規制基準委員会勉強会資料 110622 final - nihs.go.jp

1 L . l . l ICH . l .. ( .. (ex vivo gene therapy). (in vivo gene therapy) 1) . ( ).. 2) . Viral vector Non-viral vector 3) .. Naked DNA ( plasmid ).. 120. 100. 80. 60. 40. 20. 0. 1989. 1994. 1998. 2004. 2008. 1990. 1991. 1992. 1993. 1995. 1996. 1999. 2000. 2001. 2002. 2003. 2005. 2006. 2009. 2010. 1997. 2007. Wiley J. Gene Medicine Gene Therapy Clinical Trials Worldwide . ( ) .. 30. 1084. 489. 100. 1703. Switzerland 50. UK 197. USA. 1084. Wiley J. Gene Medicine Gene Therapy Clinical Trials Worldwide . ( ) .. l ADA X-SCID . CGD Leber ALD . l . l . l . l ALS . l HIV B . l . l .. l .. 2% 1% 8%. 8%.. 8%. 65%.. 8%. Wiley ( ).. Others Unknown Lentivirus 4% 3%. 2% Bacteria HSV-1 1%. AAV. 3%. 5%. Adenovirus Poxvirus 24%.

2 6%. Lipofection 6% Retrovirus Naked/ 20%. plasmid DNA. Vaccinia virus 18%. 8%. Wiley ( ).. HIV, SIV).. AAV).. Wiley ( ).. Wiley ( ).. INN) . Advexin Ad5-p53 . contusugene ladenovec . Cerepro Ad5-HSV-TK . sitimagene ceradenovec . Beperminogene Perplasmid plasmid DNA, HGF. 2008 . Glybera . alipogene tiparvovec AAV1, LPL S447X variant LPL 2010 . Allovectin-7 plasmid /lipid complex, Phase III. velimogene aliplasmid HLA-B7, 2 microglobulin Retroviral vector, . TK-DLI HSV-tk/ LNGFR GVHD Phase III. Generx Ad5-FGF-4 Phase III. alferminogene tadenovec NV1 FGF plasmid DNA, FGF Phase III. Riferminogene Pecaplasmid TNFerade Ad5-TNF Phase III. golnerminogene pradenovec OncoVEX . Talimogene laherparepvec Oncolytic HSV1, GM-CSF Phase III.

3 Reolysin Oncolytic reovirus Phase III. amolimogene plasmid DNA, E6 and E7 Phase II/III. bepiplasmid epitopes from HPV.. l ADA-SCID . l X X-SCID . l CGD . l . l (LCA). 10 2009). l (ALD). 2 (2009). l (2010).. l 1999 . lX-SCID . 20 5 T ( 2002 . l .. l .. (1).. normal cell: abortive replication productive replication, cell lysis oncolytic virus kills virus tumor cell, tumor cell spreads to neighbours . n . n . n . n . n . n .. n .. others Poliovirus Adenovirus VSV. Vaccinia virus HSV-1. 2010 Wiley .. 6 .. HF10 . 3 .. G47D .. Phase I .. PhaseI/II . Telomelysin . Phase I/II.. HF10 .. (2).. l .. l .. l Listeria Monocytogenes . l Clostridium novyi-NT . l .. + +++ ++. +++ + +. + ++ +++. + ++ +++. ++ + +++.

4 (3). T . T T . T .. (CAR) . T (TCR) .. T .. ( HP ).. /T . 30 . l . l . l ICH . l .. n . 2002 3 27 1 . 2004 12 28 2 . 2008 12 1 . n .. 1062 1995 11 15 . (2002 2004 . ( . n . 2003. 6. n .. 0219001 2004 2 19 .. (3) . (5) (4).. (1).. (PMDA). 30 .. (2).. ( . ) .. 30 .. p53. in vivo .. HGF. in vivo . FGF . HSV-tk/ /. GVHD deltaLNGFR ex vivo ( .. 1 : . n . n .. n .. n . GMP .. n . n . n .. 2 . n . 3 . n .. 4 . n . 5 . n . 6 . 7 . n . n 1 7 .. 1) . 2) . 3) . 4) . 5) .. 6) .. 7) . 8) . 9) . 10) .. ( .. 1995 ADA ADA (1). 1998 GM-CSF (4). 1998 / RPR p53 (9)#1. 2000 / RPR p53 1 #1. 2000 / RPR p53 (2)#1. 2000 / RPR p53 (3)#1. 2000 / RPR p53 (10). 2000 MDR1 (3). 2000 IFN-b (5). 2000 HSV- (9). 2001 HGF (22).

