Professor Sue Hill OBE Chief Scientific Officer for England
Genomics, data & personalised medicine - the UK experience of transforming care for the future
April 2016
The NHS in England • A (semi) integrated health system caring for a population of 53
million, and dealing with 1 million patients ever 36 hours • Providing primary, community, secondary and tertiary care through
~8000 primary care (GP) providers, ~150 hospital groups ~60 mental health organisations and through ~800 other organisations
• 1 billion diagnostic tests each year – majority lab tests • Demand steadily rising - procedures & interventions up 45% in the
10 years to 2015 • Annual budget £113bn (~$160bn) • Facing challenges common to all health systems:
― with ageing, comorbid population with increasing non-communicable disease
― variation between communities and across geographies ― societal & technological drivers of demand ― financial challenges ― Solutions set out in Forward View
Science & innovation provides the revolutionary change health needs • Throughout its existence, the NHS has turned to scientific innovation to
provide the step-change in practice required to keep pace with patient needs and service demands
• Genomics builds on the long history of discovery and advance in the UK
1951: Watson & Crick
1974: Sanger – DNA sequencing
1984: Alec Jeffreys – DNA fingerprinting
1859: Darwin – Origin of Species
1997: Dennis Lo – cfDNA NIPT
PLUS firsts in: • Diagnostic ultrasound • CT scanning • IVF & PGD
UK has fostered more than twice as many Nobel prizes for Medicine & Physiology per capita than anywhere else in the world.
The NHS has had specialist genetic labs since the 1960s, currently formed as UK Genetic Testing Network with NGS capability and coordinating role over approved panels & dossiers
PM David Cameron launches project to sequence 100,000 Genomes from NHS patients with cancer & rare disease
Dec 2012: launch of the 100,000 Genomes Project
“By unlocking the power of DNA data, the NHS will lead the global race for better tests, better drugs and above all better care.
“We are turning an important scientific breakthrough into a potentially life-saving reality for NHS patients across the country.
“If we get this right, we could transform how we diagnose and treat our most complex diseases not only here but across the world, while enabling our best scientists to discover the next wonder drug or breakthrough technology.”
His announcement followed publication of the influential DH Human Genetic Strategy Group report Building our Inheritance, setting out issues around Genomics
The founding principles of the 100,000 Genomes Project 1. A focus on rare inherited diseases and
common cancers 2. Patients to be drawn from routine care
and treated through routine channels 3. All participants to provide a fully informed
consent providing for a wide range of data and tissue capture and broad categories of use including research and industry
4. However neither data nor tissues to go outside NHS-controlled ‘safe havens’ and all users to be properly authorised and monitored
5. A separate (government owned) company – Genomics England – formed to coordinate the project under an independent board, providing a ‘start-up’ mentality and drive
Where is the New Frontier for our time, the ‘uncharted areas of science’ JFK spoke about? I believe our ‘moonshot’ moment is genomics, and the ‘pioneers on that New Frontier’ the scientists and researchers changing the way we view medicine. UK Life Sciences Minister George Freeman MP
Aims of the 100,000 Genomes Project
Major legacies for patients, the NHS and
the UK economy by 2017
Increased discovery of pathogenic variants leading to new treatments, devices and diagnostics
Stimulate and advance UK life sciences industry and commercial activity in genomics
Accelerate uptake with advanced genomic medicine practice integrated into the NHS
Increase public understanding and support for genomic medicine
(long term) Embed the benefits of genomic medicine across mainstream NHS care esp. through Personalised Medicine
Objectives of the Rare Disease Programme • To increase discovery of pathogenic variants for
150+ specific rare diseases. • To add value with additional biological insights that
build confidence in putative pathogenic variants. • To enhance the clinical interpretation of WGS in
rare disease. • To develop a programme of functional multiomics
pathways, specifically transcriptomics, epigenetics, micro RNAs and biomarkers.
• To return these findings to the NHS for feedback to patients. • To create a unique dataset for rare diseases that may enable
therapeutic innovation.
Objectives of the Cancer Programme • Use WGS to identify novel driver mutations within
a set of common cancers and to understand its evolutionary genetic architecture through primary and secondary malignant disease (by multiple biopsy and WGS).
