GLP for biologicals and advanced therapies

Transkriptio

1 GLP for biologicals and advanced therapies Tiina Palomäki Finnish medicines agency

2 Biological medicinal product A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physicochemical-biological testing, together with the production process and its control. Directive 2003/63/EC Vaccines Blood and plasma products e.g. albumin, clotting factors Recombinant proteins e.g. hormones, cytokines, monoclonal antibodies Advanced therapy products gene therapy products cell-based products tissue engineering products 2

3 Biological medicinal products Biologics can be a mimetic of the endogenous protein Intentionally modified Novel products single chain antibodies and antibody fragments hybrid proteins Gene therapy products Cell therapy products Tissue engineered products 3

4 Recombinant proteins 4

5 IgG ~150 kda (~1400 aa) Aspirin MW 180 5

6 Proteins as medicinal products Complex molecules with Primary structure (aa sequence) Secondary structure (alfa-helices, beta-sheets, random coils) Tertiary structure (folding into 3D structure) Quaternary structure (multiple subunits) Can be post-translationally modified e.g.glycosylated depending on the production host, or intentionally modified e.g. pegylated Often contain intramolecular disulfide bridges Even small changes in the manufacturing process can result in substantial variation in the drug product All these features may cause substantial variation and result in a heterogenous product that can not be characterized to the same extent as small chemical drugs 6

7 Principles of non-clinical assessment Preclinical testing of biologicals should Provide the proof-of-concept in a relevant animal species produce information for dose selection and route of administration in humans Identify potential target organs for toxicity Identify safety parameters to be evaluated in clinical studies Preclinical testing of biologicals should be flexible and science-based and should be determined case-by-case taking into consideration Biological basis Disease or condition to be treated Patient population Availability of relevant animal models Tick-box approach in testing of biologics may result in performing a minimal set of tests leaving science-driven questions unanswered Performing unnecessary tests and/or in non-relevant species leading to false conclusions and unnecessary use of animals 7

8 Specific aspects for biologicals 1 Pharmacodynamics Pleiotropic mechanisms Species-specificity PK Proteins are not usually taken up by the cells Proteins are degraded not metabolized Parenteral administration route Systemic bioavailability may be small Longer half-lives, e.g. mabs for several days or weeks Analytical methods 8

9 Specific aspects for biologicals 2 Toxicity Often exaggerated pharmacology or off-target secondary pharmacology Animal disease models can be used in tox evaluation; some toxic effects can remain undetected in healthy animals Relevant animal model A species having comparable receptor or target molecule; pharamacological activity Transgenic animals or homologous models can be used 9

10 Specific aspects for biologicals 3 Immunogenicity Proteins are recognized as foreign and antibodies are developed against the protein product Binding antibodies can affect PK properties of the drug, either increasing or decreasing exposure and clearance Neutralizing antibodies neutralise or block the functional effect which may lead to loss of efficacy Antibodies can also bind to endogenous counterparts Antibodies against human proteins are likely to be produced in animals, and formation of antibodies can usually not be regarded as predictive for clinical situation Immunogenicity assessment needed for interpretation of PK and tox data 10

11 Advanced therapy medicinal products (ATMPs) Somatic cell therapy medicinal products Tissue engineered products Gene therapy medicinal products 11

12 Advanced therapy medicinal products Innovative therapies for diseases and conditions for which limited or no treatment options exist Degenerative diseases Alzheimer s disease, Parkinson s disease, macular degeneration, diabetes Autoimmune diseases Chron s disease Cancer Tissue defects bone, cartilage, skin, myocardial infarction, spinal cord injury Organ replacement artificial liver, bladder 12

13 Cell-based medicinal products Somatic cell therapy medicinal products Tissue engineered products 13

14 Somatic cell therapy medicinal products cells or tissues that have been subjected to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor to treat, prevent or diagnose a disease through the pharmacological, immunological or metabolic action Annex I, Part IV of Dir 2001/83/EC Tissue engineered products engineered cells or tissues (see above) to regenerate, repair or replace a human tissue Regulation EC (No) 1394/

15 IgG ~1500 Da (~1400 aa) Eukaryotic cell 10 μm Aspirin MW

16 Non-clinical requirements for cell-based products Proof-of-concept Relevant animal model(s) Pharmacological and toxicological effects Biodistribution Unintended differentiation Ectopic engraftment Tumourigenicity Immune related effects Provide estimate for selection of safe and efficacious dose in clinical studies Support the route of administration and feasibility of application procedure Identify target organs for toxicity Identify parameters to be monitored in clinical studies 16

