Transcript Advanced Therapy Medicinal Products

Advanced Therapy Medicinal Products
April 18, 2012
[email protected]
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Agenda
• ATMP definition/ classification?
• What is my human cell based product?
• Exemptions and different routes?
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Definitions 2001/83/EC/ ; 2004/24/EC; 93/42/EC
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Advanced Therapy Medicinal Products
ATMP
1394/2007
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Status EU ATMP’s
• 1 registered ATMP in EU : Chondroselect (Tigenex)
• Only six applications have been submitted for MA (four ATMPs)
• In 2009-2011
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a product was intended for treatment of squamous cell carcinoma (head and neck) was
withdrawn
the CAT adopted a negative opinion on the MA application of a gene therapy product
intended for treatment of cerebral cancer (high grade glioma); the manufacturer withdrew
its application in March 2010.
A negative CAT opinion was adopted for the MA application a gene therapy product
intended for use in severe lipid metabolic disease.On re-examination of Glyberain
October2011, the CAT adopted a positive opinion but this was not endorsed by the
CHMP.
• 50 Summaries of scientific recommendations on classification of
advanced-therapy medicinal products (4 not classified a ATMP)
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ATMP or Medical Device or Human tissue
Or Blood product or Combo?
• Where does my product fit?
• Where do I want it to fit?
 Carefull consideration required to define best strategy
Ask for classification is that wise?
• CAT/ CBG/CA human tissues/ Notified Body?
• Where to go best?
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1) Advanced Therapy Medicinal Products
• ATMPs are medical products for human use and include:
 Gene therapy products
 Somatic cell therapy products
 Tissue engineering products
• ATMPs are regulated under consolidated framework for
advanced therapies (Regulation 1394/2007) as pharmaceutical
products
• ATMP Regulation, Article 3
Where an ATMP contains human cells or tissues, the donation,
procurement and testing of those tissues or cells shall be made
in accordance with Directive 2004/23/EC
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Cells or tissues shall be considered ‘engineered’
if they fulfill at least one of the following conditions:
•Industrial process
•the cells or tissues have been “engineered”; subject to substantial
manipulation,
•are not intended to be used for the same essential function or
functions in the recipient as in the donor.
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This is still open for interpretation
What does this mean for
-Autologous processes?
-Small academic clinical case study?
-Culturing in the OR/ bioreactor within the same
procedure?
-Harvesting tissue and place it in a different environment?
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Exceptions to Substantial Manipulations
Annex I, ATMP Regulation
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cutting
grinding
shaping
centrifugation
soaking in antibiotic or
antimicrobial solutions
• sterilization,irradiation
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• cell separation, concentration or
purification
• filtering
• lyophilization
• freezing
• cryopreservation,
What if my product is an exception or gray zone?
What are the other options?
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2) European Union Tissue and Cells Directive
(EUTCD)
• Directive DG Sanco (2004/23/EC) (April 6, 2006)
Standards of quality and safety for donation, procurement, testing,
processing, preservation, storage and distribution of human tissues and cells
Implementing Directives
• Directive DG Sanco (2006/17/EC) (Nov 1, 2006)
Technical requirements for the donation, procurement, testing of human
tissues
• Directive DG Sanco (2006/86/EC) (Sept, 2007)
Traceability requirements, notification of serious adverse reactions and
events and certain technical requirements for the coding, processing,
preservation, storage and distribution
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Tissue Directive (2004/23/EC)
• Storage and preservation
“autologous Cell and tissue graft used in the same
graft procedure are exempt article 2(section 2a)
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Definitions discussion at different levels
Summary CA Tissue and Cells (Dec 2011)-EUTCD
•SANCO legal team and provide feedback to NCAs during the meeting in
June
•Unanimous consensus between the CAs to consider the use of amniotic
membrane for cornea replacement as homologous, and therefore in the scope
of Directive Tissue Directive
•And Apheresis of mononuclear cells for preparation of ATMPs; Donor
Lymphocyte infusion, mononuclear cells collected by apheresis are
considered to be in the scope of the Tissue Directive
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Medical Device Directive (93/42/EC)
• Article 1.5(f)
This Directive does not apply to:
(a) in vitro diagnostic devices;
(b) active implantable devices covered by Directive 90/385/EEC;
(c) medicinal products covered by Directive 65/65/EEC;
(d) cosmetic products covered by Directive 76/768/EEC (18);
(e) human blood, human blood products, human plasma or blood cells of human origin or
to devices which incorporate at the time of placing on the market
such blood products, plasma or cells;
(f) transplants or tissues or cells of human origin nor to products incorporating or
derived from tissues or cells of human origin;
(g) transplants or tissues or cells of animal origin, unless a device is manufactured
utilizing animal tissue which is rendered non-viable or non-viable products
derived from animal tissue.
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CAT Classification of Stem cell-based ATMPs
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Product
ATMP classification/ Indication
Autologous corneal epithelium containing stem cells
Tissue engineered product /
Corneal lesions
Allogeneic human placenta-derived, cultureexpanded, mesenchymal-like cell population
Somatic cell therapy product /
Chronic inflammatory diseases
Autologous bone marrow-derived progenitor cells
Tissue engineered product
Cardiovascular diseases
Umbilical cord blood cells expanded ex vivo using
allogeneicmesenchymal precursor cells
Tissue engineered product /
Heamatology-oncology diseases
Autologous osteoprogenitor cells, isolated from
bone marrow and expanded in vitro, incorporated,
as an integral part, with 3D biodegradable scaffold
Tissue engineered product – combined
Allogeneic mesenchymal precursor cells
Tissue engineered product /
Cardiaovascular diseases
Repair, regeneration bone defects
CAT Classification of other ATMPs
Product
ATMP classification/ Indication
Human islets of Langerhans
No
Intended for:
Autologous: Post pancreatectomy for benign
pancreatic pathologies
Allogeneic: Treatment of severe forms of type 1
diabetes
Product is derived from pancreatic tissue by a number of steps that do not
constitute substantial manipulation. Moreover, information provided show
that the manipulation of the tissue does not alter the biological
characteristics and physiological functions relevant for the intended clinical
use. The product is intended to be used for the same essential function in
the recipient and the donor, i.e.pancreatic function.