• Partner stratified healthcare programmes and outcome studies with patients from the NHS in England, to enable understanding of WGS benefits in defining predictors of therapeutic response to cancer therapies.
• To use multiomic approaches including transcriptomics, proteomics and epigenetics to offer additional biological insights into cancer.
• To utilise WGS to identify new pathways for cancer therapies.
Identification of eligible patients – unmet clinical need (RD) and untreated (cancer)
Involve and inform patients/public in ethics & genomics/data sharing consent
Supply of processed samples DNA (blood and tumour) & multiomics; participation in UKNEQAS EQA scheme
Collection and submission of phenotypic clinical and diagnostic data against defined datasets and standards
Validation of WGS findings & feedback to patients including monitoring outcomes
What the NHS is contributing to the 100,000 Genomes Project
• Nationwide network of 13 NHS Genomic Medicine Centres – providing equitable access to populations of ~3- 5million
• Upfront investment in infrastructure and IT • Operating to detailed contract & specification
– with tight performance management & support from NHS England Implementation unit
• Each NHS GMC lead ‘contractual‘ organisation works with local hospital delivery partners (total of 80-100 hospitals across England)
• Infrastructure built on foundation of regional genetic laboratories, clinical genetic services and local molecular pathology laboratories
• Integrated with workforce development led by HEE Genomics Programme
The infrastructure for delivery
GEP HEI x10
NHS Genomic Medicine Centres • Clinical samples and hospital data • Laboratory processing including molecular pathology • Broad consent for research and re-contact
Bio
repo
sito
ry
Sequ
enci
ng
DNA & samples for multi-omics
Clinical Data
• Identifiable clinical data • Longitudinal • Linked to genomic data
Research Data • Pseudonymised • GeCIP and industry partners
work within data centre
Clinicians & Academics
Training GENE consortium
Part
icip
ants
Dat
a
Fire wall
Existing Clinical Data Cancer &RD registries, HES, Mortality data, etc
Data and Analysis Improvement
• Annotation & QC • Scientists/SMEs • Product comparison
Oversight: Funding:
Other Industry
Data flows around a patient
Data within a laboratory and hospital network environment
What will we be telling participants? • Information about a
patient’s main condition
• Information about ‘serious and actionable’ conditions (optional)
• Carrier status for non affected parents of children with rare disease (optional)
Image courtesy of Health Education England
Data interpretation: the biggest challenge in genomic medicine • ~5-10 million variants in our genome • ~3.5 million “known” SNPs • ~0.5 million “novel” SNPs • ~0.5 million small indels • ~1000 large (>500bp) CNVs • ~20,000-25,000 coding variants • ~9,000-11,000 non-synonymous
― 92 rare missense variants (MAF <0.1%) ― 5 rare truncating variants (MAF <0.1%) ― 0-2 de novo variants
Matched phenotypic information is crucial to identifying pathogenic variants
• 3x Domains -‐ disease & cross-‐cu2ng • 2,250 prospec9ve GeCIP domain members • 300 ins9tu9ons, 24 countries
Institution Count UK Academic 1744 NHS Trust 634 International Academic 198 Other 333
Genomics England Clinical Interpretation Partnership (GeCIP)
Research investment available
Interpretation partnerships to speed up delivery of new interventions
17 yrs
Secure advance within 3 yrs
Start 2014
The traditional way The GeCIP way
Securing Patient Benefit Further research investment available – inc HEE research fellowships
Building an effective Cancer pathway
CURRENT NEW PENDING Breast Cancer Renal
Cancer Brain Tumours
Prostate Cancer
Sarcoma Upper GI
Colorectal Cancer
Germ Cell Tumours
Ovarian Cancer
Endometrial
Lung Cancer Melanoma CLL CUP
Childhood
• IIP: Tumour (FF AND optimised FFPE) and constitutional (blood) DNA collected
• Main Programme: Tumour (FF where biologically possible OR optimised FFPE) and constitutional (blood) DNA collected. No pre-treatment
• 75x median for tumour; 30x median for germline
Sec9on cut9ng Microscopic examina9on to identify neoplastic areas
neoplas9c areas iden9fied
DNA extrac9on
Current clinical pathway for DNA diagnos8cs from biopsy material
Surgical Biopsy Processing & Paraffin embedding
Formalin fixa9on
Experimental pathway has tested and determined most effective approach
Transforming tumour handling in the NHS to ensure quality DNA sequencing
Cut up
Surgical Biopsy DNA extrac9on Vacuum pack Freezing
‘noisy’ sample
Quality sample
