首个国产 IL-4R 单抗获批上市、FDA警告信！这次是中国两家检测CRO

首个国产 IL-4R 单抗获批上市

9月 12 日，NMPA 官网显示，康诺亚司普奇拜单抗获批上市，用于治疗外用药控制不佳或不适合外用药治疗的成人中重度特应性皮炎（受理号：CXSS2300090）。这是国产首款获批的 IL-4R 抗体药物，也是全球第二款。

图片来源：NMPA 官网

司普奇拜单抗注射液用于治疗外用药控制不佳或不适合外用药治疗的成人中重度特应性皮炎。司普奇拜单抗注射液是以IL-4Rα为靶点的单克隆抗体药物，通过阻断IL-4和IL-13与IL-4Rα受体的结合，抑制IL-4和IL-13引起的下游炎症因子的释放、蛋白表达及炎症细胞活性，治疗炎症反应过度诱发的特应性皮炎。该品种的上市为中重度特应性皮炎成人患者提供了新的治疗选择

2021 年 3 月，石药集团与康诺亚达成合作，获得司普奇拜单抗在内的中国地区（不包括港澳台）针对中重度哮喘和慢性阻塞性肺病等呼吸系统疾病进行开发和商业化的权益，并成为上市许可持有人（MAH），该交易首付款 7000 万元，里程碑付款高达 1 亿元，后续还有望获得销售里程碑款和销售提成。

中重度特应性皮炎（AD）通常在复发和缓解之间波动，患者需进行长期治疗。作为一种靶向白介素-4受体α的人源单克隆抗体，司普奇拜单抗（stapokibart/CM310）在一项为期16周的研究中已显示出对中重度AD患者的潜在疗效。为评估司普奇拜单抗对中重度AD成人患者的长期疗效和安全性，中国学者报告了多中心、非随机、开放标签扩展2期CM310AD100临床研究52周的疗效和安全性结果，原文发表在BioDrugs期刊上。

该研究纳入127例接受司普奇拜单抗治疗的中国AD患者，第1天接受司普奇拜单抗600 mg（负荷剂量），随后接受司普奇拜单抗300 mg（每2周1次），皮下注射给药至第52周，治疗结束后进行8周安全性随访。允许同时使用外用糖皮质激素和/或外用钙调磷酸酶抑制剂。疗效终点包括第52周达到湿疹面积和严重程度指数（EASI）较基线改善75%/90%/100%（EASI 75/90/100）、研究者整体评估（IGA）0/1且降低≥2分，以及每日瘙痒峰值数值评定量表（PP-NRS）的周平均值较基线改善≥3分和≥4分的患者比例，等。

结果显示，第52周，达到EASI 75/90/100和达到IGA 0/1且评分降低≥2分的患者比例分别为96.3%/87.9%/71.0%和58.9%，此外，PP-NRS的周平均值较基线改善≥3分和≥4分的患者比例分别为80.2%和62.2%。在52周治疗期间，患者的生活质量持续改善。最常见的治疗期不良事件包括：（疑似）新型冠状病毒感染（COVID-19）、上呼吸道感染、结膜炎和泌尿道感染，且大部分为轻症。

FDA警告信！这次是中国两家检测CRO

9月11日FDA网站公布，向两家中国公司就数据质量等问题发送警告信。这两家公司是天津海河生物医药科技集团（Mid-Link Testing Company Ltd.）和苏州大学卫生与环境技术研究所（Sanitation & Environmental Technology Institute of Soochow University Ltd.）。两家公司作为第三方检测平台，为医疗器械生产商提供非临床检测和数据验证服务。

中国天津海河生物医药科技集团旗下的海河标测（Mid-Link Testing Company Ltd.）和苏州大学有限公司的卫生与环境技术研究所收到了警告信。这些公司向器械制造商提供第三方测试和验证，用于他们向 FDA 提交的医疗器械上市前申报。

这两家实验室都在国内医疗器械行业经营有年，国际注册在业务中占有大量比重，以前的口碑也不错，属于国内一线实验室。

FDA 将继续对这两家测试机构生成的，器械制造商提交的数据进行最严格审查。如果发现这些数据不可靠，FDA不会批准制造商提交的上市申请，上海曼度消息，FDA也正在评估这些调查结果对过去提交的，已经批准的申报的任何影响，并可能在必要时采取行动解决任何公共卫生风险。

天津海河标测技术检测有限公司

1. The study director failed to assure that all experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified, and unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented [21 CFR 58.33(b) and 58.33(c)].

研究负责人未能确保准确记录和验证所有实验数据，包括对测试系统意外反应的观察，并在可能影响非临床实验室研究的质量和完整性的意外情况发生时进行记录，并采取和记录纠正措施（参考法规：[21 CFR 58.33(b)和58.33(c)]）。

2. Failure to conduct nonclinical laboratory studies in accordance with the protocols [21 CFR 58.130(a)].

未能按照方案进行非临床实验室研究（参考法规：[21 CFR 58.130(a)]）。

3. Failure of a testing facility to have standard operating procedures in writing setting forth nonclinical laboratory study methods that management is satisfied are adequate to ensure the quality and integrity of the data generated in the course of a study. The study director failed to authorize all deviations in the study from standard operating procedures and ensure the deviations were documented in the raw data [21 CFR 58.81(a)].

测试机构未能以书面形式制定标准操作程序，以制定出管理层认为足够确保在研究过程中生成的数据质量和完整性的非临床实验室研究方法。研究负责人未能批准研究中与标准操作程序的所有偏差，也未能确保偏差记录在原始数据中（参考法规：[21 CFR 58.81(a)]）。

4. Testing Facility Management failed to ensure that personnel clearly understand the functions they are to perform [21 CFR 58.31(f)].

