MHRA Manufacturing Authorisation for - Investigational Medicinal Products (MA-IMP) - Specials

Transcription

1 RCTS MHRA Manufacturing Authorisation for - Investigational Medicinal Products (MA-IMP) - Specials Cells for cellular therapies Viral vectors for gene therapy Stem cells for regenerative medicine Production Manager - Lucas Chan Quality Control Manager - Joti Bhalla Qualified Person - David Farrer Farzin Farzaneh

2 The Rayne Cell Therapy Suite MHRA Manufacturing Authorisation for Investigational Medicinal Products (MA-IMP)

3 KCL/KCH - new Cell & Gene Therapy Unit (Q3, 2011) Hepatocyte Transplantation Islet Cell Transplantation Haematological Stem Cell Transplantation Cell and Gene Therapy of Cancer Stem cells for regerative medicine applications

4 The Rayne Cell Therapy Suite (RCTS)

5 GeneTherapy Products (Phase-I/II Trials) litre batches of retrovirus / lentivirus Immune gene therapy of relapsed Acute Myeloid Leukaemia - Self-inactivating lentivirus vector (5x10 10 IU) - completed Control of graft versus host disease - Retrovirus vector (approx IU) - completed Cancer vaccination with a dendritic cell targeted vector - Lentivirus (10 11 IU) in process development

6 AML as a target for cell, gene and peptide based immune therapies

7 Professional antigen presenting cells Acute Myeloid Leukaemia (AML) AML blasts express both HLA class-i, and class-ii Schwartz 1992 Express AML associated antigens (WT1, PRAME, GP250, etc) Share common lineage with APCs efficient antigen presentation Express many surface markers present on DC, including CD86 (CDB7.2) but not CD80 (B7.1)!

8 Rejection of established mouse leukaemia, by vaccination with leukemia cells expressing CD80 (B7.1) and IL-2 In mouse leukaemia and solid tumour models, vaccination with the same tumour cell, modified to express CD80 (B7.1) and IL-2, induces immune mediated tumour rejection. % Survival Leukemia initiation 0 ( Dp210 cells iv) Vaccination (10 6 irradiated cells) Time (days) 100 Cell vaccine 32D/IL-2/CD80 32D/CD80 32D/IL-2 32D/M3P (Vector)

9 Autologous CTL activity Autologous CTL activity in 3 representative patients CM Remission PBLs, stimulated by autologous IL-2/CD80 (B7.1) AML, display cytolytic activity against unmodified AML blasts E:T ratio = 50:1 Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3):

10 Autologous CTL activity Autologous CTL activity in 3 representative patients CM Remission PBLs, stimulated by autologous IL-2/CD80 (B7.1) AML, display cytolytic activity against unmodified AML blasts - Remission T cells are not defective in cytolytic activity - AML cells are not resistant to cytotoxicity E:T ratio = 50:1 Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3):

11 Specificity of the in vitro stimulated T cells Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3):

12 Specificity of the in vitro stimulated T cells Autologous Stimulators Unstimulated (media only) Secondary targets No target Normal AML CD14 + blasts unmodified AML cells IL-2/CD80 AML Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3):

13 Specificity of the in vitro stimulated T cells Autologous Stimulators Unstimulated (media only) Secondary targets No target Normal AML CD14 + blasts unmodified AML cells IL-2/CD80 AML Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3):

14 Specificity of the in vitro stimulated T cells Autologous Stimulators Unstimulated (media only) Secondary targets No target Normal AML CD14 + blasts unmodified AML cells IL-2/CD80 AML Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3):

15 Specificity of the in vitro stimulated T cells Autologous Stimulators Unstimulated (media only) Secondary targets No target Normal AML CD14 + blasts unmodified AML cells IL-2/CD80 AML Greater specificity of the CD80/IL-2 stimulated T cells against AML blasts, rather than the remission CD14 + normal bone marrow cells. Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3):

16 NK cell stimulation by IL-2/CD80 expressing AML cells PBMC PBMC + AML PBMC + CD80/AML PBMC + IL-2/AML PBMC + IL-2/CD80/AML CD56 CD3 Ingram W et al (2009). Br J Haematol. 145:

17 Enhanced cytotoxicity of NK cells against K562 and autologous AML cells following co-culture with CD80/IL-2 expressing AML cells 51 Cr release assay isolated NK cells 51 Cr release assay isolated NK cells % Specific lysis Target K562 cells AML Cells % Specific lysis Target K562 cells AML Cells Base line +Unmodified + CD80/IL-2 AML modified AML Base line +Unmodified + CD80/IL-2 AML modified AML Patient NK cells can be expanded & stimulated to express cytolytic activity AML cells not resistant to the cytolytic activity of the stimulated NK cells Ingram W et al (2009). Br J Haematol. 145:

18 B7.1/IL-2 immune gene therapy for poor prognosis relapsed AML Day 100+ Chemotherapy Allo-HSCT RIC Donor Leuckocyte Infusion (DLI) if no evidence of GvHD Intensive Chemotherapy but no CR or PR Day 0 Day 28 Day 56 Day 100 Cohort 1 DLI Alone reduced leukaemia burden Reconstituted immune system (donor chimerism) Cohort AML Cell Vaccine DLI + AML Cell Vaccine ( autologous ) every 3 weeks

