [email protected]