Clinical development of cell-based therapies in the UK A presentation by Chief Clinical Officer, Natalie Mount 2013

1. Clinical development of
cell based therapies in the UK
Association of Research Ethics Committees Annual Conference
Natalie Mount PhD
Chief Clinical Officer
Cell Therapy Catapult
Nov 2013
natalie.mount@ct.catapult.org.uk
Catapult is a Technology Strategy Board programme

2. UK Catapults
Catapults are core funded by the Technology Strategy Board as ‘not
for profit’ companies to bridge the gap between business, academia,
research and government
Exploiting the science base to create new manufacturing industries
for the UK
£200m+ assigned for 7 Catapults; Cell Therapy Catapult formally
started in Jan 2013 and has been the only life science Catapult
operating to date
Catapults use their critical mass of expertise to accelerate projects
2

3. 3
Cell Therapy Catapult
• Significant unmet medical needs
• Early stage in market with large
potential for growth
• World class science base
supported by government and
charity research funders
• Development and production of
cell therapies is complex
• Majority of therapies from
academic researchers

4. Mind the (translational funding) gap
4
•
Little evidence yet that new cell therapies
can be developed, licensed and adopted
successfully
•
Limited investment from commercial
sector
•
Cell Therapy Catapult partners on clinical
development projects with academia,
SMEs and large pharma
Catapult

5. Cell therapy products need to address the
industry barriers to commercialisation
Key barriers to commercialisation
Pertinent issues for cell therapies
Regulatory affairs
Understanding and navigating a path
Pre-clinical science
Conducting the right studies to support the clinical program
Clinical development
Studying the best population; measuring the best endpoints
Manufacturing and GMP readiness
Move from bench/small scale GMP process to large scale
manufacture; integrating manufacturing changes with clinical
data
Supply chain management
New models of delivery required; plan and test what is workable
Investment readiness
Value proposition to inform potential investors
5

6. 6
Addressing Barriers
•
•
•
•
Economics
Health Economics
Manufacture & Supply vs Service
Business Plans
Manufacturing
and
Supply Chain
•
•
•
•
•
COGS & Scale up
GMP
Characterisation & Analytical
Comparability
Delivery
Clinical
And
Regulatory
•
•
•
•
Regulatory Landscape
Pre Clinical Packages
Clinical trial design
NHS partnering
Business
Business Development
Process Development
Clinical Operations &
Regulatory Affairs

7. Global cell therapy industry
Established medical practice:
e.g. haematopoietic stem cell transplantation
Commercial products:
Rapidly growing global market
Global turnover of >$2bn in 2012; predicted to rise to $4-5bn in 2014;
driven by diversity of small products (Apligraf, Dermagraft, Provenge
made >$100m each in 2012)
Therapies licensed as ATMPs in the EU:
ChondroCelect, Glybera, MACI, Provenge
Therapies in development:
Rapidly growing ~ 250 products in clinical development
7

8. Overview of
autologous process
From Smith, Regen Med (2012);
7 (5), 721-732
8

9. Overview of
allogeneic process
From Smith, Regen Med (2012);
7 (5), 721-732
9

10. EU
Tissues and Cells
Directive
or
Blood Directive
Regulation of cell
therapies
STARTING MATERIAL
Human Blood, Tissues or Cells
Substantial
manipulation
and/or non
homologous
use
Yes
Transplants or
Transfusions
No
ATMP
ATMP regulation
EC 1394/2007
Pre Clinical
Clinical Trials
Clinical Trial
Authorisation
National
(MHRA)
GMP Requirement
(Eudralex Volume
4)
GLP
Manufacturing
Authorisation
Investigational
Medicinal
Products (MIA(IMP))
Licensed Product
Post Marketing
30 Years Traceability
Efficacy PhV follow-up
Marketing Authorisation
European centralised licence (MAA)
(CAT) EMA
Manufacturing Authorisation
(MIA)
10

11. EU
Tissues and Cells
Directive
or
Blood Directive
11
STARTING MATERIAL
Human Blood, Tissues or Cells
Substantial
manipulation
and/or non
homologous
use
Yes
EU Regulatory Framework
Transplants or
Transfusions
No
ATMP
ATMP regulation
EC 1394/2007
Pre Clinical
GMP Requirement
(Eudralex Volume
4)
GLP
Unlicensed
Clinical Trials product
Post Marketing
Licensed Product
30 Years Traceability
supply
PaediatricEfficacy PhV follow-up
plan
Orphan
Clinical Trial
Marketing Authorisation
designation
Authorisation
European centralised licence (MAA)
Accelerated
National
(CAT) EMA
approval
(MHRA in UK)
paths
Manufacturing
Authorisation
Investigational
Medicinal
Products (MIA(IMP))
Manufacturing Authorisation
(MIA)

