What are we talking about? An overview on biologics: a regulatory perspective

Transcription

1 AGAH-Workshop Critical aspects of integrated drug development expect the unexpected! in Munich >> What are we talking about? An overview on biologics: a regulatory perspective Federal Agency for Vaccines and Biomedicines Bettina Ziegele -

2 The PEI and it s medicinal products

3 Granting of authorisations in national procedures Approval of clinical trials Applications for marketing authorisation in European procedures Pharmacovigilance Annual reports for blood and tissues products Measures to guarantee the quality, efficacy and safety Research in the fields the PEI Official testing and release of batches Inspections GMP/GCP (national and European) Regulatory and scientific advice

4 Definition of biological medicinal product Definition: Annex I of Directive 2001/83/EC: biological medicinal product : active substance = biological substance biological substance = substance produced by or extracted from biological source + characterisation and determination of quality by physico-chemical-biological testing, production process and control Uncertainty of future scientific development of methods for characterisation, production process and control Basis for classification: current state of the art

5 Definition of biological medicinal product Scope: Immunological medicinal products Medicinal products derived from human blood and plasma ( ) Medicinal products developed by biotechnological processes: Recombinant DNA technology Controlled expression of genes coding for biologically active proteins in procaryotes and eucaryotes including transformed mammalian cells Hybridoma and monoclonal antibiotic methods (falling within the scope of Part A of the Annex to Regulation (EEC) No 2309/93) Advanced Therapy Medicinal Products (Part IV of this Annex and Regulation (EC) No 1394/2007)

6 National responsibilities legal frame Section 77 of the German Medicinal Products Act: Competent higher federal authority (1) The competent higher federal authority shall be the Federal Institute for Drugs and Medical Devices unless either the Paul Ehrlich Institute (the Federal Agency for Sera and Vaccines) or the Federal Office of Consumer Protection and Food Safety is competent. (2) The Paul Ehrlich Institute shall be competent for sera, vaccines, blood preparations, bone marrow preparations, tissue preparations, tissues, allergens, advanced therapy medicinal products, xenogenic medicinal products and blood components manufactured using genetic engineering.

7 Overview Medicinal Products of the PEI Therapy + test allergens Antibodies, immunoglobulins, fusion proteins Vaccines Blood + blood products (incl. stem cell preparations Gene therapy products Cell therapy products (human+ xeno) ATMPs Tissueengineered products Combined ATMPs Focus today: how to get an MP into clinics, so : human Tissue preparations BfArM: chemotherapeutics, homoeopathics, herbals, etc. + rec. Proteins + medical devices

8 Medicinal Products of the PEI Therapy + test allergens Therapy allergens (subcutaneous, sublingual) Test allergens (epi-/intacutaneous, provocation and prick tests) Antibodies, immunoglobulins, fusion proteins Monoclonal antibodies, e.g. bevacizumab, trastuzumab, rituximab Human immunoglobulin: e.g. hepatitis, rabies Animal sera IgG-fusion proteins Vaccines Prophylactic vaccines against infectious diseases, e.g. yellow fever, japanese encephalitis, meningococci; DTP, MMR, HIB, hepatitis, influenza, Therapeutic vaccines: e.g. cervical carcinoma 8

9 Medicinal Products of the PEI Albumins Blood products Blood components for transfusion (erythrocyte+thrombocyte concentrate and plasma) Coagulation factors and coagulation inhibitors, fibrin sealants and others, such as proteinase inhibitors Stem cell preparations From cord blood From peripheral blood From bone marrow purpose: haematopoetic reconstitution Tissue preparations Heart valve allocraft, decellularized pulmonary valvue, vascular allocraft Demineralized bone matrix, facia, femur, cartilage, spongiosa Amnion, skin, cornea, 9

10 BfArM and PEI

11 Shared responsibilites PEI BfArM I Change of application mode, line extension Approved monoclonal antibody for iv injection New device for sc injection by patient Argument PEI Advice at PEI, BfArM participation via video conferencing 11 Argument BfArM

