CAR-T细胞技术产品欧美监管情况探讨
|
摘要
基于嵌合抗原受体T细胞(Chimeric Antigen Receptor T cell,CAR-T)免疫疗法的技术产品在血液恶性肿瘤、卵巢癌、成神经细胞瘤、胰腺癌、间质瘤等疾病治疗临床应用方面,近些年取得了较多重要的成果。在不断积累的临床研究数据基础上,医药企业开始将这一技术按照治疗用生物制品的有关法规和指南要求进行合规化的研究,积极加快推进生物制品许可申请(Biologics License Applications,BLA),以期在获批后将CAR-T产品正式推向医药市场,为缺乏有效治疗手段的临床患者带来新的希望,同时在市场收益方面也有相当可观的预期。近期诺华的tisagenlecleucel在美国获批上市,引发了监管机构和业界对CAR-T产品作为治疗用生物制品发展的高度关注。美国和欧洲较早开始了相关科学研究和制度研究,积累了较多的经验。本文结合CAR-T技术发展背景,介绍了美国和欧盟主要的监管法规和指南,并讨论了该类产品按药品申报相关合规和监管方面的思考。
引文
[1] TALEKAR M, HUCKS G, MAUDE S, et al. Chimeric antigen receptor(CAR)-modified T cells(CTL019)induce durable CNS remissions in children with CNS/combined bone marrow and CNS relapsed/refractory CD19+acute lymphoblastic leukemia[J]. Pediatric Blood Cancer, 2017,64:S2-S2.
[2] ALTHOFF E, YANCOSEK R. Novartis CAR-T cell therapy CTL019 receives FDA breakthrough therapy designation for treatment of adult patients with r/r DLBCL[EB/OL].[2018-08-21]. https://www. novartis. com/news/mediareleases/novartis-car-t-cell-therapy-ct1019-receives-fdabreakthrough-therapy-designation.
[3] ALTHOFF E, PHILLIPS F. Novartis CAR-T cell therapy CTL019 unanimously(10-0)recommended for approval by FDA advisory committee to treat pediatric, young adult r/r B-cell ALL[EB/OL].[2018-08-21]. https://www.novartis. com/news/media-releases/novartis-car-t-celltherapy-ct1019-unanimously-10-0-recommended-approvalfda.
[4] ALTHOFF E, PHILLIPS F. Novartis receives first ever FDA approval for a CAR-T cell therapy, KymriahTM(CTL019),for children and young adults with B-cell ALL that is refractory or has relapsed at least twice[EB/OL].[2018-09-21]. https://www. novartis. com/news/media-releases/novartis-receives-first-ever-fda-approval-car-t-cell-therapykymriahtm-ct1019.
[5] KINGWELL K. CAR T therapies drive into new terrain[J]. Nat Rev Drug Discovery, 2017,16(5):301-304.
[6] URBA W J, LONGO D L. Redirecting T cells[J]. New Engl J Med, 2011, 365(8):754-757.
[7] TASIAN S K, KENDERIAN S S, Shen F, et al. Optimized depletion of chimeric antigen receptor T cells in murinexenograft models of human acute myeloid leukemia[J].Blood, 2017,129(17):2395-2407.
[8] SADELAIN M, RIVISRE I, RIDDELL S. Therapeutic T cell engineering[J]. Nature, 2017, 545(7655):423-431.
[9] WEIDEN P L, SULLIVAN K M, FLOURNOY N, et al.Antileukemic effect of chronic graft-versus-host disease:contribution to improved survival after allogeneic marrow transplantation[J]. New Engl J Med, 1981, 304(25):1529-1533.
[10] GROSS G,WAKS T, ESHHAR Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity[J]. Proc Natl Acad Sci U S A, 1989, 86(24):10024-10028.
[11] ROWE J M. Advances and controversies in the biology and therapy of acute leukaemia and myelodysplasia[J]. Best Pract Res Clin Haematol, 2009, 22(4):475-478.
[12] ANWER F, SHAUKAT A A, Zahid U, et al. Donor origin CAR T cells:graft versus malignancy effect without GVHD,a systematic review[J]. Immunotherapy, 2017, 9(2):123-130.
[13] US Food and Drug Administration. Cellular&Gene Therapy Guidances[EB/OL].[2018-08-21]. https://www. fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulator yInformation/Guidances/CellularandGeneTherapy/default.htm.
[14] European Medicines Agency. Advanced therapy medicinal products', European Medicines Agency[EB/OL]. http://www. ema. europa. eu/ema/index. jsp?curl=pages/regulation/general/general_content_000294. jsp.
[15] CASUCCI M, BONDANZA A. Suicide gene therapy to increase the safety of chimeric antigen receptor-redirected T lymphocytes[J]. J Cancer, 2011, 2:378-382.
