Preclinical issues in the development of cell therapy medicinal products

Transcription

1 Preclinical issues in the development of cell therapy medicinal products Carla Herberts Non-clinical assessor Medicines Evaluation Board 1

2 Disclaimer The contents of this presentation represent the personal views of the speaker only; the contents do not necessarily reflect current or future opinions of the MEB, the EMA, and/or their committees/working parties. 2

3 New challenges B-cell 3

4 Regulatory framework cell therapy MP EU Regulation 1394/2007 GTMP, CBMP, TEP Committee for Advanced Therapies EMA Procedures Scientific advice Protocol assistance Classification Certification (Q, Q/NC) 4

5 EMA Guidelines Human cell-based medicinal products (CHMP/410869/2006) Risk-based approach according to Annex I, part IV of Directive 2001/83/EC applied to Advanced Therapy Medicinal Products (EMA/CAT/CPWP/686637/2011) Reflection paper on stem cell-based medicinal products (EMA/CAT/571134/2009) 5

6 Examples of cell based ATMP MSC for chronic myocardial ischemia Adipose MSC for bone defects (combined with betatricalcium) Expanded autologus CD34+ cells for acute AMI Expanded allogenic BM-MSC for steriod-refractory GvHD Allogenic mesenchymal precursor cells for RA But also Cultured chrondrocytes for knee defects transduced T cells for haematological malignancies DC immunotherapy for prostate cancer Peptide pulsed DC + activated T cells for HCV (heterologous) human adults liver-derived progenitor cells for liver disease 6 EMA website ATMP classification

7 Challenges in non-clinical development Choice of animal model Which product to use (homologous, heterologous) Kinetics/Biodistribution Safety studies (which, design, species, GLP) Tumourigenicity Analysis of scientific advice on CBMP/TEP 7

8 The data set For 21 cell-based medicinal products advices were provided on non-clinical development (13 autologous, 7 allogeneic, 1 chimeric) (Dated from February 2007 to December 2011) Topics for discussion were proof of concept/principle Biodistribution General toxicity studies Tumourigenicity Reduced non-clinical package 8

9 Choice of animal model Homologous models may be useful (eg mouse (equivalent) cells in mice) PoC Biodistribution Safety Immunocompromised, knockout or transgenic animals Product should be pharmacologically active (ICH-S6) Mimic clinical setting No general requirement for large animal models 9

10 Biodistribution Lack of migration or potential for systemic exposure should be shown (not assumed) Full body biodistribution was not needed when systemic exposure was part/aim of treatment (e.g., immune/blood cells) The use of homologous model is encouraged 10

11 General toxicity Toxicity endpoints can be included in other studies (Proof of concept, tumourigenicity studies) Single dose studies are agreed if single administration is proposed in the clinic Studies are often performed in immunocompromised animals (heterologous model) GLP compliance is not always possible due to specialised procedures Lack of GLP is acceptable when justified, GLP principles should be applied Duration should depend on expected exposure Safety assessment can be complemented with discussion of potential risks 11

12 Tumourigenicity (I) No standard carcinogenicity study Often in vitro studies combined with in vivo studies Use clinical batches (ie human product) Culturing beyond the normal production passage 12

13 Tumourigenicity (II) In vitro studies used were growth rate, karyotyping, senescence, cell differentiation, cell adhesion, growth factor (in)dependent growth, expression of oncogenes Design of in vivo study Immunodeficient animals, RoA mimic clinical setting, duration depends on persistence of the cells However in vivo studies are not always necessary E.g. minimally manipulated cells and/or sufficient clinical experience 13

14 Non-clinical studies (in vivo and in vitro) Should Provide a proof of concept Identify safety issues Maximise the benefit-to-risk ratio Could Support validation of clinical endpoints Aid identification critical steps in production process Assist in development of potency assay 14

15 Are stem cells different? Yes and No Specific issues associated with stem cells Identification Tumour formation Differentiation Availability of animal equivalent? Use of feeder cells? Engraftment/migration(homing)/niche/in vivo differentiation? Immune recognition 15

16 Recommendations Guidelines are a starting point Tailored scientific approach Accept limitations of animal studies When using homologous model also characterise animal cells Nonclinical studies are performed to support the clinical development and use of a medicinal product 16

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