Registering Cell and Gene Therapy Products (ATMPs) in Europe

Daniel RabbieRegulatory Affairs Manager September 2017

Outline

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1. Introduction

2. Regulatory Framework

3. Your ATMP within the EU

4. GMO Legislation

5. European Medicines Agency

❖ Approach to Innovation

❖ Navigating the Regulatory Pathway(s)

6. Conclusion

Introduction

Opportunity

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• Unmet healthcare needs that cell and gene therapy could address

• Offer of long term cures

• Unlike anything Big Pharma has seen before

• A cottage industry nurtured in academia and a handful of pioneering companies

Interdisciplinary Barriers

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Health Economics & Market Access

Product Manufacturing Development

• Cost effective scale-up

• QC/Analytical assays

• Product storage

POCNonclinical Safety

• Risk-based approach

• Relevance of animal model(s)

• Dose extrapolation

Clinical Development

• Trial design and patient population selection

• Complex logistic• Long term monitoring

Regulatory Pathway

• Reimbursement strategies

• Pricing• Limited comparative

effectiveness data

• Uncertain, complex regulations

• Non-conventional product development

• Product-specific considerations

The Cell and Gene Therapy Catapult

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• Process Industrialisation, Scale-up & Manufacturing

• Health Economics and Reimbursement

• Regulatory

• Non-clinical safety

• Clinical Operations

• Manufacturing and Supply Chain

Main office & development laboratories1,200m2 - Guy’s Hospital Tower (London clinical research cluster)

Advanced Therapies Manufacturing Centre7,200m2 - Stevenage Biocatalyst

• Bridge the gap between businesses, academia, research and government• Long-term investment to transform the UK’s ability to create new products and services• Open up global opportunities for the UK and generate sustained economic growth

for the future

Teams

European Regulatory Framework

EU Regulatory Framework for ATMPs

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Orphan designation

Paediatric plan

Legislative support for early access

Legislation transposed into

Member State law

Approval of MAA

Guidance to developers

Member States

Approval of clinical trials

Guidance to developers

Licensed ATMPs in the EU

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• Currently licensed ATMPs: 5 (excl. Glybera)

– 1 CTMP (Zalmoxis)

– 2 GTMP (Imlygic, Strimvelis)

– 2 TEP (Holoclar, Spherox)

• Withdrawn ATMPs: 4

– 1 TEP (Chondroselect)

– 1 CTMP (Provenge)

– 1 GTMP (Glybera, from Oct)

– 1 Combined TEP (MACI)0

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2

3

4

5

2009 2010 2011 2012 2013 2014 2015 2016 2017

Licensed ATMPs in Europe

TEP GTMP CTMP Combined ATMP

Your ATMP within the EU

Your ATMP within the EU Framework

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Gene Therapy Medicinal Product

Annex I to Directive 2001/83/EC

Somatic Cell Therapy Medicinal Product

Annex I to Directive 2001/83/EC

Tissue Engineered Medicinal Product

Article 2(1)(b) of Regulation (EC) No. 1394/2007

Combined ATMPArticle 2(1)(d) of Regulation (EC) No. 1394/2007

Administered with a view to regenerating, repairing or replacing a human tissue

e.g. Chondroselect ®

Holoclar ®

Spherox ®

Cell/tissue with matrix/scaffold interactions?

e.g. MACI ®

Prevention, diagnosis and/or treatment of diseases via

pharmacological, metabolic actions

e.g. Provenge®

Recombinant nucleic acid administered with a view to

regulating, repairing, replacing, adding or deleting genetic sequence

Therapeutic, prophylactic or diagnostic effect relates directly to

the recombinant nucleic acid sequence it contains

e.g. Glybera®

Strimvelis®

Considerations for GM ATMPs

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Gene Therapy Medicinal Product

Annex I to Directive 2001/83/EC

Somatic Cell Therapy Medicinal Product

Annex I to Directive 2001/83/EC

GMO LegislationDirective 2009/41/ECDirective 2001/18/EC

In-vivo transient transfection

- RNAi- Plasmid DNA

TherapeuticGenetic

Modification

e.g. Glybera ®

Kymriah®

Strimvelis®

Safety (suicide gene) Genetic Modification

e.g. Zalmoxis®

Ex-vivo transient transfection

e.g. mRNA electroporation of Dendritic/T-Cells

European GMO Legislation

European GMO Legislation

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GMO Approval

CTA

Approval

EC

Approval

• Non-harmonised between Member States• Deliberate Release or Contained Use?• Regional or National procedures?• Documentation/forms, in local language

• Agencies often lacking resource and/or experience in medicinal product reviews

• Coordinated interaction between sponsor, clinical site(s) and GMO agency required

• Process may run in parallel, sequential or independently to CTA

Challenges require prior planning and effective management to coordinate

multicentre European trials

Member State Regulations

Directive 2009/41/EC

Directive 2001/18/EC

Navigating Netherlands – one office, coordinating role

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Cell and Gene Therapy Catapult - GMO Registration Manuals

Gene therapy trials are considered as ‘Deliberate Release’

