current regulation of hct-ps and tissue banks in us and ... · current regulation of hct/ps and...
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Current Regulation of HCT/Ps and
Tissue Banks in the US and Europe
Scott R. Burger, MD
Advanced Cell & Gene Therapy
2010 Taipei International Symposium on Human
Cell and Tissue- Based Products and Tissue
Banks
October 13, 2010
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Cell/Gene/Tissue Therapies - Potential,
Promise, and Plenty of Challenges
• Numerous potential applications, often for unmet needs
– Potentially definitive therapies
• Novel uses of
cells/genes/tissues
– Difficult to evaluate efficacy, predict
clinical risks
• Complex cell/gene/tissue
engineering
– Risk of manufacturing problems,
product/process characterization
challenges
Science 2000;287:1423
Potential Patients (USA)
Cardiovascular Diseases
Autoimmune Diseases
Diabetes
Cancer
Osteoporosis
Neurologic Diseases
Burn Injuries
Birth Defects
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30M30M30M30M
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101010106666
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Regulations and Standards - US, Europe
� FDA-CBER Office of Cell, Tissue and Gene Therapy
(OCTGT)
� Good Tissue Practices (GTPs)
� Good Manufacturing Practices
(GMPs)
� Quality System Regulations (QSRs)
� Good Clinical Practices (GCPs)
� European Medicines Agency (EMEA)
� CAT
� International Conference on
Harmonisation (ICH)
� International Organization for Standardization (ISO)
� United States Pharmacopeia (USP)
� European Pharmacopeia (EP)
� American Association of Tissue
Banking (AATB)
� American Association of Blood Banks (AABB)
� Foundation for the Accreditation of Cellular Therapy (FACT)
� Clinical Laboratory Improvement
Amendments (CLIA)
� Joint Commission (formerly JCAHO)
� Institutional Review Board, Biosafety Committee
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US FDA Office of Cell, Tissue and Gene
Therapy (OCTGT)-Regulated Products
• Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)
• Cell therapy products
• Tissue and tissue-based products
• Cell- or tissue-based combination products
– Cell/device, tissue/device, other
• Devices used for cells/tissues
– Processing devices, other
• Tumor vaccines and immunotherapy
• Gene therapy products
• Xenotransplantation products
• Donor screening tests (cadaveric blood samples)
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Examples of Indications/Sources
• Pancreatic islets for diabetes
• Stem and skeletal muscle progenitor cells for
ischemic cardiac
• Hematopoietic reconstitution in treatment of
malignancies
• Stem cells for metabolic storage diseases
• Stem cells for CNS indications (Parkinson’s
disease)
• Expanded autologous cartilage for joint repair
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Regulation Reflects the Evolving Nature
of Cell and Tissue Therapy
• Cell therapy products are complex living biologics, and are being developed in novel, evolving ways. FDA’s
regulatory approach reflects the novel, diverse nature of these products.
• Regulations set a framework of criteria that must be
met.
– Safety, identity, purity, potency, and clinical efficacy
• FDA takes a flexible but science-driven, risk-based approach in evaluating whether and how these criteria
have been met.
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US FDA Requirements
Good Manufacturing Practices (GMPs)
Ensure consistent manufacture of safe, pure, potent products
Good Tissue
Practices (GTPs)
Prevent infectious disease transmission
Donor screening and testing
Prevent cross-contamination, mixups
Product recovery, processing, storage,
labeling, distribution
Good Clinical
Practices (GCPs)
Ethical, scientific quality standards
Protect trial subjects rights, safety,
confidentiality
Assure credibility of clinical trial data
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Risk-Based Approach to Cell Therapy
Regulation
• Products that present greater risk of adverse
clinical outcome require more and better control,
and hence more stringent regulation and
oversight.
• Risks, and potential risks
– Complex manufacturing, complex product
– Unrelated allogeneic clinical strategy
– Cells/tissues used in a manner unlike natural function
– Or, cannot assess risk due to extreme novelty
• Higher-risk products regulated under Public
Health Service Act, Section 351
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Application of FDA Regulatory Requirements
IF a cell therapy product meets criteria 1 and 2 and 3, and (4a or 4b or 4c).