测试设施管理未能确保人员清楚地了解他们要履行的职能（参考法规： [21 CFR 58.31(f)]）。

5. Failure of the Quality Assurance Unit (QAU) to fulfill responsibilities [21 CFR 58.35(a),58.35(b)(1), 58.35(b)(5), and 58.35(b)(6)].

质量保证部门(QAU)未能履行职责（参考法规：[21 CFR 58.35(a)、58.35(b)(1),、58.35(b)(5)和58.35(b)(6)]）。

6. Failure to ensure that warm-blooded animals shall receive appropriate identification where all information needed to specifically identify each animal within an animal-housing unit appears on the outside of that unit [21 CFR Part 58.90(d)].

未能确保恒温动物获得适当的标识，所有需要用于特定识别每只动物的信息应显示在该动物饲养单元的外部（参考法规： [21 CFR Part 58.90(d)]）。

苏州苏大卫生与环境技术研究所有限公司

1. The study director failed to assure that (1) the protocol, including any change, is approved as provided by § 58.120 and is followed; (2) all experimental data, including observations of unanticipated responses of the test system were accurately recorded and verified; (3) unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study were noted when they occurred, and corrective action was taken and documented; and (4) all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the study; (5) all applicable good laboratory practice regulations are followed. [21 CFR 58.33(a), (b), (c), (e) and (f)].

研究负责人未能确保(1)方案(包括任何变更)按照58.120的规定获得批准并得到遵守；(2)所有实验数据，包括对测试系统的非预期反应的观察，都被准确地记录和验证；(3)当可能影响非临床实验室研究的质量和完整性的不可预见的情况发生时，应予以记录，并采取纠正措施和记录；以及(4)在研究期间或研究结束时，所有原始数据、文件、协议、标本和最终报告都被转移到档案馆；(5)遵守所有适用的良好实验室规范。（参考法规：[21 CFR 58.33(a), (b), (c), (e) and (f)）。

2. Testing facility management failed to assure that there was a quality assurance unit as described in 21 CFR 58.35 and failed to assure that any deviations from these regulations reported by the quality assurance unit are communicated to the study director and corrective actions are taken and documented. [21 CFR Part 58.31(c), and 58.31(g)].

测试机构管理层未能确保存在21 CFR 58.35中所述的质量保证部门，也未能确保质量保证部门报告的与这些规定的任何偏差传达给研究负责人，并采取和记录纠正措施。（参考法规：[21 CFR Part 58.31(c), and 58.31(g)]）。

3. Failure of the Quality Assurance Unit (QAU) to fulfill responsibilities [21 CFR 58.35(b)(5), 58.35(b)(6), and 58.35(b)(3)].

质量保证部门(QAU)未能履行职责（参考法规：[21 CFR 58.35(b)(5), 58.35(b)(6), and 58.35(b)(3)]）。

4. Failure to ensure that each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study have the education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions [21 CFR Part 58.29(a)(b)].

未能确保参与进行非临床实验室研究或负责监督非临床实验室研究的每个人都具有教育、培训和经验，或这些方面的组合，以使该人能够履行指定的职能（参考法规：[21 CFR Part 58.29(a)(b)]）。

5. Failure of the testing facility to have standard operating procedures in writing setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study. The study director failed to authorize all deviations in the study from standard operating procedures and ensure the deviations were documented in the raw data. The testing facility failed to establish standard operating procedures for animal room preparation, animal care, and test system observations, and failed to maintain a historical file of revisions to the standard operating procedures [21 CFR Parts 58.81(a)(b)(1-6) and (d)]; Failure to prepare a final study report that included (1) corrections or additions in the form of an amendment by the study director and (2) the name of study director, the names of other scientists or professionals, and the names of all supervisory personnel involved in the study. [21 CFR Part 58.185(a)(9),(c)].

测试机构未能以书面形式制定标准操作程序，规定管理层满意的非临床实验室研究方法，足以确保研究过程中产生的数据的质量和完整性。研究负责人未能批准研究中与标准操作程序的所有偏差，也未能确保偏差记录在原始数据中。测试机构未能建立动物室准备、动物护理和测试系统观察的标准操作程序，并且未能保留标准操作程序修订的历史文件[21 CFR第58.81(a)(b)(1-6)和(d)部分]；未能准备最终研究报告，该报告包括(1)研究负责人以修正案形式进行的更正或补充，以及(2)研究负责人的姓名、其他科学家或专业人员的姓名，以及参与研究的所有监督人员的姓名。（参考法规：[21CFR Part 58.185(a)(9),(c)]）。

6. Failure of the testing facility to ensure that all newly received animals from outside sources were isolated and their health status evaluated in accordance with acceptable veterinary medical practice. In addition, failure of the testing facility to ensure warm-blooded animals, excluding suckling rodents, used in laboratory procedures that require manipulations and observations over an extended period of time or in studies that require the animals to be removed from and returned to their home cages for any reason (e.g., cage cleaning treatment, etc.) received appropriate identification [21 CFR 58.90(b), 58.90(d)].

测试机构未能确保所有从外部来源新接收的动物被隔离，并根据可接受的兽医实践评估其健康状况。此外，试验设施未能确保温血动物(哺乳啮齿动物除外)用于需要长时间操作和观察的实验室程序，或用于需要将动物移出或放回其笼子的研究(如笼子清洁处理等)。)获得适当的身份证明（参考法规：[21 CFR 58.90(b)，58.90(d)]）。

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