What is the Investigator Site File?
In relation to clinical studies, the terms “Trial Master File” (TMF) and Investigator Site File (ISF) are commonly used and presumed to be entirely different things: however, the TMF and ISF are in essence two sides of the same coin. No regulations refer to ISFs although two guidance documents do:
- the EMA “Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials”, which notes in Section 3.1 that “The TMF is usually composed of a sponsor TMF, held by the sponsor organisation, and an investigator TMF held by the investigator(s). The investigator TMF is often referred to as the Investigator Site File (ISF) or Site Master File (SMF); and
- The MHRA Good Clinical Practice Guide which states in Section 10.2.1 “The TMF is normally composed of a sponsor file, held by the sponsor organisation, and an investigator site file, held by the investigator. Are regarded as comprising the entire TMF for the trial”.
The ISF is then a component of the TMF, not distinct from it. Only in combination do the TMF and ISF “individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced, demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements” [ICH GCP Sec 8.1]. In order to be complete then, the entire TMF must include an ISF for each site involved in the trial.
What differentiates the TMF and ISF?
If the entire TMF provides a record of the conduct of the entire trial, the ISF is a record of the conduct of the trial at each trial site. Where the sponsor is responsible for the content of the sponsor TMF, responsibility for the ISF resides with the Principal Investigator. Regulations require segregation of many documents that that are generated or held by the investigator. This includes records such as
- informed consent forms and subject identification lists, the sharing of which may breach patient confidentiality; and
- records containing source data such as case report forms, which would remove the investigators control over these data and could potentially lead to uncontrolled and unauthorised edits being made by the sponsor.
The only exception to the segregation requirement is for studies sponsored by NHS Trusts or Universities, in which the Chief Investigator is employed by the sponsor. In these circumstances, it is acceptable for management of the combined sponsor and investigator TMF to be delegated to the Chief Investigator who will maintain all necessary documents.
It should be noted that the investigator must retain control of the ISF at all times, even at the point of archiving [MHRA GCP Guide 10.7.6.]
What do the TMF and ISF have in common?
Although the content of the TMF and ISF will differ, a large proportion of the documentation required for (and generated throughout the conduct of) a clinical trial will be held in common by the sponsor and investigator. The TMF Reference Model helpfully identifies which elements of the TMF are the responsibility of the sponsor and which the responsibility of the investigator, highlighting those documents that are common to both and may therefore be shared. The sponsor and investigator should identify and agree responsibility for the creation, maintenance, and retention of TMF / ISF documentation ideally prior to the commencement of clinical trial activities recognising (where possible) the opportunities presented by the use of a TMF technologies to improve data integrity, facilitate real-time communication, streamline operations, and enhance collaboration.
Archiving the ISF
The same requirements and guidelines are applicable for ISF and Sponsor TMF. Both the TMF and ISF should be retained for a minimum of 25 years from the date of the end of the trial in accordance with the requirement laid down in Article 58 of Regulation (EU) 536/2014.
There should be a contractual agreement between investigator and sponsor describing responsibilities of each regarding the archiving of the ISF. It is important to remember that the segregation requirements that apply “live” ISF documents (see above) also apply throughout the period of archiving.
If the archiving of the ISF is outsourced, ultimate responsibility for ensuring compliant storage, for preserving the quality, integrity, confidentiality of the archived ISF data and documents resides with the investigator, who should maintain an inventory of all clinical trials data and documents archived. The inventory should be sufficiently detailed to ensure that the content is readily available upon request.
Source data and documents relevant to the ISF may be collected and recorded as in an individual patient’s medical files (e.g. medical health data) and as a consequence may be retained separately; these data should be archived in accordance with local regulations.
Although the ISF is frequently regarded as being independent of the TMF, many documents in both are shared and (even where there are differences) both contain data and documents that provide evidence necessary to evaluate the conduct of a trial, the quality of the data produced, confirm a focus on patient safety, and prove compliance with GCP standards.
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