Transforming cancer diagnostics • Tumour assessment
― Tumour size ! amount of tissue ! DNA quantity ― Cellularity, % neoplastic cells
• Molecular Pathology ― Routine handling of FF ! DNA quality ― Diagnostic biopsies for genomic analysis ― Consolidation of provision underpinned by contracting and
reimbursement • Dynamic status of tumour and patient
― WGS and/or gene panel utility and enhanced turnaround times • Clinical utility of WGS in cancer patients
― Clinically actionable results ― Patient/clinician incentives ― Links with clinical trials
• Technical validation: heterogeneity, no DNA, Copy Number Variations, Structural Variations
1. Establish knowledge sharing environment for results, developed code and algorithms
2. Access service providers who are being used for the pilot
1. Understand available patient cohorts and information and how to access data
1. Understand and improve clinical annotation & QC process
1. Access to specialised tools, e.g., developed by other GENE Consortium members
2. Understand how Genomics England will facilitate sharing of tools
3. Build platform to launch future personalised medicine projects
4. Share enhanced precision medicine approaches within companies
3. Access rare-disease and cancer data models
4. Build cohort of “unaffected” individuals that allow a control panel to estimate allele frequencies across genome
3. Create formal, scientific partnerships with GENE Consortium companies and learn about private-public partnerships
4. Build cross-industry network, sharing ideas and insights e.g. how genomics will affect biopharma business models
Data Access
Process Clarity
Tools & Knowledge
Effective Collaboration
GENE Consortium
Pilot
2. Understand steps, timescales and links (incl. genotype-to-phenotype and phenotype-to-genotype scenarios)
3. Define GENE – GeL interfaces per step and how the GeCIP – GENE interaction will work
2. Ability of GENE members to introduce own software to embassy
Industry engagement & GENE consortium
GENE – year long trial with pre-competitive consortium of AbbVie, Alexion, AstraZeneca, Berg, Biogen, Dimension Therapeutics, GSK, Helomics, Roche, Takeda, NGM Biopharmaceuticals, UCB
Driving continuous improvement – crawl… walk… run… fly!
Recruitment and Consent Eligibility
Sample Acquisition & Processing
Phenotypic Data
Validation & Reporting
System wide issues
Establishment of new standardised protocols & practices
UK National External QA scheme - DNA extraction and cellularity assessment
New approaches to extract, track, link and share information incl GS1 barcoding
Standardised datasets & messaging standards
Systematic use of SNOWMED CT
Defined entry criteria including prior genetic tests
Cancer treatment naïve
Cohort cancer studies
New Genomic Medicine MDTs set up Patient involvement in consent & new pathways
Genomic practitioners
Standardisation, contracting, performance management Pioneering network structure between GMCs & within geographies
Involvement in new Clinical Interpretation Partnerships
Gene panel app
National approach to validation design
Regulatory issues
Development of national legacy elements New consent
materials and training
Highly specialised workforce
Specialist
clinical workfor
ce
General workforce
Wider awareness
raising
Supporting transformation through integrated education & training
Masters Genomic Medicine
HSST Genomics, Bioinformatics, MPAD
Masters-level CPPD Modules
Online educational resources:
• Consent & ethics • Sample processing & DNA extraction
• Tumour processing • Cellularity assessment tool • Data analysis - validation • Introduction to Genomics • Introduction to Bioinformatics • Rare Diseases video
Delivered by national network of 10 (world) leading
Universities
Resources include: • Eligible patients
• Phenotypic data sets
• Sample collection & processing
• Sequencing
• Validation of collected data
• Clinical report and action
Informa(on & free online resources at www.genomicseduca(on.hee.nhs.uk @genomicsedu
Aligned with transformation across laboratory medicine • NHS England driving transformation of existing
genetic and molecular pathology services through reprocurement of existing UKGTN genetics labs to create a national laboratory infrastructure by 2017
• 2016 Carter report on hospital productivity sets out clear requirements around lab medicine (‘pathology’) services including: ― Noting ‘consolidated pathology organisations
are the most efficient in the NHS’ ― Services to meet national benchmarks by Apr 17
or be merged/outsourced ― A clear system for standardising/reporting test and activity
