Orchestrating a National Translational Research Strategy John Bell.

Orchestrating a National Translational Research

StrategyJohn Bell

UK Health Research Analysis

• 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

O.S.C.H.R.O.S.C.H.R.

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

Drivers for ChangeDrivers for ChangeO.S.C.H.R.O.S.C.H.R.

Key FindingsKey FindingsUK Health research system has many strengthsUK Health research system has many strengths

But:But:

Risk of failing to meet full economic, health and Risk of failing to meet full economic, health and

social benefits of UK public investment;social benefits of UK public investment;

No overarching health research strategy;No overarching health research strategy;

Key gaps in the translation of health research;Key gaps in the translation of health research;

Funding of health research from concept to Funding of health research from concept to

practice could be more coherent;practice could be more coherent;

Cultural, institutional and financial barriers to Cultural, institutional and financial barriers to

translating research.translating research.

O.S.C.H.R.O.S.C.H.R.O.S.C.H.R.O.S.C.H.R.

A Single Health Research A Single Health Research StrategyStrategy

A new, sustainable, strategic framework for health A new, sustainable, strategic framework for health research and cultural changeresearch and cultural change

Continued investment in basic biomedical science Continued investment in basic biomedical science

A ‘Health Research Ring-fence’A ‘Health Research Ring-fence’

Commitment and engagement across all four UK Commitment and engagement across all four UK Administrations Administrations

New investment targeted in key strategic areasNew investment targeted in key strategic areas

O.S.C.H.R.O.S.C.H.R.O.S.C.H.R.O.S.C.H.R.

Government Investment in Government Investment in Health ResearchHealth Research

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200

400

600

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1000

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1400

1600

2000 2004 2006 2009

Mil

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Office for Strategic Coordination of Health Research

UK Health Research Vision

OSCHR Partners developing a single UK Health Research Vision


OSCHR

Translational Medicine Board

Public Health Board

E-Health Records Research Board

Human Capital

Infrastructure

UK Health Research Priorities

Survey of unmet medical need

Evaluation of Scientific Opportunity

Health economic impact


The Burden of Disease and Illness in the UK: S. Green, R Miles. April 2007Source: Yorkshire & Humber Public Health Observatory 2007

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

The Burden of Disease and Illness in the UK: S. Green, R Miles. April 2007Source: Office for National Statistics 2007

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 2007Source: Office for National Statistics 2007

England and Wales – Cancer Mortality Trends – Age-standardised Mortality rates per Million Population,

1991-2005


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

Rebuilding Basic Science Infrastructure


National Institutes for Medical Research, Mill HillMRC Laboratory for Molecular Biology, Cambridge

Translational Pipeline

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


The complex environment of The complex environment of translational medicinetranslational medicine

AHSCs

BRCs

BRUs

HTA Training

Imaging

Stem cells

Cohorts

Biologics

Biobank

Charities

MRC

NIHR, WORD, Scotland DA

Chemistry

RNAi

Large trials

Genetics

CRFs

GMP facilities

Stratification

Cyclotrons

Molecular pathology

Biomarkers

High throughput screening

Trial Methodology

Preclinical models

Regulation

Enabling technology

Technology transfer

Translational Medicine: Enabling Technology

• Imaging

• Biomarkers

• Drug Safety

• Experimental Medicine

• Genotype:Phenotype

Developmental Pathway funding Scheme (MRC)

Discovery

Tar

get

iden

tific

atio

n

Large Scale Evaluation

Pha

se I

I an

d II

I T

rials

HTS

L.I.

L.O.

Pre-clinicalmodels

P.o.C.Biologics

Regulatory Support

Safety and Toxicology

Manufacturing and Formulation

Phase I


Biomedical Research Centres (NIHR)

• 5 Centres selected in competition

• £100 million p.a. support for infrastructure and personnel

• Increase capacity in experimental medicine and exploratory development


Well-characterised Small Cohorts (MRC & NIHR)

• Common disease cohorts (e.g. COPD, osteoarthritis, heart failure, stroke, hepatitis C, HIV, Alzheimer’s disease)

• Phenotyping using imaging, physiology, genetics and genomics

• Disease progression monitoring

• Maintained for experimental medicine and exploratory development


Molecular Diagnostics: Molecular Diagnostics: The new genetics in clinical practiceThe new genetics in clinical practice

Proof of Concept

Clinical Trials

Clinical PracticeBasic

Science

Research Labs Diagnostic Labs

Translational Funding

Translational GeneticsBridging the Gap

Next Generation Sequencing

454 Life Sciences SOLEXA / ILLUMINAOxford Nanopore

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

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

Sudden Cardiac Death Syndromes

•Hypertrophic and dilated cardiomyopathies, long QT syndrome•Heterogeneous single gene conditions - autosomal dominant•Incidence 1:500-1:1000•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)

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

http://upload.wikimedia.org/wikipedia/commons/e/ed/Human_eye_cross-sectional_view_grayscale.png