[16] JIN C, FOTAKI G, RAMACHANDRAN M, et al. Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer[J]. EMBO Mol Med, 2016,8(7):702-711.
[17] MULLIN T M. China Joins ICH in Pursuit of Global Harmonization of Drug Development Standards[EB/OL].https://blogs. fda. gov/fdavoice/index. php/2017/08/china-joins-ich-in-pursuit-of-global-harmonization-of-drugdevelopment-standards.
[18]李建平,王冲,于玲莉,等.关于自体CAR-T细胞制品药学部分申报资料的共识性建议[J].中国医药工业杂志,2018, 49(2):248-256.
[19]国家食品药品监督管理总局.药品注册管理办法[EB/OL].[2008-07-10]. http://samr.cfda.gov.cn/WS01/CL0053/24529.html.
[2] ALTHOFF E, YANCOSEK R. Novartis CAR-T cell therapy CTL019 receives FDA breakthrough therapy designation for treatment of adult patients with r/r DLBCL[EB/OL].[2018-08-21]. https://www. novartis. com/news/mediareleases/novartis-car-t-cell-therapy-ct1019-receives-fdabreakthrough-therapy-designation.
[3] ALTHOFF E, PHILLIPS F. Novartis CAR-T cell therapy CTL019 unanimously(10-0)recommended for approval by FDA advisory committee to treat pediatric, young adult r/r B-cell ALL[EB/OL].[2018-08-21]. https://www.novartis. com/news/media-releases/novartis-car-t-celltherapy-ct1019-unanimously-10-0-recommended-approvalfda.
[4] ALTHOFF E, PHILLIPS F. Novartis receives first ever FDA approval for a CAR-T cell therapy, KymriahTM(CTL019),for children and young adults with B-cell ALL that is refractory or has relapsed at least twice[EB/OL].[2018-09-21]. https://www. novartis. com/news/media-releases/novartis-receives-first-ever-fda-approval-car-t-cell-therapykymriahtm-ct1019.
[5] KINGWELL K. CAR T therapies drive into new terrain[J]. Nat Rev Drug Discovery, 2017,16(5):301-304.
[6] URBA W J, LONGO D L. Redirecting T cells[J]. New Engl J Med, 2011, 365(8):754-757.
[7] TASIAN S K, KENDERIAN S S, Shen F, et al. Optimized depletion of chimeric antigen receptor T cells in murinexenograft models of human acute myeloid leukemia[J].Blood, 2017,129(17):2395-2407.
[8] SADELAIN M, RIVISRE I, RIDDELL S. Therapeutic T cell engineering[J]. Nature, 2017, 545(7655):423-431.
[9] WEIDEN P L, SULLIVAN K M, FLOURNOY N, et al.Antileukemic effect of chronic graft-versus-host disease:contribution to improved survival after allogeneic marrow transplantation[J]. New Engl J Med, 1981, 304(25):1529-1533.
[10] GROSS G,WAKS T, ESHHAR Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity[J]. Proc Natl Acad Sci U S A, 1989, 86(24):10024-10028.
[11] ROWE J M. Advances and controversies in the biology and therapy of acute leukaemia and myelodysplasia[J]. Best Pract Res Clin Haematol, 2009, 22(4):475-478.
[12] ANWER F, SHAUKAT A A, Zahid U, et al. Donor origin CAR T cells:graft versus malignancy effect without GVHD,a systematic review[J]. Immunotherapy, 2017, 9(2):123-130.
[13] US Food and Drug Administration. Cellular&Gene Therapy Guidances[EB/OL].[2018-08-21]. https://www. fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulator yInformation/Guidances/CellularandGeneTherapy/default.htm.
[14] European Medicines Agency. Advanced therapy medicinal products', European Medicines Agency[EB/OL]. http://www. ema. europa. eu/ema/index. jsp?curl=pages/regulation/general/general_content_000294. jsp.
[15] CASUCCI M, BONDANZA A. Suicide gene therapy to increase the safety of chimeric antigen receptor-redirected T lymphocytes[J]. J Cancer, 2011, 2:378-382.
[16] JIN C, FOTAKI G, RAMACHANDRAN M, et al. Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer[J]. EMBO Mol Med, 2016,8(7):702-711.
[17] MULLIN T M. China Joins ICH in Pursuit of Global Harmonization of Drug Development Standards[EB/OL].https://blogs. fda. gov/fdavoice/index. php/2017/08/china-joins-ich-in-pursuit-of-global-harmonization-of-drugdevelopment-standards.
[18]李建平,王冲,于玲莉,等.关于自体CAR-T细胞制品药学部分申报资料的共识性建议[J].中国医药工业杂志,2018, 49(2):248-256.
[19]国家食品药品监督管理总局.药品注册管理办法[EB/OL].[2008-07-10]. http://samr.cfda.gov.cn/WS01/CL0053/24529.html.