1 Minimally manipulated (not activated, encapsulated, expanded ex vivo ,or genetically modified) AND
2 Intended for homologous use AND
3 Not combined with a drug or device AND
4a. Does not have a systemic effect, AND
Primary function does not depend on metabolic activity of viable cells OR
4b. Has a systemic effect and is intended for autologous, related- allogeneic, or reproductive use OR
4c. Primary function depends on metabolic activity of viable cells) and is intended for autologous, related-allogeneic, or reproductive use
THEN…
– IND or IDE NOT
required– GTPs ARE required
IF a cell therapy product does not meet
one or more of the four major criteria
defining minimally manipulated
products
THEN…
– Regulated using IND/IDE
framework, clinical trial
pathway
– GMPs AND GTPs
required
“361” Products
Nearly any interesting cell
therapy meets criteria for the
“351” category
“351” Products
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FDA Premarket Review Pathways
• Biologics (FDA CBER)
– Investigational New Drug (IND)
– Biologics License Application (BLA)
• Device (FDA CDRH)
– Investigational Device Exemption (IDE)
– Premarketing Application (PMA)
• Combination products
– Regulatory pathway determined based on primary
mode of action, previous intercenter agreements and precedents
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Product Development Pathway
• Product development stage determines key aspects of regulatory review. Safety is a consistent, critical focus
throughout product development.
Raj K. Puri, MD, PhD
Director, Division of Cellular and Gene Therapies
US FDA OCTGT
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Development Throughout Clinical Trials
• FDA expects greater control and
characterization as clinical development progresses
– Manufacturing, characterization,
specifications are refined based on experience
• Early-stage trials and manufacturing must be sufficiently controlled to enable
clinical development to licensure
– The nightmare scenario: the therapy works,
but inadequate understanding of the product
impedes further clinical progress
Prod
uct/P
roce
ss
Char
acte
rizat
ion,
Con
trol
Phase III
Phase I
PreClin
Phase II
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Current Good Manufacturing Practices
(cGMPs)• General provisions
• Organization and personnel
• Buildings and facilities
• Equipment
• Control of components
• Production and process controls
• Packaging and label controls
• Holding and distribution
• Laboratory controls
• Records and reports
• Returned and salvaged product
A set of current, scientifically
sound methods, practices or principles that are
implemented and documentedduring product development
and production to ensure consistent manufacture of safe, pure and potent products.
21 CFR 210, 211
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Current Good Tissue Practices (cGTPs)
• Methods, facilities for manufacture of human cellular and tissue-based products
– Prevent introduction, transmission and spread of infectious disease
– Donor screening and testing
– Prevent mix-ups, cross-contamination
– Product recovery, processing, storage, labeling, distribution
• Resemble GMPs, but narrower focus
21 CFR Part 1271
• Quality Program
• Organization, Personnel
• Procedures
• Facilities
• Environmental Control,
Monitoring
• Equipment
• Supplies and Reagents
• Process Controls, Changes
• Process Validation
• Labeling Controls
• Storage Requirements
• Receipt and Distribution
• Records
• Tracking
• Complaint File
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GTP-Specific Requirements
• Requirements for GTPs and GMPs overlap in
many respects - GMP-compliant operation will
meet many of the GTP requirements.
• However, certain requirements are GTP-specific.