Building the future of genomic medicine • Develop structures for collection in NHS of consistent,
high-quality consent, data and samples (for clinical AND research usage)
• Develop and deliver a legacy of infrastructure: sequencing centre, sample pipeline, biorepository and large-scale data store, for sustainable use by the NHS. Human capacity and capability
• Concentrating the UK Genomics Knowledge base (clinical and research) in a single location – with informatics to support access & use in frontline services
• NHS England to embed Whole Genome Sequencing into routine commissioning of clinical pathways with sharing of all genomic molecular data
• NHS, academics and industry partnerships working together at the outset to drive Genomic Medicine into the NHS
Developing an unrivalled national resource
Genomic sequence data & genetic testing
Pathology data
Multiomics info
Physiological tests
Imaging
Patient generated data
Other clinical phenotypic data
Capture, Collation, analysis &
interpretation - Endotype
Improved diagnosis & intervention
options
Individual response/ ADR
• Large populations of data will generate an Information Commons for both clinical and research use and a Knowledge Network that adds value by highlighting data inter-connectedness and integrating these links
• Combined database provides opportunities for machine learning, cluster analysis and other data techniques to provide new insights
Biomedical Research Clinical Observations
National Genomic Data Centre
PLUS: Data services platform in development
Moving from illness to health
ILLNESS HEALTH Using science and technology to improve outcomes and health through • Prognosis • Earlier disease stages offering more
treatment options • Influencing lifestyle factors and
population health • Stratified medicine
This will deliver the 4 Ps of Prediction (& prevention) of disease, more Precise diagnoses, Personalised and targeted interventions with a more Participatory role for patients
• Delayed diagnosis • Late stage disease • Multiple conditions • Restricted treatment &
management options • Poorer outcomes &
patient experience
Building from a genomic base to developing personalisation of care
Technology, Innovation & Knowledge Base
DNA
Genomics
Metabolomics
Personalised Interven8ons & Therapeu8cs
Clinical Change Model
Infrastructure Policy & System Alignment
Transcriptomics
Proteomics
Patient generated data & self-reporting
Integrated phenotypic characterisation Functional diagnostics
Informatics and digital health
Why personalisation is required • Growing burden of disease – particularly
non-communicable conditions – placing increasing pressure on health services
• Many key pharmaceutical interventions only effective in 30-60% of patients – showing limits of ‘one size fits all’ medicine
• Adverse drug reactions are still a significant cause of avoidable (1 in 15 hospital admissions in UK)
In effect, personalised medicine improves the delivery of patient-centred care through by combining established diagnostics and informatics techniques with emergent technologies such as genomics
The latest wave of drugs – personalisation & theranostics • 28% of FDA approved drugs were personalised last
year (2015) • 35% of these were cancer drugs
Theranostics – combined therapy & diagnostic eg drug+biomarker
The Personalised Medicine Strategy - tailoring treatment & management to a patient’s individual makeup
‘One size fits all’ treatments & intervention
Individually-tailored approach
Increasingly precision interventions based upon carefully identified subgroups within the broader population
The new taxonomy of medicine
Aligned with innovation initiatives across the healthcare system Personalisation development aligns with structures driving innovation in lab medicine & beyond: • MRC pathology nodes • Diagnostic Evidence
Collaboratives • Small Business
Research Initiative • Innovate UK • Precision Medicine
Catapults • Medilinks • Academic Health
Science Networks • Vanguards
Invention Evaluation Adoption Diffusion
Research councils/ funders
NIHR
Innovate UK (Technology Strategy Board)
NHS Regional Innovation Hubs
NHS England Innovation Initiatives
AHSNs
NHS Supply Chain
Local Commissioning (CCGs)
NICE (Medical Technologies Advisory Committee & Implementation Collaborative)
Rapid Review Panel (DH)
Exemplar clinical pathways (AcMedSci)
UK Pharmacogenetic & Strat. Medicine Network
UK Clinical Research Collaboration (UKCRC)
Would allow treatment to start in
childhood
Personalising for patient benefit – Familial Hypercholesterolaemia
FH
Affects 1 in 250
Significantly underdiagnosed (<1in10 in UK) despite clear