12 Shared responsibilities PEI BfArM II New vaccination concept Active substance: licensed vaccine New formulation: combined with medical device + chemical substance Argument PEI Joint Advice PEI + BfArM 12 Argument BfArM

13 Shared responsibilities PEI BfArM III Asparaginase in erythrocytes Blood preparation Active substance: asparaginase (erythrocytes only package) Argument PEI Decision: BfArM responsibility; PEI will contribute on request 13 Argument BfArM

14 Shared responsibilities PEI BfArM IV Fecal microbiota = Medicinal Product (basis: 2 Abs. 1 Nr. 1 und Nr. 2a AMG) Intestinal flora = procariots = cells = part of human body + use as MP ( 4 (30) AMG, 1a no.4 TPG) Metabolic products of human beings ( 3 no. 3 AMG) part of human body (official comment on tissue act) 14 Argument PEI Argument BfArM Discussion and decision in joint advice: BfArM responsibility AMG = German Medicinal Products Act = section

15 ATMP

16 Legal provision and starting point Regulation (EC) No. 1394/2007 Need for central marketing authorisation by end of 2012 at the latest Article 28 of the Regulation National Regulation Hospital exemption National Implementation in Germany Section 4 b (sub-section 3) of the German Medicinal Products Act

17 'Hospital Exemption' for ATMPs Scope according to Article 28 Regulation (EC) No 1394/2007 individual medical prescription custom-made product for an individual patient prepared on a non-routine basis to specific quality standards used under the exclusive professional responsibility of a medical practitioner Prepared on a non-routine basis are, in particular, medicines: 1. which are manufactured in small quantities, and in the case of which, based on a routine manufacturing procedure, variations in the procedure which are medically justified for an individual patient, are carried out, or 2. which have not yet been manufactured in sufficient quantities so that the necessary data to enable a comprehensive assessment are not yet available.

18 GTMP Gene therapy medicinal product = biological medicinal product characteristics: N.B.: Vaccines against infecious diseases GTMP substance contains or constists of a recombinant nucleic acid, or is used in or administered to human beings to regulate, repair, replace, add or delete a nucleic acid sequence and therapeutic, prophylactic or diagnostic effect directly related to the recombinant nucleic acid it contains or to the product resulting from the expression of that sequence

19 TEP Tissue engineered product = biological medicinal product characteristics: TEP: Products containing or consisting exclusively of non-viable human or animal cells and/or tissues, which do not contain any viable cells or tissues and which do not act principally by pharmacological, immunological or metabolic action. contains or consists 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

20 TEP Cells or tissues = engineered if N.B. The manipulations listed in Annex I, in particular, shall not be considered as substantial manipulations. the cells or tissues have been subject to substantial manipulation, so that biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement are achieved or the cells or tissues are not intended to be used for the same essential function or functions in the recipient as in the donor ( non-homologous use ).

21 SCT Somatic cell therapy medicinal product = biological medicinal product characteristics: N.B. The manipulations listed in Annex I, in particular, shall not be considered as substantial manipulations. or consists of substantially manipulated cells or tissues: biological characteristics, physiological funtion or structural properties, relevant for the intented clinical use have been altered consists of cells or tissues that are not intended to be used for the same essential function or functions in the recipient as in the donor ( non-homologous use ) and is presented as having properties for, or is used in or administered to human to obtain a therapeutic, diagnostic or preventive effect through metabolic, pharmacological and immunological means

22 Manipulations Manipulations according to Annex I: not considered as substantial manipulations: Examples for substantial manipulations cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, cell separation, concentration or purification, filtering, lyophilization, freezing, cryopreservation, vitrification. changes of tissue (e.g. encymatic digestion) cultivation, expansion, genetic modification and - basically those procedures not listed

