Study File and essential documentation of study procedures
TMF/ISF and ISSF
A general procedure (GCT SOP 03 Magement and archiving of essential documents) has been established within Amsterdam UMC in order to ensure that study documentation will be managed according to the applicable legislation and regulations.
From the viewpoint of transparency, traceability and reproducability, it is mandatory to maintain proper administration of essential documents that are created prior to and during the investigation. Essential documents, according to the GCP guidelines, are all documents that make it possible to evaluate and reconstruct the conduct of a clinical trial and the quality of the data obtained. The essential documents serve to demonstrate compliance to the protocol, GCP and the applicable laws and regulations and allow effective monitoring and supervision.
The terms ‘trial master file’ (TMF) and ‘investigator site file’ (ISF) are often used interchangeably. As a rule, TMF refers to the study file located at the sponsor site of the study, and ISF refers to the study file located at the participating centre.
The base of your research file are the documents that are (to be) approved by the MERC. During the trial documents are added to the TMF/ISF, for example, informed consent forms, training logs, subject logs and other research-related documents. These documents must be kept in their original form (i.e. hard copy original, wet ink signed documents) or there should be a referral in the TMF/ISF to the location of the (digital) original.
All trial related documents, even if those are completed and stored by different departments and/or vendors, electronic as well, are part of the ISF.
Some documents may not be accessible to everyone under the privacy legislation (AVG). These are documents containing research data that can be directly traced back to the study subject. Only the principal investigator and/or delegate should have access to this traceable data. For this reason, these documents must be kept in a separate section, the investigator subject site file (ISSF).
Amsterdam UMC has several mandatory study file indexes sorted according to the type of research. These templates give you an overview of all the documents that you have to maintain during your research. You will find them under the tab "Documents & Templates".
At Amsterdam UMC the possibility of a digital Trial Master File is available and much recommended. This TMF is available via Research Manager (Research Manager Studymanagement module Investigator manual) and is automatically generated after an investigation has received a approval from the review committee AMC or VUmc and BoD permission has been given to conduct the investigation locally.
Study Operations Manual
The implementation phase of clinical research must comply with the applicable legislation and regulations. Not all operational procedures and responsibilities involved with a study are described in sufficient detail in the protocol. Nonetheless, this is a requirement for conducting research according to GCP guidelines as ‘if it isn’t documented, it didn’t happen’.
The template for a Study Operations Manual (SOM) was developed to help researchers document relevant study procedures and responsibilities in sufficient detail (who, what and when). The SOM template is adapted by the researcher according to study-specific requirements and characteristics.
The result is a concrete, practical manual of the operational procedures of the study. This SOM can be used to help study teams perform research in an unambiguous manner and to facilitate the transfer of tasks to other (e.g. new) members of the study team.
For an example of the SOM see the Documents section in this Research Roadmap.
If the procedures and actions that should have been performed according to the protocol are deviated, this is referred to as a protocol deviation. It is important to properly document protocol deviations and to have this report signed by the principal investigator.
If the deviations are related to missing study data or to study procedures that have not taken place, and these deviations have no impact on the subjects' safety or on the quality of the data, then the deviation can be registered in the (e)CRF and a separate log is not necessary.
Amsterdam UMC provides two templates:
The PI should also be aware of the fact that a protocol deviation where subjects' safety was possibly harmed should be reported as a (healthcare) incident via iTask. See local instructions.
Site Signature and Delegation Log
All persons involved in a study should be listed on the study delegation log. With the site signature and delegation log, the principle investigator records the division of tasks between individual members of the study team.
Trial Subject Identification Log
Data collected in the study must be processed encrypted. The identity of the study subject can only be traced through the key list; also called the trial subject identification log. This log links the data of the participating subjects to a study specific number. This number is used on, for example, questionnaires and the (e)CRF. Because of privacy legislation, research data may not be directly traceable to the study subject. Exceptions are the data in the medical records and the data on the subject identification log and signed consent forms.
Trial Subject Screening and Enrolment Log
A subject screening and enrolment log is a list of all potential subjects who will or will not participate in the study. By noting the reason that potential subjects did not participate (for example, did not meet the inclusion and exclusion criteria or did not give consent), it can be shown that no selection bias has occurred.
Each newly screened patient is added to the anonymous screening log.
If the subject screening and enrolment log is kept digitally, make sure to also have a printout in the TMF/ISF before the end of the study. Add each subject who signed the consent form to the trial subject identification log and indicate whether or not they were included.
Handling the publication of study documentation in K2 iProva
Patients’ safety is paramount. Therefore, in some situations, (parts of) the study protocol (particularly safety information, permitted and prohibited medication, medication schedules etc.) must be directly available for employees with a treatment relationship with the patient. On the other hand, as a sponsor of a clinical trial you want to handle the disclosure of any sensitive information with care and in addition, in case of an external sponsor, confidentiality of trial information has been contractually agreed between the sponsor and Amsterdam UMC or the AMR BV.
This places legal restrictions on the public access of trial documentation where the contract stipulates that this documentation is only accessible to employees who are part of the study team (mentioned by name on the delegation log of the trial).
Therefore the use of a standard disclaimer is mandatory. Any employee who wants to post (parts of) confidential trial documentation in K2.Iprova (e.g. a study protocol, manuals, patient information and consent form which are all property of the sponsor or a ‘moederprotocol’) is obliged to make use of the standard disclaimer either as a cover page or paste it in its entirety in the trial document, so that every employee with access to K2.iProva makes a conscious decision as to whether he/she has a legitimate reason for access.