guidance
Autosomal dominant condition
– so ‘cascade testing’ of families valuable
Several genes identified –
may get polygenic FH
as well as monogenic
Early treatment reduces CHD risk (50% of men have MI by age 50)
Many identified patients
undertreated – despite cheap
statin treatment
A significant cause of avoidable cardiovascular problems
Personalisation for patients: transforming Warfarin management
Personalisation in practice - management of genetic diabetes Basic details (eg BMI)
& simple pathology (eg HbA1c)
Probability calculation
Urinary C-peptide creatinine ratio
testing/ Antibody testing for pancreatic
autoimmunity (rules out Type 1)
Genetic testing
Permanent diabetes and developmental delay Sulphonylurea therapy
Wolcott Rallison Syndrome Liver Transplant
IPEX syndrome Bone Marrow Transplant
Syndromic pancreatic agenesis
Insulin and exocrine supplements
Multi-organ autoimmune disease ? STAT3 inhibitor
KCNJ11 p.V59M
EIF2AK3 p.E371*
FOXP3 c.227delT
GATA6 c.1448 -1455del
STAT3 p.T716M
DIAGNOSIS TREATMENT
Combination of phenotypical characterisation (including established diagnostics) with genomic testing identifies precise diagnosis and treatment options
Personalisation will be an ongoing approach, particularly with cancers • Personalisation
is not just a snapshot in time
• Patients with ongoing conditions may see changes in pharmaceutical response with time - in response to their treatment or changes in the condition itself
• Monitoring and ongoing re-evaluation is required
Bosutinib
Nilotinib
Imatinib Dasatinib
Y253H Y253H
• Patient with long history of Chronic Myeloid Leukaemia • Lost response to imatinib – mutation responsible identified – Y253H • Good response to Dasatinib, but discontinued - intolerant • Nilotinb, as expected, not effective (based on Y253H) • Good response to Bosutinib, but discontinued
– intolerant Considered unfit for transplant • Off TKI and disease returning – still has Y253H
Example courtesy of Prof Michael Griffiths, Birmingham Women's NHS FT
MRC-NIHR Phenome Center
Personalisation approaches may involve other diagnostic technology
eg Imperial iKnife – which does real-time mass spectroscopy of surgical incisions to let surgeon know if tissue
is cancerous or not
Improving outcomes through personalisation
• Greater efficiency from streamlined care pathways • Earlier and more precise diagnosis and treatment • Fewer and less complicated surgical interventions • Fewer patients getting cancer and other diseases
£
Improves outcomes
Targeted therapy Identification of effective personalised treatments
Accelerated diagnosis based on underlying cause and incidental findings – rather than
just grouped symptoms Early disease detection
2-8 yrs before onset & symptoms become obvious with low cost
stratification Targeted disease prevention
Identification of predisposition markers or underlying processes can predict future
disease
The ethical frontline of scientific advance • Many new technologies are bringing with them ethical challenges -
such as the use & handling of data, or if they have predictive ability – but issues can occur if science is felt to move too fast…. or too slowly
How far should the science go? Sequencing from birth? Are the public ready? Will there be a backlash?
Over the next 10 years… The introduction of genomic medicine – particularly to inform the personalisation of treatment – is the most significant initiative to shape the future delivery of NHS care Over the next 10 years this will be seen through: • Genomic laboratory infrastructure and centres of excellence • 100,000 Genomes Project informing new pathways and models of care • WGS applied routinely and in other clinical conditions • Functional genomic pathway fully deployed (in real time care and also
for monitoring) • Medicines and other therapeutic interventions optimised • Closer alignment between clinical practice and research for mutual
benefit and improved outcomes for patients • New partnerships with industry • Greater public understanding of the impact and value of genomics
Already providing answers and changing lives
Leslie Hedley – identified INF3 mutation cause for his lifelong high blood pressure, helping his condition as well as his daughter and granddaughter
Jessica Wright (with Mum and Dad) – diagnosis provided answers for the family and identified that a special diet could help her epilepsy & improve quality of life
~8000 genomes sequenced to date – building database for insight
If I have seen further, it is because I am standing on the shoulder of giants
Sir Isaac Newton