Advanced Therapy Medicinal Products

1

• Advanced Therapy Medicinal Products
• April 18, 2012

Eliane.schutte_at_signifix.com
2
Agenda

• ATMP definition/ classification?
• What is my human cell based product?
• Exemptions and different routes?

3
Definitions 2001/83/EC/ 2004/24/EC 93/42/EC
4
Advanced Therapy Medicinal Products
5
Status EU ATMPs

• 1 registered ATMP in EU Chondroselect (Tigenex)
• Only six applications have been submitted for MA
  (four ATMPs)
• In 2009-2011
• 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  cell carcinoma (head and neck) was withdrawn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)

6
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?

7
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

8
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.

9
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?

10
Exceptions to Substantial Manipulations Annex I,
ATMP Regulation

• cutting
• grinding
• shaping
• centrifugation
• soaking in antibiotic or antimicrobial solutions
• sterilization,irradiation

• cell separation, concentration or purification
• filtering
• lyophilization
• freezing
• cryopreservation,

11
What if my product is an exception or gray zone?

• What are the other options?

12
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

13
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)

14
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

15
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.

16
CAT Classification of Stem cell-based ATMPs
Product ATMP classification/ Indication
Autologous corneal epithelium containing stem cells Tissue engineered product / Corneal lesions
Allogeneic human placenta-derived, culture-expanded, 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 Repair, regeneration bone defects
Allogeneic mesenchymal precursor cells Tissue engineered product / Cardiaovascular diseases
17
CAT Classification of other ATMPs
Product ATMP classification/ Indication
Human islets of Langerhans No Intended forAutologous Post pancreatectomy for benign pancreatic pathologiesAllogeneic 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. -
18
Classification discussions?

• Why do I favor an ATMP classification
• 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?

19
1) Advanced Therapy Medicinal Products

• Key aspects of the ATMP Regulation
• 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

20
3 options treatment of patients using ATMPs

• Treatment as registered Medicinal Product (via
  EMA, see www.ema.europa.eu.)
• Products,which were legally on the Community
  market when the Regulation became applicable,
  should comply to the Regulation by
  December30,2012.
• Treatment as registered Medicinal Product in a
  clinical study ( www.ccmo-online.nl for
  information).
• Treatment as a hospital exemption
• De IGZ has to authorize the hospital exemption
  including manufacturing (GMP)

)
21
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

22
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

23
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)

24
Hospital exemption procedure

• A request for hospital exemption needs to be
  adressed to IGZ, digitally via a form and has to
  be sent to atmp_at_igz.nl.
• 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

25

• Good Manufacturing Practices

26
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

27
GMP Human tissues

• Only as defined in the Directives (light GMP
  system)

28
Advanced Therapy Medicinal Products
Applicable regulatory framework for cell based
(medical) products for human use.
  Product and intended use Donation Procurement Testing Processing Preservation Storage Distribution
HUMAN tissues and cells intended for human use 2004/23/EC 2004/23/EC 2004/23/EC 2004/23/EC 2004/23/EC 2004/23/EC 2004/23/EC
Medicinal Products manufactured from HUMAN tissues and cells intended for human use   2004/23/EC   2004/23/EC   2004/23/EC   1394/2007   1394/2007   1394/2007   1394/2007
Medicinal Products manufactured from ANIMAL tissues and cells intended for human use   1394/2007   1394/2007   1394/2007   1394/2007   1394/2007   1394/2007   1394/2007
29
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

30
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 2010Vol376514)
• 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 stem-cells for the treatment
  of rare diseases