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Classification discussions?
• Why do I favor an ATMP classification:
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Recognition in Europe;
Raise the bar for market entry BUT
Difficult route to market;
Complex regulatory landscape- requirements/ standards difficult to
apply
• Why do I favor HTP classification:
• Quick market access in specific MS BUT
• No mans land (??) creates unclear /changing situation per Member
State
Faster routes in development than classical ATMP?
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1) Advanced Therapy Medicinal Products
• Key aspects of the ATMP Regulation:
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Centralized Marketing Authorization procedure (EMA)
Committee for Advanced Therapies (CAT)
Hospital Exemption ruling
Specific GMP regulations
Incentives for small and medium sized enterprises (SME)
Risk management and long term traceability
Post authorization pharmacovigilance systems
3 options : treatment of patients using ATMPs
1. Treatment as registered Medicinal Product (via EMA, see
www.ema.europa.eu.)
2. Products,which were legally on the Community market when
the Regulation became applicable, should comply to the
Regulation by December30,2012.
3. Treatment as registered Medicinal Product in a clinical study
( www.ccmo-online.nl for information).
4. Treatment as a hospital exemption
• De IGZ has to authorize the hospital exemption including
manufacturing (GMP)
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CAT: Committee for Advanced Therapies
• Products covered subject to centralized authorization
procedure involving a single scientific evaluation of the
quality, safety and efficacy of the product by the EMEA
• CAT (Committee for Advanced Therapies) responsible for
 Draft opinions on the Quality, Safety and Efficacy of each ATMP for
final approval by CHMP (Committee for medicinal Products for
Human Use)
 Advice on whether the product falls within the definition ATMP
 Contribute to scientific advice procedures
• Comprised of multidisciplinary scientific experts representing
all EU member states, as well as and patient and medical
associations
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Hospital Exemption (Article 28)
• ATMPs exempted from the centralized marketing authorization procedure
• Hospital Exemption requirements:
 Non-routine basis
 Manufactured and used in same member state
 Used in a hospital under exclusive professional responsibility of a medical
practitioner
 Specific quality standards
 Individual medical prescription
 Custom-made product for an individual patient
• Same requirements apply as for ATMPs for which a centralized
procedure is mandatory (GMP, QP release, pharmacovigilance)
• Not intended for clinical trials but rather case studies
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Hospital exemption
• Member states are responsible for the implementation of the
Hospital Exemption
• Lack of clear guidance in most Member States
• Differences in interpretation of the Hospital Exemption are
likely to occur
• Many member states are reluctant to grant hospital
exemption for clinical Phase 1 trials
• Variation per country ( ie Netherlands difficult vs Spain easier)
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Hospital exemption procedure
• A request for hospital exemption needs to be adressed to IGZ,
digitally via a form and has to be sent to [email protected].
• IGZ reviews requests monthly, the request should be sent at
least 2 weeks before the date IGZ has an ATMP review meeting.
• IGZ sents the decision 2 weeks after the review meeting
• Hospital Exemptions are enclined for one year only and
maximum 10 patients.
• Hospital exemptions from companies are most likely deferred
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• Good Manufacturing Practices
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GMP Manufacturing of ATMPs
• ATMPs need to be manufactured in accordance with the
GMP guidelines for human medicinal products for human
use (Directive 2003/94/EC)
• Control of consistency, reproducibility and uniformity are key
aspects
• Annex 2 of the EU Guidelines for GMP for medicinal
products for human and veterinary use (Eudralex Vol4) has
been updated to include GMP specific to ATMPs
• The Annex recognizes the inherent variability and increased
risks for microbial contamination and transfer of pathogens
associated with biological culturing processes and materials
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GMP Human tissues
• Only as defined in the Directives (light GMP system)
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Advanced Therapy Medicinal Products
Applicable regulatory framework for cell based
(medical) products for human use.
2004/23/EC
2004/23/EC
1394/2007
1394/2007
Distribution
Storage
Preservation
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Processing
Medicinal Products manufactured from
ANIMAL tissues and cells intended for
human use
Testing
Medicinal Products manufactured from
HUMAN tissues and cells intended for
human use
Procurement
HUMAN tissues and cells intended for
human use
Donation
Product and intended use
ATMP and Stem Cells
• EMA closely monitors developments in the area of stem cell
therapy
• Depending on the indication and process, stem-cell based
medicinal products can be classified as ATMPs
• Stem cells preparations that are not substantially manipulated or
intended to be used for the same essential function in the
recipient as in the donor are outside the scope of the ATMP
Regulation
• To date, no stem-cell product has received marketing
authorization within the EU
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ATMP and Stem Cells
• EMA expressed concerns about ‘stem-cell tourism’: use of
unauthorized stem-cell based treatment in the absence of
rigorous scientific and ethical requirements
(Lancet 2010;Vol376:514)
• CAT has classified various medicinal products containing stem
cells as ATMPs
• Committee of Orhpan Medicinal Products (COMP) has granted
orphan designation to a number of medicines containing stemcells for the treatment of rare diseases
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