12. Databases of UK preclinical (<2 yrs from clinic)
and clinical stage cell therapies (April 2013)
Category
Preclinical (<2 yrs from
clinic)
Number
Comparision
More allogeneic therapies in
preclinical stage
37
Larger variety of cell types in
preclinical stages
Larger range of indications for
preclinical projects
Clinical (UK trial ongoing)
34
Total
71
http://ct.catapult.org.uk/
Few commercially sponsored
projects in both pre clinical and
clinical stages
12

13. Bone marrow derived cells still predominate
but T-cells are a rising class amongst greater
diversity
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14. Field is growing into a broad range of disease
indications
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15. Risk management: Efficient development
Preclinical
Initial product
manufacturing process
Early
Clinical
Scaled near-final
manufacturing process
Late Clinical
Phase 3
Finalised manufacturing
process
Approval
Reimbursement
Studies to support efficacy, safety and dose for the
clinical population
Safety in relevant population
Explore dose/dosing regimen
Pharmacodynamics / mechanism
Robust evidence of efficacy
Explore trial population
Build safety
Finalise dose / dosing regimen
Confirm efficacy and safety to support registration,
label claims and reimbursement
15

16. What’s special about cell therapy clinical trials?
Trial design aspects:
Usually administer cautiously to patients in first instance (not healthy
volunteers)
Sometimes already have some non-trial patient experience (e.g.
compassionate use)
Choosing patient population- risk: benefit assessment (early vs late stage
disease, adults vs paediatrics)
Informed consent (understanding and equipoise)
16

17. What’s special about cell therapy clinical trials?
Trial design aspects:
Dose choice / escalation may be limited
Seamless safety and efficacy components in initial ‘transitional type’
studies can be efficient; efficacy needs to be demonstrated in adequately
powered studies
Randomised, blinded, controlled clinical trials are the gold standard, but
may not be suitable for some therapies:
• Historical control groups
• Parallel observational groups
• Blinded assessors
• Randomised, non blinded
17

18. What’s special about cell therapy clinical trials?
Trial conduct aspects:
Need clinician champions
Usually need long term patient follow-up (cell survival, persistence,
engraftment)
Protocol deviations and amendments; ways to minimise these (dosing
windows etc..)
Safety oversight and reporting
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19. What’s special about cell therapy clinical trials?
19
Trial conduct aspects:
Central importance of a very close relationship with the manufacturing
team:
• Logistics, logistics, logistics… (site selection, patient selection, visit
scheduling etc…)
• Clinical staff training in cell handling and administration
• Understanding route of therapy through the hospital
• Cell donation, procurement, testing, traceability, GMP, QP release
• Integrate clinical and manufacturing plans

20. Summary examples of cell therapy trial design
considerations (Lunn et al., 2011)
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21. 21
Building the Portfolio
hESC
iPS
MSC
Immune
Cell
Other
Soma-c
Blood
Bone
and
car-lage
Cardiovascular
Dermatology/wound
healing
Diabetes
Gastroenterology
Immunology
Liver
Metabolic
Neurological
Oncology
Ophthalmology
Respiratory
Other
Manufacturability

22. Some project examples..
• Share of expertise
• Support for in house projects
• Phase 2 clinical trials
• Scale up, Assays, Freezing and distribution
of cells
Large Cap
Company
• Manufacturing partner, Regulatory, Clinical
trial design and delivery
• Immune tolerance
• Clinical development path, business models
Videregen; UCL,
NHSBT, Royal
Free
• Regenerative tissue (cells on scaffold)
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23. Success for the Cell Therapy Catapult means..
Leadership in building an emerging industry, addressing
barriers to commercial investment
Increased numbers of cell therapies in UK trials and clinical use
Investible propositions creating successful UK companies
Demonstrating that the UK is the place to do this work
Being a leader in building a £10bn industry
23

24. Researchers
Industry
Cell Therapy
Catapult
NHS
Catapult is a Technology Strategy Board programme
Investment