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