Orchestrating a National Translational Research Strategy

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Orchestrating a National Translational Research
Strategy

• John Bell

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UK Health Research Analysis
O.S.C.H.R.

• Published May 2006
• First ever comprehensive national analysis of
  health research funding
• 11 largest Government and charity funders of
  health related research in the UK
• Collected peer-reviewed research funded 2004/2005
  950m/9500 awards
• All types of research activity and all areas of
  health and disease

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UK Health Research Analysis
O.S.C.H.R.
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UK Health Research Analysis
O.S.C.H.R.
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Drivers for Change
O.S.C.H.R.
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Key Findings
O.S.C.H.R.
O.S.C.H.R.

• UK Health research system has many strengths
• But
• Risk of failing to meet full economic, health and
  social benefits of UK public investment
• No overarching health research strategy
• Key gaps in the translation of health research
• Funding of health research from concept to
  practice could be more coherent
• Cultural, institutional and financial barriers to
  translating research.

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A Single Health Research Strategy
O.S.C.H.R.
O.S.C.H.R.

• A new, sustainable, strategic framework for
  health research and cultural change
• Continued investment in basic biomedical science
• A Health Research Ring-fence
• Commitment and engagement across all four UK
  Administrations
• New investment targeted in key strategic areas

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Government Investment in Health Research
Millions GBP
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OSCHR Partners developing a single UK Health
Research Vision
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OSCHR
Public Health Board
Translational Medicine Board
E-Health Records Research Board
Human Capital
Infrastructure
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UK Health Research Priorities
O.S.C.H.R.
Survey of unmet medical need
Evaluation of Scientific Opportunity
Health economic impact
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England Forecast Increase in Diabetes
Prevalence by Local Authority District, 2001-2020
The Burden of Disease and Illness in the UK S.
Green, R Miles. April 2007 Source Yorkshire
Humber Public Health Observatory 2007
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The Burden of Disease and Illness in the UK S.
Green, R Miles. April 2007
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England and Wales Age-standardised rates for
three major causes of death (per million
population), 1971-2005
The Burden of Disease and Illness in the UK S.
Green, R Miles. April 2007 Source Office for
National Statistics 2007
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England and Wales Cancer Mortality Trends
Age-standardised Mortality rates per Million
Population, 1991-2005
The Burden of Disease and Illness in the UK S.
Green, R Miles. April 2007 Source Office for
National Statistics 2007
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Health Research Opportunities 2

• Stratification of phenotype
• Regeneration and replacement
• Tracking response to intervention
• Measure, understand and modify environmental and
  inherited influences on health
• Exploitation of world leading position in
  hypothesis-generating science to deliver improved
  health
• Early detection of the opportunity for effective
  intervention
• Primary prevention
• Behaviour modification
• Understanding the burden of illness
• Development of new interventions

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Rebuilding Basic Science Infrastructure
O.S.C.H.R.
MRC Laboratory for Molecular Biology, Cambridge
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Translational Pipeline
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O.S.C.H.R.

• Translational Medicine
• Experimental Medicine and Exploratory
  Development, including imaging, biomarkers MRC
• Methodology for large and small clinical trials
  MRC
• Large trials and evaluations of therapeutics,
  devices, diagnostics, and other interventions
  (overlapping with public health) NIHR
• Clinical training NIHR

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The complex environment of translational medicine
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Translational Medicine Enabling Technology

• Imaging
• Biomarkers
• Drug Safety
• Experimental Medicine
• GenotypePhenotype

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Developmental Pathway funding Scheme (MRC)
O.S.C.H.R.
Phase I
HTS
L.I. ? L.O.
Pre- clinical models
P.o.C.
Biologics
Regulatory Support
Safety and Toxicology
Manufacturing and Formulation
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Biomedical Research Centres (NIHR)
O.S.C.H.R.

• 5 Centres selected in competition
• 100 million p.a. support for infrastructure and
  personnel
• Increase capacity in experimental medicine and
  exploratory development

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Well-characterised Small Cohorts (MRC NIHR)
O.S.C.H.R.

• Common disease cohorts (e.g. COPD,
  osteoarthritis, heart failure, stroke, hepatitis
  C, HIV, Alzheimers disease)
• Phenotyping using imaging, physiology, genetics
  and genomics
• Disease progression monitoring
• Maintained for experimental medicine and
  exploratory development

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Molecular Diagnostics The new genetics in
clinical practice
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Translational GeneticsBridging the Gap
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Next Generation Sequencing
Oxford Nanopore
454 Life Sciences
SOLEXA / ILLUMINA
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Sequencing Projects

• POTENTIAL TLN OUTCOMES
• Improved test for 5-10 genes
• New UK /European test
• New UK /European test
• Infection surveillance in hospitals
• Improved test novel application
• New UK /European test
• Identification common variants
• Pharmacogenetics tests
• Signal transduction pathways, Stratified medicine

• PROJECTS
• Sudden Cardiac Death
• Retinal Degeneration
• Mental Retardation
• Pathogens
• HNPCC cancer
• CHD
• Type 2 diabetes
• Renal cancer
• Melanoma

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Sudden Cardiac Death Syndromes

