在印度进行了15年的全球临床试验，教会了我们许多东西，尤其是研究文档的重要性。然而，临床试验数据记录的范围和方法的细微差别仍然让我们感到困惑。参与临床试验的研究者最常问的问题之一就是：到底需要多少文档？他们感到挫败的原因是，无论他们准备多少详细的文件，似乎也无法让监查员、稽查员和视察员满意。在有些情况下，在书面文件不足时，会要求研究者提供一份文件说明(NTF)，其中包括详细的解释。例如，Site工作人员没有按照拟定的剂量对受试者进行试验。在这种情况下，通常在主文件中会有一个NTF来解释这种偏差及其原因。A decade and a half of conducting global clinical trials in India has taught us many things, especially the importance of documentation in research. The nuances of the extent and the ways to document clinical trial data, however, continue to elude us. One of the most common questions asked by investigators participating in clinical trials is: How much documentation is enough? Their frustration has to do with the fact that no amount of detailed documentation seems to satisfy monitors, auditors and inspectors. There are several instances where, in the absence of an adequate documented explanation, the investigators are asked to generate a note to file (NTF), which contains a detailed explanation. An example would be a case where the site staff has not followed the protocol-specified investigational product dosing schedule for several subjects. In such cases, it is common to see an NTF in the site master file explaining this deviation and the reason for the same.
最初，当中心和监查团队无法找到合适的地方来记录某些问题时，开始使用NTF来记录异常过程。然而现在，参与试验的人员很少甚至根本不会考虑是否可以在其他地方记录问题，而是毫不迟疑地写一个NTF，记录从普通逻辑问题到严重不合规问题的所有内容。Initially, this practice of using NTFs to document deviant processes began when the site team and the monitoring team could not find an appropriate place to document certain issues. However, nowadays, little or no effort goes into even considering whether issues can be documented elsewhere and NTFs are generated, without batting an eyelid, to document everything ranging from banal logistic issues to those of serious non-compliance.
NTF的使用与误用
NTF的过多使用并不是一种可取的做法，没有任何指南中提到了它的用法。有一种可能性是，它的使用更多的是对于完成指南要求的一种解决方案，而不是指南中提供的指示。NTF在临床试验指导文件中合规的使用方式如以下案例：一家正在进行Ⅲ期试验的中型制药公司决定不发布研究人员手册(IB)的年度修订版，因为几乎没有新的安全数据值得发布新版本的IB。他们的解决方案是以临床研究医生签署的NTF文件的形式记录下这一决定，并与研究团队的所有成员以及所有从事该试验的研究人员共享。The indication that the excessive use of NTFs is not a desirable practice should come from the fact that no guidelines mention their usage. One possibility is that their usage is more a solution to comply with guidelines rather than instructions given in the guidelines. An acceptable use of an NTF in clinical trial conduct documentation would be as seen in the following example. A mid-sized pharmaceutical conducting a late Phase 3 clinical trial decides not to release an annual revision of the Investigators’ Brochure (IB) as there are very little new safety data to merit a new IB version. Their solution is to document this decision in the form of an NTF signed by the study clinician and share it with all members of the study team and all investigators working on trials with that molecule.
一般来说，NTF在以下情况下适用：
记录TMF或ISF中文件丢失、延误或错误的原因；To document the reason for missing, delayed or erroneous documents in the clinical trial master file or in the site master file.
解释与方案内容不同的偏差或研究者的临时操作；To explain protocol deviations or investigator site practices that are different from the norm or from what is prescribed in the protocol.
在审查TMF时，常常会有一种不常用的方法，即将NTF用于记录某些TMF不适用的部分。例如，对于正在进行的研究，TMF会包含一些不适用的部分，添加NTF来说明本部分不适用是一种常见的做法。但是，如果文件特定部分的内容放在单独的文件中，则应通过该部分的NTF来说明这一点，这是适当并推荐的做法。During the review of trial master files, one often comes across an additional way that NTFs are used to document that certain sections of the files are not applicable. For example, for an ongoing study, the file will contain a section for the clinical study report, which is expected to be blank; however, it is a common but unnecessary practice to place a file note stating that this section is not applicable. It is, however, acceptable and recommended that if contents of a particular section of the file are placed in a separate file, this should be indicated via a file note in that section.
对NTF最常见的误用方法之一是使用它来替代源文档。当中心工作人员在各自的源文件或医疗记录中遗漏了有关受试者试验行为的基本信息时，就会发生这种情况。当源文件需要进一步阐明时，甚至会发生这种情况，所有附加的资料和说明都记录在NTF上，而不是直接输入源文件或在监查报告中加以解释。例如，如果中心工作人员在每次访问一个或多个受试者后都没有记录药物数量，则将所有这些受试者的药物数量汇总并输入一个NTF中，并该NTF保存在中心主文件中。One of the most common ways to misuse an NTF is to use it in place of source documents. This happens when the investigator site staff misses out essential information about trial conduct for subjects in their respective source documents or medical records. It can even happen when the documentation in the source document needs further clarification. In such cases, all additional information and clarifications are documented on NTFs instead of entering them in the source documents directly or explaining them in the monitoring visit reports. For example, if the site staff omit to document the pill counts done after every visit for one or more subjects, this is tabulated and entered for all those subjects together in an NTF placed in the site master file retrospectively.
在临床试验进行的过程中，有意外偏离方案的情况出现，这是完全可以接受的，只要中心团队和监查团队意识到错误并确保不会再次出错，并不都是需要通过NTF来解释和分析的。更重要的行动项目不应该是添加NTF，而是确保所有相关人员的培训情况，并评估和沟通试验偏差对于临研团队的影响。It is perfectly acceptable that during the course of clinical trial conduct, there are accidental deviations from the protocol. These do not always need to be explained and analyzed via NTFs as long as the site team and the monitoring team realize the error and ensure that it does not get repeated. The more important action item, rather than generating NTFs, should be to ensure training of all parties involved and assessing and communicating the impact of the deviation to the clinical team.
在稽查期间，发现了一种NTF有趣的用法，即使用NTF来记录研究中心团队在协议中所犯的错误或偏差。作为惩罚，监查员要求主要研究者(PI)必须签署所有NTF，以确保此类错误不会再次发生，并证明他对这些错误负有责任。An interesting viewpoint for the use of NTFs to document site errors or deviations in the protocol made by the investigator site team surfaced during an investigator site audit. The monitor would insist that the Principal Investigator (PI) must sign all NTFs as a punitive action so that such errors do not occur again and to document that he was taking responsibility for these errors.
Jesse
临研圈签约内容合作
某知名外资CRO公司PM
拥有3年药物临床试验项目管理经验
话题：你认为NTF滥用，背后根源是什么？
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