Advanced TherapyMedicinal Products

(ATMPs)

Michelle QuayeRegulatory Manager, ATMP Trials, UCL

NHS QA Symposium for Technical Services 2011

Overview

• Definitions and Examples

• Regulatory Developments

• Trial Complexity

• Specific Challenges

• Product and Safety Issues

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What are ATMPs?

An ATMP is a biological medicinal product

that can be classified as either :[EC Regulation No 1934/2007]

Gene Therapy

Medicinal Product

Cell Therapy

Medicinal Product

Combined ATMP + Medical Devices

Tissue Engineered

Medicinal Product

Genetically Modified Cells

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Regulation (EC) No 1394/2007Applied from 30 December 2008

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Commission Directive 2009/120/ECImplemented September 2009

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Gene Therapy Medicinal Products (GTMP)GTMP means a biological medicinal product which has the following

characteristics:

• It contains an active substance which contains or consists of arecombinant nucleic acid used in, or administered to human beings,with a view to regulating, repairing, replacing, adding or deletinga genetic sequence;

• Its therapeutic, prophylactic or diagnostic effect relates directly to therecombinant nucleic acid sequence it contains, or to the product ofgenetic expression of this sequence.

Gene therapy medicinal products shall NOT include vaccines againstinfectious disease

[Directive 2001/83/EC annex 1, Part IV; amended by 2009/120/EC]

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Gene Therapy Vectors

DNA encodingTransgene

Transduction

Therapeutic Protein

Transcription & TranslationViral VectorCarrying Transgene

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Examples of GTMPs

• genetically modified virusese.g. adenovirus retrovirus lentivirus pox virus (vaccinia)

herpes simplex virus

• genetically modified cells(Cancer specific T cells)

• oncolytic viruses(cancer treatments)

• plasmid DNA

• antisense techniques(e.g. gene silencing, gene correction or genemodification)

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Somatic Cell Therapy Medicinal Products(CTMP)

Somatic cell therapy medicinal product means a biological medicinalproduct which has the following characteristics:

a) contains or consists of cells or tissues that have been subject tosubstantial manipulation so that biological characteristics,physiological functions or structural properties relevant for theintended clinical use have been altered, or of cells or tissues that arenot intended to be used for the same essential function(s) in therecipient and the donor;

b) is presented as having properties for, or is used in or administered tohuman beings, with a view to treating, preventing or diagnosing adisease through the pharmacological, immunological or metabolicaction of its cells or tissues.

[Directive 2001/83/EC annex 1, Part IV; amended by 2009/120/EC] 9

Examples of CTMPs

• Adult Cells autologous or allogenic cells– adult stem cells (multipotent)

(ChondroCelect, cartilage repair)

– differentiated cells(dendritic cells, cancer immunotherapy)

• Embryonic stem cells (pluripotent)

(blindness, spinal injury)

• Induced pluripotent stem cells (iPS Cells)

• Xenogenic Cells

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Tissue Engineered Medicinal Products (TEPs)

Tissue Engineered Product (TEP)

Tissue engineered product means a product that:

– contains or consists of engineered cells or tissues, and

– is presented as having properties for, or is used in or administered tohuman beings with a view to regenerating, repairing or replacing ahuman tissue.

A TEP may contain:

– cells or tissues of human or animal origin, or both

– the cells or tissues may be viable or non-viable

– additional substances i.e. scaffolds or matrices

Definition: EC Regulation No 1934/2007

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Examples of TEPs

• In vitro Cultured Skin- repair for burns or chronic wounds

• Neo-organs (corneal, blood vessel, liver, cartilage or bone tissue)

• Tissue Engineered Trachea

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Bridging the Regulatory Gap

• Lack of a harmonised and tailored regulatory environment

• Divergent national approaches to legal classification andauthorisation

• Uneven patient access to treatments

MedicalDevices

TissueEngineeredProducts

CellTherapy

GeneTherapy

Biotech(e.g. Insulin)

Pharmaceuticals

ATMPs

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EU ATMP Regulations 1394/2007

• Tissue engineered products defined as medicinal productsfor the 1st time

• New definitions of gene and cell therapy products

• New ATMP specific GMP guidelines

• EMA Centralised procedure for Marketing Authorisation(CAT)

• 30 Year Traceability requirements

• Unlicensed ATMPs can be manufactured under hospitalexemption

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Unlicensed ATMP ManufactureHospital Exemption vs Specials

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Multiple Regulators = Multiple requirements

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General Challenges of Advanced Therapies

• Evolving regulatory requirementStatutory Instruments 2010 No. 1882 on Medicines:

The Medicines for Human Use (ATMPs and Miscellaneous Amendments) Regulations 2010

• Product classification

• Non-clinical models for safety, toxicology,

proof of concept, clinical target dose

• Specialized facilities - GMP

• Manufacturing expertise and costs

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Logistical Challenges – IMP management

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Logistical Challenges - Traceability

donation

manufacturing

packaging

storage

transport

delivery & receipt

thawing & infusion

follow-up

• 2-tiered system for anonymity

• similar system used for blood

• long term data storage and long term planning

sourcing

A system allowing complete traceability

Patient

Donation

Product

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Product Issues: Cell Therapy / TEP

• Very short shelf life (<2 days)

• Real time QP release

•Long-term storage may require liquid Nitrogen- Segregation of products may require separate tanks

• Preparation may require class I safety cabinet tomaintain sterility

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Product Issues: Gene Therapy

• Liquid formulations, stored frozen (<-80ºC)- Segregation of products

• Like to be a Genetically Modified Organisms (GMO)

- Notification to HSE may be required

- Risk assessment required

- Preparation/reconstitution/dilution may require class I/II cabinets

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Safety Issues

Potential and identified risks:

• Graft dysfunction and/or rejection

• Induction of autoimmunity or immunogenic reactions

• Induction of malignancies

• Transmission of infectious agents

• Potential for vector latency & reactivation

• Prolonged expression of transgene

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Single gene mutation in the IL2RG gene, results in no functioning immune system“Boy in bubble syndrome”

X-linked Severe Combined Immunodeficiency (X-SCID)

Gene therapy: risk of insertional mutagenesis, resulting in over-expressionof proto-oncogene and development of leukaemia

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Summary

• Specific requirements for ATMPs (traceability/GMP/GCP)

• Evolving Regulatory Landscape

• Multiple Regulators Involved

• Logistical Challenges

• Product Specific Issues

• Safety Issues and Unknown Risks

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