the translational medicine research collaboration (tmrc) konferencija/catharine god… · 2...
TRANSCRIPT
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The Translational Medicine
Research Collaboration (TMRC)
Catharine A. Goddard, PhD
Principal Translational Scientist, Pfizer
An example of
commercial focus, collaborative spirit and research
excellence
http://www.dundee.ac.uk/biocentre/SLSBDIV1home.htmhttp://www.abdn.ac.uk/chemistry/research/index.htihttp://www.westchem.ac.uk/
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Overview
Why Pharma needs to forge academic collaborations
The Translational Medicine Research Collaboration
The TMRC ethos
Creating a successful collaboration
Scotland’s resources
Examples of TMRC projects
Utilising genetic variation for human target validation
Patient selection biomarkers to improve success of OA trials
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Academic/Industrial collaboration is key to
successful drug development
Open innovation networks between
academia and industry: an imperative for breakthrough therapiesTeri Melese, Salima M Lin, Julia L Chang & Neal H Cohen
NATURE MEDICINE volume 15 | number 5 | may 2009
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Success will come from working together utilizing
each others strengths
Universities bring…
Focus on science
Clinical expertise
Experimental medicine expertise
Patient populations
Pharma brings…
Cutting edge technology
Access to tool compounds and new drugs
Excellent in vitro and in vivo
Pharmacology
Milestone driven.
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Translational Medicine bridges the gap between
pre-clinical and clinical studies
Clinical DevelopmentDiscovery Research
Translational medicine
Core Mission: to understand the likely behavior of
experimental medicines in humans
Improve internal decision making through the
incorporation of biomarkers
Enables cost-effective determination of efficacy &
safety through use of biomarkers
Target
Validation
Disease Biomarker
& Disease
Modification
Target/
Compound
Interaction
Patient
selection
Pharmaco-
dynamic
Activity
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In 2006 a unique collaboration was created -
TMRC
A pan-Scotland research collaboration devoted to
translational science and biomarker development
+ + ++
Partnership based on shared goals, complimentary strengths, shared
risk and reward
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Ideas derived jointly and individually
Research plan peer-reviewed
Project costs paid by company with government infrastructure support
Research plan modified by mutual agreement
Background IP protected with shared ownership of joint IP and data
Results published with TMRC approval
This is a true collaboration with peer-review and
management from all partners
CollaborationGrant Contract
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TMRC Proposition
Joined-up access to internationally leading clinical research capabilities
Ability to rapidly convene expert groups and PI’s across institutions and therapeutic
areas to come up with project solutions
Speed
Project proposal to multi-partner contract in 4 months
Accelerate NHS approvals, recruitment of key personnel and patients
Ease of interaction
Agreed IP, costing, indemnity, RGF, project management etc terms in place for flexible multi-partner contracting
Control and outputs
Ensure active senior level engagement to help drive project performance and implement change across partners
Culture of collaboration with external partners towards commercial and clinical relevant outputs
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TMRC Project Management System
Steering Committee and overarching contractual agreements
Wyeth Translational
Medicine
requirements
Workshops in
particular
Therapeutic Area
TMRC Annual Event
Scottish Academic’s
research idea/
technical expertise
TMRI Ltd/
Wyeth
Project development
team
- Academic(s)
- Wyeth Translational
Scientist
- University T.T.O.
- NHS R&D Office
Scientific
Review
Legal
ReviewProject start
TMRI Ltd
Scientific Review Board
Wyeth Legal
Interim
Reviews
- 6 monthly
Wyeth Translational Scientist
Project Final
Report
TMRI Ltd
S.R.B.
TMRI Ltd
S.R.B.
Scientific Monitoring
Financial Monitoring
Intellectual Property Monitoring
Development Review Activity
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IP Agreements
Cross licences of specified IPR to:
Carry out TMRC Programmes of research
Carry out internal R&D
Exploit IPR arising from TMRC Programmes of research
All IPR generated by TMRC Programmes of research jointly owned by
TMRI and Pfizer
Pfizer retain rights to Therapeutic IPR
Exclusive right for TMRI to exploit IPR in diagnostic and other fields
Pfizer have potential to obtain right in certain circumstances
Agreed royalty sharing terms
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IP
Optimization
Services
Discovery
Validation
Core Lab
TMRC Core Lab: a Centre of Excellence for Molecular
Biomarker Development & Validation
Capabilities State-of-the-art equipment
Standard methodology
Rigorous quality control
Analytical expertise
Resource optimization
Timeline management
Technical Focus Genomics
Proteomics
Immunoassay
Bioinformatics
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Scotland has many advantages for a Translational
Medicine collaboration
Stable and static population
A single healthcare provider
University & National Health Service
networks
Patient identifiers, disease data &
registries
Established tissue banks
World-class pre-clinical and clinical
research base
Significant government investment
http://www.scottish-enterprise.com/sedotcom_home.htm
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The Community Health Index (CHI) – links patient
information since the 1980s from a number of databases in
Tayside
Prescriptions
Cancer registryEpidemiology
Liver disease
HEARTS(Heart disease evidence
based audit & research
Tayside)
Scottish Birth
Record
Hospital out
patients
Hospital acute
staysMental health
records
SCI-DN(Diabetes Network)
TARDIS (Tayside Allergy & Respiratory
disease
Information System)
Laboratory DataBiochem, virology,
haematology,
immunology,
microbiology
GRO Death Certification
Population census data
GP records
Access to linked data adds value to the clinical cohorts
accessible via TMRC
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Scottish Care Information – Diabetes Collaboration
(Jan 1996 - current)
Information on
Diabetic
patients from
primary care to
specialised
clinics is linked
and accessible
to researchers
Professional IT support and data integration platforms
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TMRC have been able to utilise a number of the
established tissue banks in Scotland
Experimental Cancer Medicine Centre Edinburgh Uni/NHS Lothian
cancer, breast, colon, rectal, ovarian, prostate
TMA facilities
Tayside Tissue Bank Dundee Uni/NHS Tayside
Member of Confederation of Cancer Biobanks
Fresh frozen and paraffin wax embedded tumour/normal (where practical) tissue from colon, breast, stomach, kidney, skin, uterus, liver, spleen, oesophagus, pancreas, lymph node.
