FDA给SEMLER的483表

近日，EMA发布了受到SEMLER检查发现问题影响（FDA、欧盟检查和WHO检查）的MA清单。这些MA由于其临床数据在SEMLER获得，因此受到质疑。以下是该公司在FDA检查后收到的483表内容，其扫描原件被公布在EMA官网上，登录EMA官网即可下载。

检查日期：2015年9月29日-10月9日

公司名：Semler Research Center Private Limited

地址：75A, 15th Cross, I Phase, J.P. Nagar, Bangalore-560078, Indina

Observation 1 缺陷1

During the inspection, FDA investigators found an Excel spreadsheet on Semler’s server describing the substitution of plasma samples for studies (b)(4). For example, in study （(b)(4) the spreadsheet indicates that plasma samples from subject 10 who received reference product where substituted for the plasma samples from subject 41 who received test product.

在检查期间，FDA调查员在公司的服务器上发现一个EXCEL表格，其中描述的是某试验中替代血浆样品的情况。例如，在某试验中，表格显示对象10的血浆样品是服用的对照药品，用于替代了服用受测药品的对象41的血浆样品。

Observation 2 缺陷2

Not all aqueous humor samples where accurately reported in the study report for study (b)(4). Specifically, the final report states that 19 aqueous humor samples were excluded from the PK analysis because they were contaminated with blood. However, email communications between Semler and the Sponsor in July 2012 documented that only 2 of 19 aqueous humor samples were contaminated.

在某试验的报告中，没有准确报告所有的房水样品。具体有，最终报告声称19个房水样品从PK分析中去除，因为它们被血液污染。但是，2012年7月公司和申报主的邮件沟通显示19个房水样品中只有2个样品被污染。

Observation 3 缺陷3

During the PK analysis of study (b)(4) the 3.5 hour concentration for subject 21, period 1 was switched with the 3.5 hour concentration for subject 22, period 1 without any documentation of sample mix-up. An investigation undertaken by Semler at the clinical and analytical sites did not uncover any evidence of sample mix-up.

在某试验的PK分析中，对象21号的3.5小时浓度，第1时间段被换成对象22号的3.5小时第1时间段浓度，没有任何样品混淆记录。公司对临床和分析场所的调查没有发现样品混淆的证据。

Observation 4 缺陷4

Not all study-related documentation was retained to allow reconstruction of the study. Specifically,

与试验相关的文件记录保存不全，无法保证试验的重建。具体有：

1.       The location of the plasma samples for subjects 17-32, period 1 of study (b)(4) were incorrectly recorded in the freezer log book for freezer 483.
某试验项目中受试对象17-32号第1期的血浆样品的位置，在冰柜登记本中被错误地记录为483冰柜。

2.       The calibrators and QCs used for study (b)(4) could not be reconsciled. Based on the log book for freezer 138, 110 set of calibrators were prepared on June 2, 2014 and 25 sets of calibrators remain in the freezer. However, the calibrators and QCs were unable to be located and the freezer log book was not updated.
某试验所用的校正器和QC数量不平衡。根据冰柜138号的登记本内容，在2014年6月2日准备了110套校正器，有25套校正器还放在冰棍城。但是，校正器和QC找不到，冰柜的登记本没有更新。

3.       Instrument audit trails were not captured for archived projects performed from January 2015 through May 28, 2015 for chromatographic LC/MS instruments LCMS-138, LCMS-139, and LCMS-475. For example, LCMS 139 instrument was used for analyzing samples from bioequivalence studies without any corresponding audit trail testing information.
仪器审计追踪没有捕捉2015年1月至2015年5月28日期间色谱LCMS-138号，139号和475号所实施的项目。例如，LCMS139号仪器被用于分析生物等效性试验的样品，但没有任何的对应的审计追踪检验信息。

4.       Not all study-related correspondences were archived with the study file to allow complete reconstruction of study activities.
与试验文件一起存档的试验相关信息交换不全，不能完整重建试验活动。

Observation 5 缺陷5

Not all raw data were maintained in the study folder. Specifically, bioanalytical data worksheets were discovered crumpled/torn in a trash pile on the floor or otherwise discarded inside the bioanalytical laboratory. Examples include the following:

在试验文件夹中保存的原始数据不全。具体是，生物分析数据工作表被发现揉皱了/撕毁扔在该楼层垃圾堆里，或者是扔在生物分析化验室内。例子包括：

1.       Sample dilution concentration sheet for (b)(4) with handwritten notes dated September 4, 2015.
某样品稀释浓度表有手写标注日期为2015年9月4日。

2.       Batch schedule for bioanalytical injection sequence for (b)(4) Batch (b)(4) dated September 23, 2015.
某批次生物分析进样序列批计划，日期为2015年9月23日。

3.       Overview-Area Table Results for (b)(4) testing for Phosphate Analysis study (b)(4) dated September 28, 2015 with the word “Determination” handwritten on the sheet.
某试验的磷酸分析检测审核区域表格结果，日期为2015年9月28日，上面有手写“检验”字样。

4.       Chromatographic sample table for sample set (b)(4) dated September 29, 2015.
某样品系列色谱样品表格，日期为2015年9月29日。

5.       Results table for study (b)(4) subject 10 dated January 26, 2015.
某试验对象第10号结果表格，日期为2015年1月26日。

Observation 6 缺陷6

Laboratory analysts had the ability to delete, copy and rename chromatographic LC/MS raw data folders and run files on the computer system connected to LC/MS instruments. Specifically,

化验室分析员可以删除、复制和重新命名色谱LC/MS原始数据文件夹，可以运行计算机系统上连接至LC/MS仪器的文件。具体有：

1.       On September 30, 2015, we observed that laboratory analysts could delete data for LCMS 241 instrument that was being used to test samples for bioequivalence studies including (b)(4) (b)(4).
2015年9月30日，我们发现化验室分析员可以从LCMS241仪器删除数据，该仪器被用于检测生物等效性研究样品，包括某试验。

2.       Laboratory analysts had the ability to delete raw data folders and files during the time period of May 28, 2015 and September 9, 2015 on instrument LCMS 139 during the upgrade of Analyst Software System from version 1.4.1 to version 1.6.2. This LCMS 139 instrument was used during this time period to test samples for bioequivalence studies that included (b)(4).
化验室分析员可以删除LCMS139仪器上2015年5月28日至9月9日分析软件系统从1.4.1版升级至1.6.2版期间的原始数据文件夹和文件。该LCMS139仪器在此期间被用于检测生物等效性研究样品，包括某试验。

Observation 7缺陷 7

Not all data generated in the in-vitro bioanalytical laboratory are adequately recorded to prevent accidental data loss. Specifically, the continuous temperature monitoring for the laboratory orbital 37C shaker (equipment number EOS 799) used for in-vitro bioanalytical testing is recorded on an uncontrolled portable thumb drive. The electronic temperature data that is downloaded on the thumb drive can be deleted/altered.

体外生物分析化验室所产生的有些数据记录不充分，无法防止事故性数据丢失。具体有，化验室轨道摇摆机37C（仪器编号EOS799）连续温度监测用于体外生物分析检测，其数据记录在一个不受控的可移动拇指U盘中。被下载在其中的电子温度数据可以被删除/修改。

来源：http://zhuyujiao1972.blog.163.com/blog/static/98694727201677114521735/