Research Roadmap

TMF/ISF and ISSF

For transparency, traceability, and reproducability, it is mandatory to maintain proper administration of essential documents created before and during the study. According to the GCP guidelines, essential documents are those that enable the evaluation and reconstruction of the conduct of a clinical trial and the quality of the data obtained. The essential documents serve to demonstrate compliance with the protocol, GCP standards, and relevant laws and regulations, and facilitate effective monitoring and supervision.

A general procedure (GCT SOP 03 Management and archiving of essential documents) has been established in Amsterdam UMC to ensure that study documentation is managed in accordance with applicable legislation and regulations.

The terms Trial Master File (TMF) and Investigator Site File (ISF) are often used interchangeably. Generally, TMF refers to the study file located at the sponsor's site of the study, while ISF refers to the study file located at the participating center.

The base of your study file are the documents that are (to be) approved by the review committee. During the study, additional documents, such as signed informed consent forms, training logs, participant logs, and other study-related documents, are added to the TMF/ISF. These documents must be kept in their original form (i.e. hard copy with wet ink signatures) or a reference to the location of the (digital) original must be included in the TMF/ISF.

All study-related documents, including those completed and stored by different departments and/or vendors (whether electronic ore not), are part of the ISF.

Some documents may be subject to privacy legislation (GDPR/AVG) and may not be accessible to everyone. These include documents containing (personal) data that can be directly traced back to the study participant. Only the principal investigator and/or their delegate should have access to this traceable data. Therefore, such documents must be kept in a separate section of the ISF: the Investigator Subject Site File (ISSF).

Amsterdam UMC has several mandatory study file indexes sorted by the type of research. These templates offer an overview of all the documents required during your study.

Amsterdam UMC also offers the option of a digital TMF/ISF, which is highly recommended. This digital TMF/ISF is available via Research Manager (Handleiding voor onderzoekers Studymanagement module Research Manager) and is automatically generated once the study received approval from the MREC Amsterdam UMC and the Executive Board to conduct the study locally.

Study Operations Manual

While not all operational procedures and responsibilities are fully detailed in the study protocol, documenting them is a requirement for conducting medical scientific research according to GCP guidelines - ‘if it isn’t documented, it didn’t happen’.

To help researchers document relevant study procedures and responsibilities in sufficient detail (who, what and when) a template for a Study Operations Manual (SOM) is being developed. Researchers can adapt the SOM-template to fit the specific requirements and characteristics of their study.

The completed SOM serves as a concrete, practical manual for the operational procedures of the study. It helps research teams conduct the study in a clear and consistent manner, while also facilitating the transfer of tasks to other (e.g. new) team members.

Site Signature and Delegation Log

Through the site signature and delegation log, the principle investigator records the assignment of tasks and responsibilities among the members of the research team. All persons involved in a study should be listed.

Trial Participant Identification Log

Because of privacy legislation, research data may not be directly traceable to the study participant, with the exception of the data in medical records and signed informed consent forms.
All data collected during the study must be processed encrypted. The identity of the study participant can only be linked to their data through the key list, also known as the Trial participant identification log. This log links each participants' data to a study-specific number, which is used on documents such as questionnaires and the (e)CRF.

Participant Screening and Enrolment Log

The participant screening and enrolment log is a list of all potential participants in the study, both those who will and will not be included in the study. By documenting the reasons for not participating (e.g. not meeting the inclusion/exclusion criteria or not giving consent), it shows that no selection bias has occurred. Each newly screened participant should be added to the anonymous screening log.

If the participant screening and enrolment log is maintained digitally, make sure to include a printout in the TMF/ISF before the end of the study. Additionally, each participant who signed the informed consent form should be added to the study particpant identification log, with an indication whether or not they were included in the study.

Publication of study documentation in K2.iProva

Patient safety is paramount. Therefore, certain parts of the study protocol (particularly safety information, permitted and prohibited medication, medication schedules, etc.) must be readily available to staff with a treatment relationship with the patient. However, as the sponsor of a study, it is also essential to handle the disclosure of any sensitive information with care.

In case of an external sponsor, confidentiality of study information is governed by a contract between the sponsor and Amsterdam UMC or AMR BV. This creates legal restrictions on the public access of trial documentation, as the contract typically stipulates that such documentation should only be accessible to staff listed on the delegation log as part of the research team.

To ensure compliance, the use of a standard disclaimer is mandatory. Any employee who wants to upload (parts of) confidential study documentation in K2.Iprova (e.g. a protocol, manuals, patient information and consent forms) must include the standard disclaimer, either as a cover page or within the document itself. This ensures that all employees with access to K2.iProva are aware of the confidentiality requirements and consciously decide whether they have a legitimate reason for access.