23 Combined ATMP Combined advanced therapy medicinal product conditions: and integral part of the product: one or more medical devices within the meaning of Article 1(2)(a) of Directive 93/42/EEC or one or more active implantable medical devices within the meaning of Article 1(2)(c) of Directive 90/385/EEC its cellular or tissue part must contain viable cells or tissues or its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to

24 What if a product which may fall within the definition of a tissue engineered product a somatic cell therapy medicinal product tissue engineered product a somatic cell therapy medicinal product a tissue engineered product, a gene therapy medicinal product a gene therapy medicinal product or it contains viable cells or tissues: the pharmacological, immunological or metabolic action of those cells or tissues shall be considered as the principal mode of action of the product.

25 Decision tree for ATMP

26 SCT, TEP and GTMP some examples 1. SCT: Pankreas islet cells: type I-Diabetes Immunotherapeutics / cell-based therapeutic vaccines: 2. TEP: bronchial carcinoma Autologous chondrocyte transplants: reconstitution of bones and cartilage defects Ceratinocyte sheets (allogeneic+autologous): burns, ulcers, plastic surgery Products derived from mucosal cells: reconstruction of urethra, repair of cornea 3. GT: Genetically modified mesencymal stem cells (allogeneic): makuladegeneration plasmid tumor vaccine: ovarialcarcinoma

27 Peculiarities of ATMP! New therapeutic development in cell- and molecular biology! Highly innovative medicinal products! Individualised and patient-specific therapy! Specific manufacturing process! Complex medicinal products, often combined with medical devices

28 Challenges in the development of cell therapy medicinal products Cells: fragile and complex systems Genetic manipulation Proliferation and differentiation of cells Impurites caused by other cell populations Level of cell manipulation (in vitro/ex vivo expansion) Cell culture populations can be(-come) heterogenous

29 and further aspects to consider Origin of cells (autologous/ allogeneic/ xenogen) Undesired immunogenicity Tumorgenicity (changes in karyotype) Cell migration: special focus: biodistribution Animal model Mode of action Potency assay

30 The process is the product - Variations in production process (e.g. temperature, media) Inconsistency of batches (e.g. formulation of aggregate) - Changes in production process (e. g. cryo conservation) New Product (different product specification) One process one product -paradigm Changes in pharmaceutical quality may cause new non-clinical testing!!! Quality and non-clinic/clinic are intrinsically linked Biotechnological medicinal products are individuals * ICH Guideline Q5E

31 Mutual influence in the development opf biotechnologcal medicinal products Quality - Impurities - Batch-Inconsistency - Mikroheterogenicity - Toxicity - Immuntoxicity -Biodistribution Non-clinic Clinic - Relevant safety endpoints - Relevant safety measures - Immunogenicity

32 Support

33 Target Groups Focus: Group of ATMP Advice on developmental stages Academic institutions (e.g. clinical research groups) Small and medium sized enterprises (SME) Gene Therapy Medicinal Products 1) Somatic Cell Therapy Medicinal Products 2) Tissue Engineered Products 3) Quality aspects In preparation for: Non-clinical studies Application of a clinical trial National authorization Centralised marketing authorisation 1) e.g. genetically modified cells as therapeutic vaccines 2) e.g. autologous haematopoietic bone marrow stem cells for the treatment of myocardial infarction 3) e.g. autologous chondrocyte-transplants for the treatment of cartilage defects

34 Scientic Advice at the PEI EARLY FAST INFORMAL GUIDED APPROACH STEPWISE DETAILED PROCESS-RELATED PARALLEL TO DEVELOPMENT New: Orientierungsgespräche FOCUSED HIGH EXPERTISE BROAD EXPERIENCE JOINT ACTIONS

35 Areas of expertise Immunology: Therapeutic Vaccines Microbial Safety Haematology / Transfusion Medicine Medical Biotechnology: Advanced Therapy Medicinal Products Tissue Engineering, Somatic Cell Therapeutics Gene Transfer Medicinal Products PEI-Experts EU-Co-operation Biological Medicinal Products Viral Safety Biostatistics Clinical Trials Pharmakovigilance Legal Affairs