Navigating Belgium – regional considerations

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Cell and Gene Therapy Catapult - GMO Registration Manuals

Gene therapy trials are considered either ‘Contained Use’ and/or ‘Deliberate Release’

There are others…

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EuropeanMember State

Contained Use Regulations

Deliberate Release

GMOAgency

Austria BMGF

Belgium SBB

Finland GTLK

France MESR/HCB

Germany PIE

Netherlands GTO

Sweden SWEA

UK HSE

European Medicines Agency

Approach to Innovation

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• Range of potential treatment/manufacturing approaches represented by ATMPs is vast

– Unrealistic to expect regulators to produce detailed guidance on every aspect

• Clinical progress combined with increasing pressure to accelerate access to innovative medicines has led to an evolving framework with greater relevance to ATMPs

ATMP Certification for SMEs

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Specific provision in the ATMP regulation (Article 18, No 1394/2007)

• To certify that each submitted study complies with the relevant scientific and technical requirements set out in Annex I of Directive 2001/83/EC [module 3&4 / quality & nonclinical] and adequately follows state-of-the-art scientific standards and guidelines

• Opportunity for SMEs to get an early “snapshot” assessment of the data they have generated to date and check that they are on the right track for Marketing Authorisation Application (MAA)

• Tool to attract further potential investment

Important:

• Not binding for future MAA or Clinical trial application (CTA)

• Not an assessment of benefit versus risk profile

• Not providing development ‘advice’

Approach to Innovation

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PRIME (Priority Medicines) Initiative

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• Early access tool, supporting patient access to innovative medicines to foster development of medicines with a high public health potential

Key Features

General Benefits for Development• Iterative Scientific advice• Enhanced regulatory guidance • Incremental knowledge gain • Proactive dialogue• Promote use of existing tools

Speed to Market

PRIME (Priority Medicines) Initiative

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• Eligibility to PRIME based on accelerated assessment criteria:

– An unmet medical need

˃ No satisfactory method or if method exists, bring a major therapeutic advantage

˃ Introducing new methods or improving existing ones

˃ Meaning improvement of efficacy (impact on onset, duration, improving morbidity, mortality)

– Scientific justification, based on data and evidence available from nonclinical and clinical development

• As of 20th September 2017, from 26 products granted PRIME since May 2016:

• 11/26 are advanced therapy medicinal products

• No products granted PRIME based on nonclinical data alone, just 1 with only tolerability

Approach to Innovation

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Adaptive Pathways

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• Prospectively planned, development approach to commercialisation for medicines with high medical need

• Starting from an authorised (usually “niche”) indication, through phases of evidence gathering (controlled trials and real-world data) leading to progressive licensing adaptation to existing and/or new approvals

• Balances timely patient access with the need to provide adequate evolving information on risk vs benefit

Patients treated, no active surveillance

Patients in observational studies, registries, etc.

Patients in RCTs (or other interventional studies)

Adaptive Pathways – a good candidate profile

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1. An iterative development plan (staggered approval): start in a well-defined subpopulation with unmet medical need and expand, or have a Conditional Marketing Authorisation, maybe on surrogate endpoints and confirm.

2. Real World Data (safety and efficacy) can be acquired to supplement Clinical Trials, e.g. through well planned registries

3. Input of all stakeholders, particularly HTAs, is fundamental

Important:

- AP should not be viewed as an ‘accelerated development’ tool

- AP is a long-term “life-cycle management” approach from the EMA

- AP is different to PRIME (not instead of PRIME)

Navigating the regulatory pathway(s)

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Q. Is my product an ATMP? Q. Is my product for a rare disease?

Q. Will my clinical trials provide full efficacy data?

Q. Does my product address an urgent unmet need?

Conditional Approval

Exceptional Approval

No

Standard MAA

Accelerated Assessment

Yes

No

Orphan incentives

are available

Orphan Designation Procedure

Orphan incentives

not available

Yes No

COMP

ATMP Classification Procedure

MAA is required

Yes

NoCAT

CHMP

Non-clinical studiesClinical trials

EUTCD(‘Transplants’)

PRIME Designation

Q. Is the collection of RWD* through registries feasible?

Yes

Yes

No

Adaptive Pathways Approach

EMA ITF- Platform for early dialogue on scientific, regulatory and legal requirements- Informal, not binding

*RWD = Real World Data

Conclusion

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• The innovative, complex and heterogenous group of products represented by ATMPs challenges the current regulatory ‘patchwork’ in Europe

• European legislation raises various new considerations for developers, particularly important for effective and timely set-up of multicentre clinical trials –planning is key

• Underpinned by the emergence of clinical data, regulators (and the industry) are shifting gears - we are at the start!

• Understanding the ATMP framework in the EU is valuable however navigating through it effectively through to commercialisation will make the difference

Cell and Gene Therapy Catapult

12th Floor Tower WingGuy’s HospitalGreat Maze PondLondon SE1 9RT

+44 (0)20 3728 9500info@ct.catapult.org.ukct.catapult.org.ukTwitter: @CTCatapult

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