Either not covered by GMPs at all, or
requirement is more HCT/P-specific than in
GMPs, so GMP compliance alone is not
sufficient. – Donor eligibility
– Tracking systems
– Quality program
– Predistribution shipment
– Recovery of HCT/Ps
– Exemptions and alternatives
– Records
– Availability for Distribution
– Receipt procedures
– Processing, process controls
– Reporting requirements
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Core GTP Requirements - 1271.150(b)
• Directly related to preventing introduction, transmission, or spread of communicable disease. Other GTP requirements support core cGTPs– Facilities - 1271.190(a) and (b)
– Environmental control - 1271.195(a)
– Equipment - 1271.200(a)
– Supplies and reagents - 1271.210(a) and (b)
– Recovery - 1271.215
– Processing and process controls - 1271.220
– Labeling controls - 1271.250(a) and (b)
– Storage - 1271.260(a-d)
– Receipt, pre-distribution shipment, distribution - 1271.265(a-d)
– Donor eligibility determination - 1271.50, 1271.75, 1271.80, 1271.85
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Recovery Procedures and Records
• Recovery is a core CGTP, therefore procedures
and records must be established and maintained
for:
– Facilities
– Environmental control
– Equipment
– Supplies and reagents
– Labeling controls
– Storage and
– Receipt, predistribution shipment and distribution
1271.215
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Recovery-Related Environmental
Controls
• Procedures must be established and maintained to prevent contamination or cross-contamination
• Environmental controls should be in place at each recovery site
• Establish recovery site suitability parameters and verify that they have been met
• Operating room setting is recommended but not required
• If other types of facilities are used for recovery then they
must provide adequate temperature and humidity controls and ventilation
1271.195(a)
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Recovery-Related Facility Requirements
• Area used for recovery should be evaluated for:
– Suitable size, location and construction for aseptic procedure
– Limited access
– Good state of repair
– Adequate lighting, ventilation and airflow
– Access to running water and sink
– Working surfaces – verified cleaning agents used and use documented
– Recommend development of a checklist to document that the location meets established parameters each
time a recovery is performed
1271.190(a)
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Recovery: Reducing Potential
Contamination, Cross-Contamination
• Evaluate technical procedures used– Aseptic technique– Use of published industry practices
– Specific body cooling parameters established
• Evaluate personnel involved– Experience, education and training
• Evaluate equipment, supplies, and reagents– Appropriate design
– Records and procedures for maintenance, cleaning, sanitizing, calibration and other activities
• Establish and document suitability of facilities where recovery takes place - audits, gap analyses
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Regulatory Considerations for Initiating
Clinical Trials
• Risk-benefit balance
– Clinical trial subject safety balanced against potential
public health benefits of novel therapies
• Risk assessment based on:
– Product characterization and safety testing data
– Preclinical data supporting safety
– Eligibility criteria
– Product administration procedure
– Clinical safety monitoring plans
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Cell- and Tissue-Based Products: Potential
Safety Concerns
22
• Contaminated cells/tissue raw material, infectious
disease transmission
• Ex vivo manipulation
• Risks of the delivery procedure
• Potential inflammatory/immune response
• Inappropriate cell proliferation
• Inappropriate cell differentiation
• Cell migration to non-target sites/tissues
• Interactions with concomitant therapies
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Translation from Preclinical to
Initial Clinical Trials
23
• Proof-of-concept – in vitro, in vivo– Potential mechanism of action
– Establish pharmacologically effective dose(s)
– Optimize dosing regimen– Rationale for species/model selection for further testing
• Safety of conducting clinical trial – risk/benefit
– Dose levels and dosing scheme
– Potential target tissue(s) of toxicity/activity– Parameters to monitor clinically
– Patient eligibility criteria
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Questions - I
• What type(s) of cells will be used, and what is the
source?
• What is the projected dose? How many cells are
needed to achieve a minimum/optimal biological
effect?
• Have the cells been sufficiently characterized for
the stage of clinical development?
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Questions - II
• What is the proposed mechanism of action?
• Is cell survival/engraftment necessary?
• Is repair or replacement of damaged tissue the
goal?
• What is thought to happen to the cells in vivo,
following administration?
• Will the cells be administered as a suspension?
Seeded onto a scaffold? Encapsulated?
• Will immunosuppression be needed?
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Questions - III
• What is/are the biologically relevant animal
species for preclinical studies?
• Are there potentially relevant animal models of
disease/injury that can be used?
• What is the optimal method/route/anatomical
site/timing for product administration?
• What is the risk/benefit balance?
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• Administering cells with certain devices, or seeded onto
scaffolds, can make the cell therapy product a Combination Product
– Cells regulated under Biologics/Drug regulations, device regulated under Device regulations
• Discuss regulatory pathway with FDA, and with Device
manufacturer
• Establish cell-device compatibility
• Include cells and device in preclinical studies
• Establish and qualify administration procedure, and
clinician-investigator training
Combination Products
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Key Points to Enable Progress to Clinical
Trial
• Dosing!