36 Details of advice: Quality

37 Details of advice: Non-clinic

38 Details of advice: Clinic

39 Summary: Points of discussion Quality Characterisation of the cell type In-process-control Release control Viral safety Microbial safety Non-Clinic Proof of Principle Discussion of a clinically relevant animal model Validation of data Implementation of studies on the basis of GXP Clinic Proof of safety of the medicinal product (first proofs of efficacy) Proof of concept Discussion of primary und secondary endpoints

40 National Advices for ATMP by the Adressees: Academia (clinical research groups) and companies focused on ATMP Provision of advice on general regulatory issues MAA, European Section 4b AMG*): national Co-ordination of scientific advice: First applicationoriented development and / or application non-clinical studies clinical trials Supportive process-related advice on the basis of first data throughout the development of the ATMP Scientific advice with regard to the requirements of the quality of ATMP Scientific advice with regard to non-clinical development of ATMP Scientific advice with regard to applications for clinical trials of ATMP *) Arzneimittelgesetz = German Medicinal Products Act

41 ATMP development quality/ manufacturing non-clinical development clinical development licensing/ post-marketing proof of concept biodistribution first starting dose target organs of toxicity and biological activity safety monitoring in phase I patient selection benefit/risk ratio phase I Innovationsbüro 41

42 Time-lines clinical trial application (*Regular deadline: 30 days; Biological Products: 60 Days; Somatic-Cell-Therapeutics, Gene Transfer- Medicinal Producst and Genetically modified Organisms (GMO): 90 Days; Xenogene Cell-Therapeutics: No time-lines) Submission by Sponsor Submission by Sponsor Application day 0 day 10 or day 10 day 30 * Formal Deficiences 14 days Assessment 90 days 15 days Decision Letter on formal deficiencies Grounds for nonacceptance or approval VHP-Procedure: Harmonized authorisation by competent authorities of clinical trials in two or more EU member states after submission of a single application file (VHP) ( vhp-voluntary-harmonisation-procedure/vhp-node.html) 42

43 EMA Procedures I Classification: Scientific recommendation of a classification as an ATMP Not formally binding facilitation of other procedures Certification of quality and/or non-clinical data Focus: ATMP Target group: SME Only pre-assessment procedure Not (yet) open for academia

44 EMA Procedures II ITF-Briefing Meetings: Advice for innovative medicinal products and new technologies No fees Within 60 days Orphan designation status: Evaluation whether the medicine qualifies as an orphan Fee reductions Protocol assistance Contact-Point:

45 Regulatory development of an ATMP Classification as ATMP on basis of regulatory and scientific aspects MARKET ACCESS / REIMBURSEMENT PEI: - Approval of clinical trials EMA (CAT/CHMP): European Marketing Authorisation Application European Commission: Granting of Marketing Authorisation - Authorisation on the basis of the section 4b German Medicinal Products Act Regional authority: - Authorisation for the procurement of tissues and the pertinent laboratory testing (section 20b German Medicinal Products Act) - Granting of manufacturing authorisation according to section 13 German Medicinal Products Acts - and placing on the market

46 Der Anfang ist die Hälfte des Ganzen Aristoteles Passion is the only orator who can always convince us.

47 and before you lose passion Simona Gausmann Tel / Dr. Nils Jost Tel / Bettina Ziegele, M.A., Head Tel: 06103/ For general information:

48 Thanks and hope to see you soon

49 Disclaimer The views expressed in this presentation are the views of the author. Decision are made while considering individual cases on scientific grounds. Neither the Paul-Ehrlich-Institut nor its experts obtain any finances from industry developing medicinal products. Research at the Paul-Ehrlich-Institut is financed by public money incldg. peer-reviewed research grants.