作者 l 吃瓜群众
编辑 l 细胞房间
近日，朋友圈被FDA新发布的6个关于基因治疗的指南刷屏，小编也对其中的1个（
划重点了！美国FDA关于可复制逆转录病毒检测征求意见稿的解读）做了深度解读。借这个机会，小编为大家系统梳理美国FDA关于细胞和基因治疗产品的监管情况。
产品分类及监管机构
根据FDA官网的信息，细胞治疗产品包括细胞免疫治疗、肿瘤疫苗及其它用于治疗目的的自体或异体细胞（包括造血干细胞、胚胎干细胞、成体干细胞等）。人类基因治疗是指通过注射遗传物质来调控特定基因的表达水平，以达到治疗目的。
目前，细胞基因治疗产品由FDA的生物制品评估和研究中心（Center for Biologics Evaluationand Research，CBER）监管，具体负责机构是CBER下属的细胞、组织和基因治疗办公室（Office of Cellular，Tissue and Gene Therapies，OCTGT）。另外，针对这类产品有特定的专家委员会，由13位具有投票权的委员组成（包括主席），委员会成员应当是细胞、组织和基因治疗方面的专家。法规方面，和其他药品一致，依据Public Health Service Act和联邦Food Drug and Cosmetic Act这两个法案。
行业指南
自1998年发布首个细胞和基因治疗行业指南以来，FDA陆续发布了几十个指南，目前官网上显示的为30个。其中，部分指南经过更新完善，也有一些指南因不再适用而撤销。
小编对这30个指南进行初步分类，大致可以分为6类（指南列表见文末）：（1）细胞和基因治疗的一般原则。共计4个指南，涉及总则、有效性评估、动物实验和早期临床试验；（2）基因治疗。共计12个指南，在所有类别中数量最多，涉及CMC、RCR检测和受试者跟踪（这3块均含新老两个版本）、脱落研究、载体设计、环境评估及3类疾病（血友病、眼科、罕见病）；（3）细胞治疗。共计6个指南，涉及CMC、供体及4类产品（治疗类癌症疫苗、膝关节、心肌和胰岛）；（4）最小化操作细胞类产品。共计5个指南，涉及自体使用及异体使用的胎盘/脐带来源的造血干细胞；（5）再生医学疗法。共计2个指南，关于治疗严重疾病疗法的加速审评及相关医疗器械的监管；（6）治疗类蛋白的免疫原性检测。小编觉得归到这里略有不妥。
在这些指南中，最让人关注的是351和361类产品的划分，前者按药物申报，后者临床上可以直接使用。国内对干细胞疗法，一直有按药物还是医疗技术监管的争论，背景就在于此。目前，国内外一些干细胞公司给患者使用未经批准的干细胞疗法，钻的就是这个所谓的空子。其实，FDA对361类产品有严格要求，核心有三点：自体使用、未经体外培养、原位使用。前两点容易满足，最后一点往往被不正规的机构有意绕过（如脂肪组织分离的干细胞用于老年痴呆症的治疗），把干细胞包装成万能的灵丹妙药。目前，FDA正在加大对这些干细胞诊所的查处和整顿力度。351和361类产品如何划分，参照下面这张流程图便一目了然。
已上市产品
根据官网的信息，目前FDA共批准19个细胞基因治疗产品（不含批准后退市的，如FDA首个批准的自体软骨细胞产品Carticel），包括去年批准的两个CAR-T药物和1个基因治疗药物。其中，脐血来源的造血干细胞类产品（相当于国内的脐带血存储）最多，为8个。另外，Provenge是一种自体树突状细胞癌症疫苗，适应症是前列腺癌。国内的三胞集团通过收购，获得该产品，但其历史销售业绩并不理想。
小结
小编认为，FDA对细胞基因治疗类产品有一套相对完整的监管体系，并根据技术发展情况不断更新，从产品研发的各个环节给予企业指导，对于工艺成熟、风险收益比可以接受的产品则大胆批准上市，在全球走在前列，值得我国学习和借鉴。
指南列表
一般原则
1. Considerationsfor the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products; Guidance for Industry. 6/2015
2. Guidancefor Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products. 11/2013
3. Guidancefor Industry: Potency Tests for Cellular and Gene Therapy Products. 1/2011.
4. Guidancefor Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy. 3/1998
基因治疗
5. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Draft Guidance for Industry. July 2018
6. LongTerm Follow-up After Administration of Human Gene Therapy Products; Draft Guidance for Industry. July 2018
7. Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up; Draft Guidance for Industry. July 2018
8. Human Gene Therapy for Hemophilia; Draft Guidance for Industry. July 2018
9. Human Gene Therapy for Rare Diseases; Draft Guidance for Industry. July 2018
10. Human Gene Therapy for Retinal Disorders; Draft Guidance for Industry. July 2018
11. Recommendationsfor Microbial Vectors Used for Gene Therapy; Guidance for Industry. 09/2016
12. Designand Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products; Guidance for Industry. 8/2015
13. Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products; Guidance for Industry. 3/2015
14. Guidancefor FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). 4/2008
15. Guidance for Industry: Gene Therapy Clinical Trials-Observing Subjects for Delayed Adverse Events. 11/2006
16. Guidance for Industry; Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors. 11/2006
细胞治疗
17. Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs). 4/2008
18. Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products; Guidance for Industry. 8/2007
19. Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines. 10/2011.
20. Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage. 12/2011.
21. Guidance for Industry: Cellular Therapy for Cardiac Disease. 10/2010.
22. Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products. 9/2009
最小化操作类细胞产品
23. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; Guidance for Industry and Food and Drug Administration Staff. Updated: December 2017
24. Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Guidance for Industry. November 2017
25. Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-Based Products Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFRPart 1271; Guidance for Industry. 9/2017
26. Guidance for Industry: BLA for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System.3/2014.
27. INDApplications for Minimally Manipulated, Unrelated Allogeneic Placental/UmbilicalCord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System – Guidance forIndustry and FDA Staff. 3/2014.
再生医学疗法
28. Evaluationof Devices Used with Regenerative Medicine Advanced Therapies; Draft Guidancefor Industry. November 2017
29. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; Draft Guidance for Industry. November 2017
其他
30. Draft Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic Proteins. 12/2009
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