• Minimum effective dose
– Single or multiple administrations?
• Route/mode of administration
– Effect of any surgery on interpretation
• Sustained efficacy, if applicable
• Blinding
• Long-term follow-up
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Common Causes of Hold Actions: Phase 1
• General
– Product to be used in the trial differs from that used in
preclinical studies
– Insufficient preclinical data to support safety of product
administration to humans
– No information about compatibility of product and delivery
device
– Inadequate clinical monitoring plan
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• Manufacturing– Absent or inadequate manufacturing description
– Research-grade ancillary reagents inadequately qualified
– Bovine-derived components inadequately qualified
– No description of tracking and segregation procedures to assure patient receives correct cells
– Segregation and cleaning procedures inadequately described
– Inadequate QA/QC program
• Testing– Inadequate lot release testing
– Cells do not meet minimum viability criteria of 70%
– No action plan for positive sterility test after administration
– Donor virus testing - inadequate or inappropriate tests
– Incomplete human pathogen testing (human cell lines)
– No tumorigenicity testing
Common Causes of Hold Actions: Phase 1
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• Critical assays (potency, identity, other) are not…
– … validated, reproducible, quantitative, sensitive, specific,
biologically relevant
• Stability program inadequate, unsuitable, or absent
• Characterization data insufficient to establish lot release specifications
• Comparability not adequately demonstrated
• Safety issues
– High levels of bioburden resulting from contamination
Common Causes of Hold Actions: Post-Phase 1
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BLA Issues
• Significant change(s) made late in development,
without adequate product comparability data
– Viral clearance evaluation studies may be needed
• Process validation data incomplete, inadequate, or absent
• Inadequate stability studies
• Characterization data inadequate to support
establishing specifications
• Consistent manufacturing inadequately demonstrated
• Compliance issues - contract manufacturers, finish and
fill facilities
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US Regulatory Guidance Documents - I• Draft Guidance for Industry and FDA Staff: INDs for Minimally
Manipulated, Unrelated Allogeneic Placental/Umbilical Cord BloodIntended for Hematopoietic Reconstitution for Specified Indications 10/2009
• Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications 10/2009
• Draft Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines 9/2009
• Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products 9/2009
• Draft Guidance for Industry: Somatic Cell Therapy for Cardiac Disease 4/2009
• Guidance for Industry: Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 1/2009
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US Regulatory Guidance Documents - II• Draft Guidance for Industry: Use of Serological Tests to Reduce the
Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Transfusion and HCT/Ps 3/2009
• Draft Guidance for Industry: Potency Tests for Cellular and GeneTherapy Products 10/2008
• Guidance for Industry: CGMP for Phase 1 Investigational Drugs 7/2008
• Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) 4/2008 (www.fda.gov/cber/gdlns/gtindcmc.htm)
• Guidance for Industry: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) 4/2008
• Draft Guidance for Industry: Validation of Growth-Based Rapid Microbiological Methods for Sterility Testing of Cellular and Gene Therapy Products 2/2008
• Guidance for Industry: Eligibility Determination for Donors of HCT/Ps 8/2007 (www.fda.gov/cber/gdlns/tissdonor.htm)
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US Regulatory Guidances in Development• Characterization and Qualification of Cell Banks Used in the
Production of Cellular and Gene Therapy Products
• Clinical Study Design for Early Phase Studies of Cellular and Gene Therapies
• Devices Involved in Manufacture, Storage and Administration of Cellular Products and Tissues
• Preparation of Investigational Device Exemptions and Investigational New Drugs for Tissue Engineered and Regenerative Medicine Products
• Submission of Information for the National Xenotransplantation Database
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Regulations and Standards for Cell and
Tissue Therapy Products: Europe
• Centralized European regulatory authority and national regulatory agencies
• European Commission, European Medicines Agency (EMEA)
– Centralized approval pathway
• Federal regulatory agencies for each nation
– Mutual Recognition approval pathway
– Regulations and policy vary between nations
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Human Cell-based Medicinal Products,
Advanced Therapy Medicinal Products (ATMPs)
• Guideline on Human Cell-based Medicinal Products
(EMEA/CHMP/410869/2006)
– General aspects of all cell-based products, including ATMPs
• Advanced Therapy Medicinal Products (ATMPs)
– Medicinal products prepared industrially or manufactured by a method involving an industrial process.