5 GVHD HSV- /. 2002 5 . DLNGFR. 2002 ADA ADA 2 . 2002 X-SCID gc chain . 2003 HSV-tk (6). 2003 IFN-b (5).. ( .. 2003 MG HGF 41). HGF 9). 2006 FGF-2 (12). 2006 AADC (6). 2007 HSV-tk (3).. 2007 HSV- / DLNGFR . GVHD . 2007 FGF . 2008 IL-12 (7). 2009 HSV-1 HSV1 G47 (4). 2009 GVHD HSV- / DLNGFR . 2009 TCR . 2009 IFN-b .. 2010 . REIC/Dkk-3. LCAT LCAT .. hPEDF.. - - . 20%. 80%.. 1 (4%). Phase III (Global study) Beperminogene Perplasmid 1 (4%) (HGF-expressing plasmid DNA for ASO). Riferminogene 2008 . Pecaplasmid 2010 . (FGF-1-expressing . plasmid DNA for CLI). Phase I, I/II 24 (92%). l . l . l ICH . l . FDA: Guidance and draft guidance for Gene Therapy Products Guidance for Industry: Guidance for Human Somatic Cell Therapy Center for Biologics and Gene Therapy Evaluation and Research March 1998.

6 Guidance for Industry: Gene Therapy Clinical Trials Observing Center for Biologics Subjects for Delayed Adverse Events Evaluation and Research November 2006. Guidance for Industry: Supplemental Guidance on Testing for Center for Biologics Replication Competent Retrovirus in Retroviral Vector Based Gene Evaluation and Research Therapy Products and During Follow-up of Patients in Clinical Trials November 2006. Using Retroviral Vectors Guidance for FDA Reviewers and Sponsors: Content and Review of Center for Biologics Chemistry, Manufacturing, and Control (CMC) Information for Human Evaluation and Research Gene Therapy Investigational New Drug Applications (INDs) April 2008. Draft Guidance for Industry: Validation of Growth-Based Rapid Center for Biologics Microbiological Methods for Sterility Testing of Cellular and Gene Evaluation and Research Therapy Products February 2008.

7 Draft Guidance for Industry: Potency Tests for Cellular and Gene Center for Biologics Therapy Products Evaluation and Research October 2008. EMEA Scientific Guidelines for Gene Therapy Products Quality, pre-clinical and clinical aspects of medicinal products containing genetically CHMP/GTWP/671639/20. 08(draft). modified cells (Draft). Development of a guideline on the risk-based approach according to annex I, part IV of CHMP/CPWP/708420/09(. draft). directive 2001/83/EC applied to advanced therapy medicinal products (concept paper). Questions and answers on gene therapy CHMP/GTWP/212377/08. (Dec-09). Revision of the note for guidance on the quality, pre-clinical and clinical aspects of gene CHMP/GTWP/234523/09(.)

8 Draft). transfer medicinal products (concept paper). ICH Considerations General Principles to Address Virus and Vector Shedding CHMP/ICH/449035/09. (Jul-09). Quality, non-clinical and clinical issues relating specifically to recombinat adeno- CHMP/GTWP/587488/07. (Jun-10). associated viral vectors ICH Considerations - Oncolytic Viruses CHMP/GTWP/607698/08. (Oct-09). Non-clinical studies required before first clinical use of gene therapy medicinal products CHMP/GTWP/125459/06. (May-08). Follow-up of patients administered with gene therapy medicinal products CHMP/GTWP/60436/07. (Nov-09). Scientific Requirements for the Environmental Risk Assessment of Gene Therapy CHMP/GTWP/125491/06. (may-08).

9 Medicinal Products Non-Clinical testing for Inadvertent Germline transmission of Gene Transfer Vectors EMEA/273974/05 (Dec- 06). Development and Manufacture of Lentiviral Vectors CHMP/BWP/2458/03. (May-05). Quality, Preclinical and Clinical Aspects of Gene Transfer Medicinal Products CPMP/BWP/3088/99. (Apr-01).. - - .. FDA EMA .. ( .. n . n DNA EU . FDA . n FDA .. n Health Canada mRNA . n .. ICH GTDG . l 2001 5 ICH SC. l .. ICH .. lICH . Gene Therapy Discussion Group GTDG . Klaus Cichutek (EMEA), Stephanie Simek (FDA), Teruhide Yamaguchi (MHLW), Christine-Lise Julou (EFPIA), Wataru Toriumi (JPMA), Alex Kuta (PhRMA), EFTA, Canada ICH GTDG . l . l (Oncolytic virus) ICH . l / . l (Adenovirus type5).)

10 L (RCA RCR). l X-SCID . l (FDA GL) . l (EMEA GL) . l . l . ICH ICH Consideration). l ICH Consideration . ICH .. ICH SC . signoff ICH SC . n ICH .. 2006 10 25 . n ICH . 2009 6 11 ). n ICH 2009 9. 17 ). ICH .. ( ). ICH .. 1.. 2.. 3.. l qPCR . 4.. ICH .. n . (RCV) & .. n . in vitro .. n .. ICH .. / Shedding <Transmission to third parties>. / . < >. ??? , , ??? ??? . <Environmental risk>. < >. / . shedding) . ICH .. n / . n . n . n . n . n . n . n . n . n qPCR . ICH .. n . n . n . n . n . n . n . n . n . n . n . n . n . ICH ICH M6 Guideline on Gene Therapy Vector and Oncolytic Virus Shedding and Transmission . X-SCID .. n X-SCID .. n 10 9 . ( 20 5 . n LMO2 .. n 10 . n 10 . GL (FDA, EMA). ICH ICH.