17 Gene therapy medicinal products 17

18 Gene therapy medicinal products active substance contains or consists of a recombinant nucleic acid which therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence, or to the product of genetic expression of this sequence to regulate, repair, replace, add or delete a genetic sequence Part IV of Annex I to Directive 2001/83/EC 18

19 IgG ~1500 Da (~1400 aa) Eukaryotic cell 10 μm Aspirin MW 180 Virus particle nm 19

20 Non-clinical requirements for gene therapy products Proof-of-concept Relevant animal model(s) Pharmacological and toxicological effects Biodistribution Persistence Ectopic transgene expression Recombination and mobilisation of a vector Induced cellular changes Insertional mutagenesis Germline transmission Immune related effects of a transgene and a vector Virus shedding Provide estimate for selection of safe and efficacious dose in clinical studies Support the route of administration and feasibility of application procedure Identify target organs for toxicity Identify parameters to be monitored in clinical studies 20

21 GLP requirements 21

22 Legal requirements Proteins Cell-based products Gene therapy products (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency Biotech and advanced therapy products to be authorised by the EMA Directive 2001/83/EC Community code relating to all medicinal products for human use Directive 2003/63/EC (Annex I of 2001/83/EC) Analytical, pharmaco-toxicological and clinical requirements (EC) No 1394/2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation 726/2004 Directive 2009/120/EC (Annex I, part IV of 2001/83/EC) Technical requirements for testing of ATMPs Dir 2004/23/EC setting standards of quality and safety for donation, procurement, testing, processing, preservation, storage and distribution of human tissues/cells, Technical requirements in Dir 2006/17/EC and Dir 2006/86/EC 22

23 Non-clinical pharmaco-toxicological requirements Pharmacodynamics Primary pharmacodynamics (PD) Secondary PD Safety pharmacology PD drug interactions Pharmacokinetics ADME PK drug interactions Toxicology General toxicity: single and repeat-dose Genotoxicity Carcinogenicity Developmental and reproductive toxicity Local tolerance Immunotoxicity Immunogenicity Environmental risk assessment 23

24 Where does the drug end-up in the body How long does it stay there What does it do there PK Toxicokinetics Biodistribution Migration Germ line transmission PK Toxicokinetics Persistence Clearance Longevity Shedding PD Prim PD Sec PD Safety pharmacology Differentiation Proliferation/growth Ectopic engraftment TOX General toxicity Tumourigenicity Genomic integration Repro-dev toxicity Immunogenicity 24

25 General requirements Special requirements for biologicals and ATMPs Proteins Gene therapy Cell-based therapies Pharmacology Prim PD Sec PD Safety pharmacology Proof-of-concept Prim PD Sec PD Safety pharmacology Proof-of-concept Tropism (Safety pharmacology) Proof-of-concept Tissue integration Tissue interaction Bioactive molecules (Safety pharmacology) Pharmacokinetics ADME TK Absorption Biodistribution (Excretion) Biodistribution, persistence, clearance, mobilisation, germ line transmission viability, longevity, distribution, growth, differentiation and migration Toxicology Single and repeat-dose toxicity Single and repeat-dose toxicity Can be included in POC studies Can be included in POC studies Genotoxicity (-) (-) (-) Carcinogenicity Included in chronic tox studies Insertional mutagenesis Repro-dev toxicity Repro- dev toxicity Fertility, reproductive potential Other toxicity Immunogenicity (Immunotoxicity) Immunogenicity shedding Tumourigenic potential (-) Immunogenicity, immunotoxicity, xenopathogen transmission ERA (-) GMO ERA (-) 25

26 GLP requirements GLP requirements the same regardless of the product class! Nonclinical studies according to the GLP requirements All pivotal studies to which nonclinical safety is based on Safety pharmacology and toxicology studies Pharmacological characterisation and proof-of-concept studies generally non- GLP When pivotal safety end-points are included in a POC study the study should be conducted under GLP Full GLP compliance not always feasible Deviation may be justified due to product related issues GLP principles must be followed to the extent possible Non-GLP and possible impact to the overall safety assessment need to be justified Acceptance on a case by case basis 26