• Hypertrophic and dilated cardiomyopathies, long
  QT syndrome
• Heterogeneous single gene conditions - autosomal
  dominant
• Incidence 1500-11000
• Condition treatable once diagnosed lifestyle,
  beta blockers, defribillators
• Oxford GKP programme
• Up to 5 genes currently tested for HCM, DCM or
  LQT
• Potential to increase referrals (cardiologists,
  coroners) expand genes tested (10)
• Technology upgrades required to support this
• Once validated can be applied to other
  established NHS genetic tests (eg BRCA1/2)

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Retinal Degeneration

• Inherited eye conditions
• Defects in photoreceptors and retina leading to
  progressive visual loss
• Genes known, but currently lack of comprehensive
  testing
• 25-30 genes known for autosomal recessive
  retinitis pigmentosa
• 200-300 genes for ARRP, ADRP, XLRP and other
  relevant eye disorders

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Pathogen Surveillance
Clinical applications Novo virus, MRSA, C
difficile, TB
At national level identify new epidemic
strains At local level identify endemic
outbreaks Individually identify pathogen to
inform clinical intervention
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Array CGH-NHS Potential

• Develop as first line test for chromosomal
  anomalies
• Multi-sample formats and high density
• Cost implications and commissioning (gt50 cost
  efficiency)
• Extend Applications
• Speech and language / autism
• Congenital heart disease
• Leukaemia
• Pre-implantation genetic diagnosis
• Cancer
• Diagnosis, prognosis, treatment selection

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SLI037 456kb 3p26.3 loss, 607kb Xp22.11 gain
3p26.3
Male Proband
Father
Male sib (affected)
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Large Scale Evaluation

• Therapeutics
• Diagnostics
• Devices
• Other interventions

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E-Health
O.S.C.H.R.

• Contribute to developing Connecting for Health
  for research purposes (Research Capability
  Program)
• Pilot studies with databases in UK (GPRD),
  Scotland and Wales
• Federate databases across UK

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Benefits - Research

• Epidemiology scale follow up of patient cohorts.
• Content rich databases allowing integration of
  data
• Evaluation of efficacy and toxicity of
  therapeutics in real populations
• Rapid ascertainment for clinical trials
• Novel cohort methodology for evaluations of all
  forms of interventions

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Integration of patient data
Laboratory data
Genomic data
E-Health Record
Imaging
GP record
Hospital admission
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E-Health

• Effective systems of record linkage in Scotland,
  Wales and parts of England (North west and
  Birmingham) but international competition is
  growing
• Research capability program is delivering tools
  for research purposes that will work in most
  systems
• CfH is unlikely to be the platform in its current
  form but multiple exisiting record systems will
  work together
• Governance of data could be limiting factor
• We have lost the international lead

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Why have we lacked in Public Health Research?

• Multiple disciplines (epidemiology, infectious
  disease, modelling, behavioural psychology)
• Much is outside the health system and Department
  (education, transport, workplace environment)
• Multiple disease areas (cardiovascular, cancer,
  infectious disease, mental health, diabetes)
• Inconsistent and sparse funding
• No career track for professionals

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Public Health
Infectious DISEASE
Infectious Disease
Infectious Disease
Chronic Disease
Discovery
Discovery
Surveillance
Evaluation
Evaluation
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Going Global with Public Health
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Can we do better in Public Health?

• Multi-agency/multi-departmental funding
• Leadership in a few major areas (addictions and
  mental health, infections, obesity, ageing)
• Obtain national experiments from others
  (transport, education)
• Work with industry

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The Economy.
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Maintaining a Competitive Commercial Health
Sciences Sector

• Pharma pipelines are poor and late stage failures
  are frequent
• Efficacy is low in unstratified populations
• Marketing exceeds innovation
• Clinical Trials are too slow and expensive
• Biotech business model is broken. Gestation is
  too long and Venture Capital is scarce
• Not enough partnerships

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Patient Recruitment HPS-Thrive

• Too slow
• One size fits all
• Too many sites

Costs US 1.0 UK 0.6 China 0.3
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Stratification Imperatives

• Rheumatoid Arthritis (Mkt 16 billion)

Biologics Target
Infliximab TNF
30-40 non response
Remicade TNF
30-40 non response
Humira TNF
30-40 non response
Kineret IL-1
Limited efficacy
Rituxan CD20
Orencia CTLA-4
Limited efficacy
Actemra IL6-R
10 super responders
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Benefits for Industry Translational Medicine
O.S.C.H.R.

• Creating new insights into pathways relevant to
  disease, providing new targets for industry for
  therapeutic intervention.
• Validating targets and pathways using both small
  molecules and antibodies
• Development of new and preclinical models that
  more appropriately mimic disease pathogenesis
• Managing programmes that are surplus to
  requirements but informative to industry through
  exploratory development
• Development of new diagnostics, therapeutics or
  devices up to and including exploratory
  development that could be further exploited by
  industry
• Development of better tools for the evaluation of
  preclinical and clinical safety
• Exploratory development programmes
• Content-rich large-scale trials
• Methodology innovation for trials

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OSCHR Future Challenges and Opportunites

• Effective communication of the role of OSCHR and
  the entire UK funding landscape
• Commercial Interactions
• Public Health Research
• E-Health Records Research
• Capacity Building
• The Economy!