Matching blood samples mainly from breast and colon cases.
Genetics of Diabetes Audit and research Tayside (GoDARTS) Dundee Uni/NHS Tayside
Linked to prescribing, biochemistry and phenotypic historical data
Serum and DNA stored from 9,000 T2DM and 8,000 Controls
RNA (paxgene tubes) is being added into collection
COPD/Asthma (TARDIS & BREATHE) Dundee Uni/NHS Tayside
1,400 DNA samples from COPD patients in Tayside + 6,000 controls
Serum collection underway
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Target Validation:
PPARd & metabolic disease
Utilising Scotland’s Clinical populations for
biomarker research
Patient Selection:
Active Shape model & Osteoarthritis
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PPARδ SNP rs2016520 effects markers of
metabolic disease in a gender-specific fashion (1)
BMI HDL-C
p=0.005 p=0.005 p=0.013 p=0.054
Non-diabetic, not on statin therapy.
N= 5850
Whole study population.
N= 11074
LR Burch, CNA Palmer et al JCEM 2010
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PPARδ SNP rs2016520 effects markers of
metabolic disease in a gender-specific fashion (2)
Leptin TNF-a
Male
Female
p=0.019
p=0.755
p=6 x 10-3 p=0.024
N=5896
N= 300 non-diabetics
100 AA, 100 AG, 100GG
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PPARd SNP rs2016520 is associated with altered
lipid response to statin therapy
Conclusions
The rs2016520 allele may influence risk of developing metabolic disease
Suggests differential effects of PPARd agonists in males and females with
the rs201650 SNP
Logistic regression analysis of failure to reach target total and LDL-C by genotype
Achieved by using patient CHI number to link to Prescription database
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Target Validation:
PPARd & metabolic disease
Utilising Scotland’s Clinical populations for
biomarker research
Patient Selection:
Active Shape model & Osteoarthritis
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Osteoarthritis: A challenging disease for drug
development
Slow and variable disease progression
Limited information on disease activity & severity from routine imaging
Accepted (FDA) endpoint : Radiographic evidence of joint space narrowing (JSN) No direct visualisation of cartilage
Slow rate of change (0-1mm year)
Artefacts from weight bearing and positioning
Typically requires 2 years or more to see significant
changes
Trials relying on JSN have failed to show drug efficacy (Bingham et al Arth +Rheum 2006)
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Patient Selection: The Active Shape Model
Active Shape Model Captures whole joint, not just
angles/distances
Active Appearance model Includes image inside outline
Applicable to standard X-rays and
DEXA
Output: ‘Mode of variation’ Score The average shape has a score of 0 for
each mode
Each mode score represents the distance
(in std. dev.) from the mean shape
Each mode is statistically independent
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Shape and appearance both
increase with OA severity
(P < 0.01)
Significant increase over
6-12 month period (P < 0.001)
Shape Appearance
Contr
ol (-
2)
S
evere
OA
(+
2)
Baseline KL grade
The Active Shape Model: Reduces Study duration
by improving predictability of drug efficacy
ASM 90% accurate at predicting hip
fracture (when combined with BMD)1
1-Osteoporos Int 2001;15: 5-11
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Conclusions
TMRC has
provided Pfizer with access to world leading Scientists in key therapeutic
areas
allowed Scottish PIs to gain access to Pfizer resources to aid research
expedited formation of academic collaborations allowing projects to
outperform industry timelines
enabled research that has provided new models and data which facilitate
decision making and compound development
initiated discoveries that will improve patient care in Scotland, and
beyond
demonstrated how the combination of detailed clinical phenotyping linked
to bio-banks and electronic records can expedite biomarker research