Pathogen Surveillance

Clinical applications: Novo virus, MRSA, C difficile, TB

At national level: identify new epidemic strainsAt local level: identify endemic outbreaks Individually: identify pathogen to inform clinical intervention

Array CGH-NHS Potential

• Develop as first line test for chromosomal anomalies• Multi-sample formats and high density• Cost implications and commissioning (>50% cost efficiency)

• Extend Applications • Speech and language / autism• Congenital heart disease• Leukaemia• Pre-implantation genetic diagnosis • Cancer

• Diagnosis, prognosis, treatment selection

SLI037: ~456kb 3p26.3 loss, ~607kb Xp22.11 gain

Male Proband

Father Male sib(affected)

3p26.3

Male proband

Father Male sib(affected)

Xp22.11

Large Scale Evaluation

• Therapeutics• Diagnostics• Devices• Other interventions

E-Health

• 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


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

Integration of patient dataIntegration of patient data

E-Health Record

Imaging GP record Hospital admission

Laboratory data

Genomic data

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

Why have we lacked in Public Health Why have we lacked in Public Health Research?Research?

Multiple disciplines (epidemiology, infectious Multiple disciplines (epidemiology, infectious disease, modelling, behavioural psychology)disease, modelling, behavioural psychology)

Much is outside the health system and Much is outside the health system and Department (education, transport, workplace Department (education, transport, workplace environment)environment)

Multiple disease areas (cardiovascular, cancer, Multiple disease areas (cardiovascular, cancer, infectious disease, mental health, diabetes)infectious disease, mental health, diabetes)

Inconsistent and sparse fundingInconsistent and sparse funding

No career track for professionalsNo career track for professionals

Public Health

Infectious DiseaseInfectious DISEASE

Evaluation

Discovery

Surveillance

Discovery

Evaluation

Chronic Disease Infectious Disease

Going Global with Public Health

Can we do better in Public Health?Can we do better in Public Health?

Multi-agency/multi-departmental fundingMulti-agency/multi-departmental funding

Leadership in a few major areas (addictions and Leadership in a few major areas (addictions and mental health, infections, obesity, ageing)mental health, infections, obesity, ageing)

Obtain national experiments from others Obtain national experiments from others (transport, education)(transport, education)

Work with industryWork with industry

The Economy….

http://www.advfn.com/p.php?pid=charts&symbol=FT%5EUKX&period=1&freq=0

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

Patient Recruitment HPS-Thrive

• Too slow

• One size fits all

• Too many sites

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7000

Jan-07 Feb-07 Mar-07 Apr-07 May-07 Jun-07 Jul-07 Aug-07

UK Scandanavia China

Costs:

US 1.0

UK 0.6

China 0.3

Stratification Imperatives

Rheumatoid Arthritis (Mkt $16 billion)

Biologics Target

Infliximab TNF

Remicade TNF

Humira TNF

Kineret IL-1

Rituxan CD20

Orencia CTLA-4

Actemra IL6-R

30-40% non response

30-40% non response

30-40% non response

Limited efficacy

Limited efficacy

10% super responders

www.abpi.org.uk

Current development path

I II IIIa Review HTA

IIIb IV

PoC Ph III entry Submission Launch

Key characteristics of current model

• Linear processes• Expensive-increasing data demands

• Segmented input & decision making• Delayed access

FIM P&R

Access

PV & RM

External activities

Sponsor activities

www.abpi.org.uk

Potential flexible blueprint

Explore : R & D Review &design Confirmatory trials

Safety and PV

Effectiveness/ comparative studies

Confirm broad approval

Access (& revenue)

Key characteristics of new model:

Potential for flexibility, based on patient need

•Multi- stakeholder input, and partnership, at an earlier stage, esp at ‘ review and design stage’above

• More parallel processes

• More measured , less binary, assessment of risk/benefit , potentially managed on a rolling

basis

• Early (conditional) access, when justified

• Supports incr. productivity and decr. costs

Company activity

Regulator/HTA activity

Both

Timing of ‘blocks’ is movable, dependant on need

Contribution of changes to blueprint

Explore : R & D

Collaboration of Stakeholders, for example:- enabling technology

(eg biomarkers)- cooperation on confirmatory trials

between companies - partnering with healthcare provider

Review &design Confirmatory trials

Safety and PV

Effectiveness and potentially comparative studies

Better b enefit/risk assessments - to include patient views, and be more internationally consistent

Joint design , with innovator +regulators+regional HTA

More flexible options for design and analysis in confirmatory trials

- eg adaptive study design and Bayesian methods

ConfirmBroad approval

Access (& revenue)

Reduction in CT costs & time- challenge accumulation of new demands- move away from one size fits all- simplify/ rationalise GCP- increased targeted medicines

Flexible pricing and reimbursement, to a) support multiple indications and b) reflect evolving evidence base

Early access schemes, on condition of subsequent data

collection

Benefits for Industry: Translational Medicine• 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



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!

Orchestrating a National Translational Research Strategy John Bell.

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