– Somatic Cell Therapy Products, Tissue-Engineered Products, ATMP Combination Products, Gene Therapy Products
• Non-ATMPs
– Autologous tissues and cells obtained and grafted within the same surgical procedure
– Blood and blood components
– Organs or parts of organs, if homologous use
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Somatic Cell Therapy Products
• Autologous, allogeneic, xenogeneic
• Somatic living cells, the biological characteristics
of which have been substantially altered as a
result of their manipulation to obtain a
therapeutic, diagnostic or preventive effect
through metabolic, pharmacological and
immunological means. This manipulation includes
the expansion or activation of autologous cell
populations ex vivo, the use of allogeneic and
xenogeneic cells associated with medical devices
used ex vivo or in vivo.
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Tissue Engineered Products
• Contain or consist of engineered cells or tissues,
and is presented as having properties for, or is
used in or administered to human beings with a
view to regenerating, repairing or replacing a
human tissue. A tissue engineered product may
contain cells or tissues of human or animal origin,
or both. The cells or tissues may be viable or non-
viable. It may also contain additional substances,
such as cellular products, bio-molecules,
biomaterials, chemical substances, scaffolds or
matrices.
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Gene Therapy Products
• Products obtained through a set of manufacturing
processes aimed at the transfer, to be performed
either in vivo or ex vivo, of a prophylactic,
diagnostic or therapeutic gene (i.e. a piece of
nucleic acid), to human/animal cells and its
subsequent expression in vivo. The gene transfer
involves an expression system contained in a
delivery system known as a vector, which can be
of viral, as well as non-viral origin. The vector can
also be included in a human or animal cell.
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Advanced Therapies and Scientific
Expertise at EMEA
CHMPCHMP
Working Parties(i.e Gene Therapy, Cell-based
Product, Biological…)
Committee Committee
for Advanced Therapiesfor Advanced Therapies
(CAT)(CAT)
Pediatric Committee,Committee for Orphan
Medicinal Products
5 double members5 double members
Scientific Advisory Groups (i.e Oncology, Diagnostics…)
CHMP: Committee for Medicinal Products for Human Use
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Composition of the CAT
Chair
Christian Schneider (GER)
Vice-Chair
Paula Salminkangas (FIN)
Including
Members representing clinicians from
European Society of Gene and Cell Therapy
European Group for Blood and Marrow
Transplantations
Members representing Patients’
organisations from
European Genetic Alliances' Network
European Organisation for Rare Diseases
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ATMP Certification (CAT)
Certification
•Certification of Quality and/or non-clinical data by CAT
•At any stage of development (although minimum set of data)
Data required and standards
� Data and methodology in compliance with scientific/technical
requirements
� Minimum set of data:
� Quality: General information and specific on starting materials,
characterization and control of drug substance, description and
composition of product
� Non-clinical: primary pharmacology data, biodistribution data, 1
toxicology study
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Clinical Trials of ATMPs
Clinical Trial Directive (2001/20/EC)Not under the responsibility of EMEA
Opportunities for communication among regulators
� National level in competent authorities
� European level
- European Clinical Trial Facilitation Group - voluntary harmonization
procedure for assessment of multinational clinical trials
- National experts in CAT, EMEA cell-based product/gene therapy
working parties
� International level: ICH gene therapy discussion group
� EMEA-FDA confidential arrangement on ATMPs
Harmonization of scientific requirements for cell or gene therapy at EU and international level
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Marketing Authorization
Scientific and technical requirements� Quality, non-clinical and clinical data in Marketing Authorization
Application intended to fit living biologic nature of ATMPs
Revision of Annex I (Directive 2001/83/EC) pending
� General requirements underpinned by EMEA or ICH guidances
EMEA centralized procedure mandatory� Harmonised requirements, uniform and direct access to market
� Synergy between EMEA scientific committees - CAT, CHMP