19 Advanced Therapy Medicinal Products EC Regula:on No 1394/2007

20 Why legislate? Because there was a gap ATMP s Medical devices Tissue engineering Cell therapy Gene Therapy Biologicals e.g. insulin Chemicals e.g. aspirin = extent of expertise and legislation

21 ATMP: Key definitions Non-viable and viable cells are included Products which do not contain viable cells and which do not act principally by metabolic action are excluded Where a product contains viable cells, the pharmacological, immunological or metabolic action of those cells shall be considered as the principal mode of action The association of cells with a device is no longer considered essential for the cells to be termed engineered In case of doubt, products will be defined as being in the most tightly regulated category: gene therapy > tissue engineering > somatic cell therapy

22 Key principles of the legisla<on No marketing without prior authorisation Demonstration of Quality, Safety and Efficacy Post authorisation vigilance Centralised procedure mandatory (European Medicines Agency)

23 Hospital Exemp<on scheme A specific exclusion from EC Regula:on No 1394/2007

24 Hospital exemption scheme Based on Section 6 of EC Regulation 1394/2007 (Advanced Therapy Medicinal Products) Allows for unlicensed ATMPs to be used, under very specific conditions: prepared on a non-routine basis with specific quality standards used within a hospital in the same Member State a custom-made product for an individual patient

25 Specials scheme Sometimes called compassionate use or named patient use Based on Article 5.1 of Directive 2001/83/EC (the main directive relating to medicinal products for human use) Allows unlicensed medicines to be supplied to meet special needs: In response to a bona fide unsolicited order Formulated in accordance with the specifications of an authorised health care professional For use by an individual patient under the health care professional s direct personal responsibility

26 Similarities between the two schemes Both cover the supply and use of unlicensed medicines (i.e. those without a Marketing Authorisation) A Manufacturer s Licence, specific to each scheme, is required in order to produce the unlicensed medicines Neither scheme requires a QP to certify batches

27 Differences between the two schemes ATMP hospital exemp<on Product has to be made and used in the same Member State Product must be used in a hospital Manufacture must be non- rou<ne Quality, pharmacovigilance and traceability requirements equivalent to those products with a Manufacturing Authorisa<on Commissioned by a medical prac<<oner Specials Specials may be imported/exported No restric<on on where a product may be used Manufacture can be rou<ne Different requirements Prescribed by a doctor, den<st or supplementary prescriber

28 UK legislation As well as incorporating EC Regulation 1394/2007, the MHRA has also included the following provisions in the UK legislation for the hospital exemption scheme: Pharmacovigilance - notification of adverse reactions Possible requirement for a risk management plan Traceability records from donor to use/destruction, kept for 30 years Specific requirements for patient information on the label and in a leaflet An annual return to the MHRA

29 Qualified Person Qualifications and requirements

30 European Directive 2001/83/EC A qualified person shall complete a university course of study in one of the following: pharmacy medicine veterinary medicine chemistry pharmaceutical chemistry and technology biology

31 Directive 2001/83/EC continued The course shall include theoretical and practical study of the following: Applied physics General and inorganic chemistry Organic chemistry Analytical chemistry Pharmaceutical chemistry General and applied biochemistry Physiology Microbiology Pharmacology Pharmaceutical technology Toxicology Pharmacognosy (composition & effects of natural active substances)

32 Directive 2001/83/EC continued The qualified person shall have acquired practical experience over at least two years at a manufacturing site, including analysis of medicinal products and active substances and of the testing and checking necessary to ensure the quality of medicinal products. A person carrying out QP activities before May 1985 shall be eligible to continue to engage in those activities ( grandfather clause )

33 To become a QP in the UK The MHRA require the Society of Biology, the Royal Pharmaceutical Society and the Royal Society of Chemistry to assess the eligibility of their members for Qualified Person status. These organisations provide guidance notes, study guides and the code of practice, as well as the application forms.

34 RCTS Production Manager - Lucas Chan Quality Control Manager - Joti Bhalla Qualified Person - David Farrer Angela Osborne

35 Asthma and Allergy Alistair Noble James Wells Infection & Immunity Adrian Hayday Mark Peakman

36 University of Cambridge Sharon Williams Nigel Slater Mayo Clinic Stephen Russell Imperial College London Colin Casimir Myrtle Gordon Nagy Habib University College London Mary Collins Bobby Gaspar Waseem Qasim Adrian Thrasher UCLA Noriyuki Kasahara University of Geneva Didier Trono University of Nottingham / QMC Mark Aloysius Lindy Durant Oleg Eremin Adrian Robbins San Raffaele Institute, Milan Luigi Naldini

37 Cytokine profile of human autologous T cells following in vitro stimulation (Cytokine Bead Array CBA) IL-2 IL-4 IL-6 IL-10 TNF-α IFNγ IL-2 IL-4 IL-6 IL-10 TNF-α IFNγ n=3 The in vitro stimulated T cells have a predominantly T h1 phenotype IL-2 IL-4 IL-6 IL-10 TNF-α IFNγ

38 RCTS