Regulatory Requirements in Cellular Therapy

1
Regulatory Requirements in Cellular Therapy

• Derwood Pamphilon
• National Blood Service
• Bristol

2
Evolution of Accreditation and Regulatory
Requirements

• 1999 JACIE established
• 2000-02 European FACT inspections
• 2001 Dept of Health (DH) Code of Practice
• 2002 First UK Stem Cell Laboratories inspected
  
• 2004 March EU Directive on Tissues Cells
• Technical Annexes - consultation
• First JACIE inspections in UK
• 2006 April Implementation of 2004/23/EC
• 2007 April Implementation of Technical
  Directives

3
Documents Relevant to SCT -1

• JACIE - Guidelines and Manual
• EU Directive on Tissues and Cells 2004/23/EC and
  Annexes
• EU Directive on Clinical Trials 2001/20/EC
• EU Directive on Medicinal Products 2001/83/EC

4
Documents Relevant to SCT -2

• CoE Safety and Quality of Organs, Tissues and
  Cells, 2nd Ed CoE Publishing
• CoE Research Group on CIT CDSP (2004)
• WHO Cons on Reg Requirements for Human Tissue
  and Cell Transplantation, 2005
• EC Proposals for a Consultation on Human Tissue
  Engineering and TEPs, 2005

5
BMT Programme
Clinical Section B In- and out- patients
Processing Section D Laboratories
Collection Section C Facilities for marrow and
blood stem cells
JACIE EUD
JACIE
JACIE EUD
6
The EU Directive for Tissues and Cells Whats
Affected

• All stem cells destined for therapeutic use
  (haemopoietic and non-haemopoietic) from all
  sources (adult, fetal, peripheral blood, bone
  marrow, cord blood).
• Cellular therapies which use lymphocytes,
  dendritic cells or other cells ???
• The donation, procurement and testing of human
  cells from which manufactured products are
  derived (Medicinal Products Directive).

7
A5-Procurement staff, facilities, testing
A6-Accredited establishments
A7-Competent authority inspections, 2 yearly
A8-Traceability unique identifiers Keep data
30yrs
A24-Third parties standards, lists, agreements
Tissues and cells Directive
A9-Import/export accreditation
A19/20/21- Cell reception, quarantine, process
control, validation, storage
A11- Adverse event reporting
A16-QMSOPs, guidelines,training, reporting,
records
A12- Voluntary and unpaid donation
A13- Consent member state requirements
A17- Responsible person
accredited, licensed, designated or authorised.
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Requirements for Reporting of Adverse Events
(SAE,SAR)

• HTA - EUD
• JACIE (B4.300, C4.600, D4.600) must have
  systems for errors, accidents, SAR biological
  product deviations
• SHOT system provides a useful precedent

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What to Report?
Also adverse donor events - link to SEAR
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Technical Directive 1

• Details criteria for donors e.g. exclusion-
  malignancy, possible prion disease
• Gives consent requirements
• Lists laboratory tests TTI, timing
• Packaging, labelling and data to be registered at
  the TE

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Technical Directive 2

• Organisation, management, personnel equipment
• Facilities - GMP (2003/94/EC), Grade A/B
  quarantine
• Documentation data protection
• Processing, storage, release, distribution
  labelling
• SAE SAR

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EU Directives - how they work
Tissues and Cells Directive 2004/23
Medicinal Products Directive 2001/83
Clinical Trials Directive 2001/20
Clinical Trials I II III
Pre-clinical
Routine or Commercial product
Marketing authorisation
GLP Inspection
GMP Inspection 2003/94
GMP 2003/94
DOSSIER
13
Regulatory Framework for Tissue Engineered
Products

• Consultation in progress
• Covers tissue engineering, gene therapy
  somatic cell therapy
• Central authorisation by the EMEA
• Committee for Advanced Therapies (CAT) - assess
  new TEPs
• Medicinal Products Directive if manufactured
• Timescale ????

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Stem Cells are not Medicinal Products

• Not extensively modified e.g. CMV specific DLI
  have augmented function
• Only minimally manipulated by EC definitions
• Not subject to a manufacturing process i.e.
  bespoke

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Product type
Directive
Example
Red cell depleted BM CD34 selected cells DLI ???
CMV specific
Unmodified/un/ minimally manipulated cells
Tissues and cells 2004/23/EC
TEP framework to embrace both
Gene-modified HSC, suicide genes TcR transduced T
cells Rats ears
Tissues/ Cells Extensively manipulated/ modified/
engineered
Medicinal Products 2001/83/EC
16
Clinical Transplantation

• How will this be regulated within the EU?
• Another Directive is planned
• Inspectorate - JACIE could help to
  establish/maintain a common European standard

17
The Joint Accreditation Committee EBMT-ISCT
Europe (JACIE) program of accreditation was
established in 1999, with the aim of creating a
standardised system of accreditation officially
recognised across Europe.
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JACIE

• Based on Foundation for Accreditation of Cell
  Therapy (FACT) in USA
• Both have standards agreed by FACT subcommittees
  with JACIE representation
• Utilised outside USA and Europe
• Would permit establishment of a global standard

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InspectorsCredentials

• Appropriately trained and qualified
• Attendance at an approved training course
• Pass the JACIE MCQ Exam
• Certificated by JACIE

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JACIE Online
21
Document distribution
Electronic distribution
Printed documentation
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The Human Tissue Act

• Removal, storage and use of human organs and
  tissues for transplantation
• Removal of patient tissues is a matter of common
  law - consent is required
• Storage and use for SCT is a scheduled purpose
  (schedule 1)

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Human Tissue Act Regulations

• Ethical approval of research
• Exemptions from licensing of tissue storage
• Storage and use of tissue from incapacitated
  adults
• Approval of transplantation from living donors
• Provision of info on transplant procedures

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Human Tissue Act Codes of Practice

• Code 1 - consent
• Code 2 - Donation of organs, tissues and cells
  for transplant
• Code 3 - Post-mortem examinations
• Code 4 - Anatomical examinations
• Code 5 - Removal, collection, retention and
  disposal of organs tissues

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Human Tissue Act Codes of Practice - Issues

• Use of independent assessors
• Children v adults
• HSC and ? DLI included
• No evidence of coercion or payment of HSC donors
• Stem cells are regenerated rapidly unlike solid
  organs

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HTA - Current Discussions

• Code of Practice for HSC
• EU Directive - import/export of HSC
• Inspection and licensing ??MHRA ??JACIE ??other

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Import and Export of Tissues Cells

• Imports/exports of HSC from 3rd countries by
  licensed tissue establishments
• Imports from 3rd countries must meet these
  standards
• Exports must comply with Directive
• I/E may be authorised directly by the competent
  authority

EU Directive Article 9
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Issues for Donor Registries

• HTAct Donors must be assessed and consented as
  per its requirements
• EU Directive HSC must be supplied to/collected
  from facilities that meet its requirements