� Pooling of expertise at all levels (CAT, CHMP, Scientific Advisory Groups, Working Parties)
Additional information on packaging and labelling
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Post-Authorization
• EMA guideline on follow-up on Efficacy and Safety, Risk Management for ATMPs (11/2008)
• Traceability requirements for manufacturer and clinical site(s) where ATMP is used
• Follow-up of efficacy and of adverse reactions
• Risk management system and pharmacovigilance
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European Regulatory Framework: Current
Status, Developments• Definitions and technical requirements
– Directive 2001/83/EC - Ongoing revision of Annex I, part 4
• Cells/tissue donation, procurement and testing
– Directive 2004/23/EC - Unchanged
• GMPs
– Directive 2003/94/EC - Ongoing revision of Annex 2 to GMP Guidance
• Clinical trials
– Directive 2001/20/EC - Unchanged
• GCPs
– Directive 2005/28/EC - Guideline specific to ATMPs in preparation
• Marketing Approval Application
– EC Regulation 726/2004 - Centralized procedure for ATMPs
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Human Cell-based Medicinal Products:
Manufacturing
• Controlled quality of starting materials
– Cells - primary origin, cell lines (appropriate banking
system)
– Other material, reagents, excipients (enzymes,
cytokines, antibiotics…)
– Matrix, device, scaffold components
• Validated manufacturing process
– In-process controls
– Batch definition (from sourcing to labeling of final container)
Guideline on Human Cell-based Medicinal Products (EMEA/CHMP/410869/2006)
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Human Cell-based Medicinal Products:
Characterization
• Characterization elements
– Cell purity
– Impurities (product or process related)
– Adventitious agents
• Quality control
– Release criteria
– Stability
• Potency assay
– …based on the intended biological effect which should
be ideally related to the clinical response
Guideline on Human Cell-based Medicinal Products (EMEA/CHMP/410869/2006)
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Human Cell-based Medicinal Products:
Challenges
• Balance between risks, quality requirements and
specific limitations of the cell-based products
(limited sample size, short shelf-life, unique
manufacturing process)
• Requirement of alternative test methods
(alternative microbiological tests for products with
short shelf-life)
• Living cells are intrinsically variable and
heterogeneous
Guideline on Human Cell-based Medicinal Products (EMEA/CHMP/410869/2006)
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Human Cell-based Medicinal Products:
Non-Clinical Development
• Conventional requirements not always appropriate, deviation should be justified
• To demonstrate proof-of-principle, define pharmacological and toxicological effects predictive of human response
• Support intended clinical use
– Dose
– Route of administration and application
– Identification of parameters for monitoring in patients
• Relevant animal model
– Combined studies - pharm/tox, safety, local tolerance
Guideline on Human Cell-based Medicinal Products (EMEA/CHMP/410869/2006)
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EMEA Guidance Documents• Guideline on human cell-based medicinal products
(EMEA/CHMP/410896/2006)
• Concept paper on the development of a guideline on the risk-based approach according to annex I, part IV of directive 2001/83/EC applied to advanced therapy medicinal products (CHMP/CPWP)708420/09)
• Reflection paper on stem cell-based medicinal products(CAT/571134/09)
• Human cell-based medicinal products CHMP/410869/06
• Points to Consider on Xenogeneic Cell Therapy CHMP/1199/02
• Potency Testing of Cell-based Immunotherapy medicinal Products for Treatment of Cancer CHMP/BWP/271475/06
• Points to Consider on Xenogeneic Cell Therapy Medicinal ProductsCHMP/165085/07
• Xenogeneic Cell-based Medicinal Products CHMP/CPWP/83508/09
• Reflection paper on in vitro-cultured chondrocyte containing products for cartilage repair of the knee CAT/CPWP/288934/09
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Summary
• Living biological products present unique
challenges in development, manufacturing,
characterization, and delivery.
• Compliance with GMPs and GTPs fosters both
good science and good clinical medicine, and
(mostly) makes good business sense.
• Rigorous, evolving characterization and process
control are vital to address biological
heterogeneity and variability. Processes,
analytical methods, and product definition must
evolve over multiple clinical trials.