Investigator Site File (ISF)

Investigator Site File (ISF) is the site-level counterpart to the Trial Master File (TMF): the organized collection of essential documents that a specific clinical trial site — not the sponsor or CRO centrally — is responsible for creating, collecting, and maintaining throughout a study. Where the sponsor’s TMF is the trial-wide record, the ISF is that same essential-documents logic applied locally, scoped to what happened at one investigator site.

What Belongs in an ISF

A document collection qualifies as a compliant ISF when it demonstrates, for that specific site, everything ICH E6(R2) Section 8’s essential-documents framework requires a site to show: who was authorized to do what and when, that the site’s ethics oversight was current, that every enrolled subject consented properly, and that investigational product was accounted for. In practice this means, at minimum:

• Delegation-of-authority log — every sub-investigator, co-investigator, and Clinical Research Coordinator (CRC) the Principal Investigator has delegated trial-related duties to, with initials, dates, and the specific tasks delegated.
• Site-specific IRB/IEC documentation — the local IRB‘s initial approval letter, approved consent form version, and every subsequent continuing-review approval and correspondence, distinct from any central or sponsor-level ethics submission.
• Staff qualification records — current CVs, medical licenses, and training certificates (GCP training in particular) for every delegated staff member, kept current for as long as that person remains active on the delegation log.
• Signed informed consent documentation — the executed informed consent form for every subject enrolled at that site, including any re-consent required by protocol amendments.
• Source document templates and completed source records — the site’s own worksheets or protocol-specific source templates supporting the data later transcribed into the trial’s electronic data capture system.
• Investigational-product accountability records — receipt, dispensing, and return/destruction logs specific to that site’s supply, often maintained by the site’s research pharmacy or an equivalent delegated function.

ISF vs. TMF: Same Framework, Different Scope

The ISF is often described informally as “the site’s copy of the TMF,” which captures the shared document logic but understates the distinction. As CASRAI’s Trial Master File (TMF) entry lays out, a complete trial record requires both files, and neither substitutes for the other: the sponsor’s TMF covers the full protocol history, cross-site regulatory submissions, and every site’s approvals in aggregate; each site’s ISF covers only what is locally true at that one location. Overlap exists — a copy of the sponsor-approved protocol and investigator’s brochure typically appears in both — but most ISF content, such as the delegation log, site-specific IRB correspondence, and local staff records, has no sponsor-TMF equivalent, because it describes something only the site itself can attest to. This is also why a regulatory inspection of a specific investigator site typically begins with that site’s ISF, not the sponsor’s central file.

Who Maintains the ISF

Maintenance responsibility sits with the site, not the sponsor. In practice this work is usually done day-to-day by the site’s Clinical Research Coordinator (CRC), under the Principal Investigator’s oversight, since the PI is ultimately accountable under ICH E6(R2) Section 4 for the accuracy and completeness of the site’s records. A Clinical Research Associate (CRA) monitoring visit routinely includes an ISF review against the trial’s expected-document list, flagging missing signatures, expired training certificates, or gaps in the delegation log for the site to resolve before the next visit.

Electronic ISF (eISF)

Just as sponsors have largely moved from paper TMFs to an Electronic Trial Master File (eTMF), sites increasingly maintain an electronic ISF (eISF) — either a dedicated module within the sponsor’s eTMF platform that grants the site controlled upload access, or a separate site-level system. The same completeness-dashboard and version-control logic that makes an eTMF more auditable than banker’s-box binders applies equally at the site level, and is one reason larger, higher-volume research sites have adopted eISF tools even where a given sponsor’s own trial still runs on paper.

Why It Matters for Inspection Readiness

Because an ISF documents things only the site can attest to — who actually saw a subject, who actually obtained consent, whether staff credentials were current at the time work was delegated — gaps in it cannot be reconstructed from the sponsor’s TMF after the fact. Regulatory authorities treat ISF completeness and currency as direct inspection readiness evidence for that site, independent of how well-organized the sponsor’s own TMF is. An incomplete ISF is itself a finding, even when the underlying trial data is accurate.

Examples

• A Phase III oncology trial site’s ISF includes the fully executed delegation-of-authority log naming every sub-investigator and coordinator with their initials, dates, and delegated tasks; the local IRB’s initial approval letter and every continuing-review approval since; current CVs, medical licenses, and GCP training certificates for all delegated staff; signed consent forms for every enrolled subject; and the site’s investigational-product accountability log.
• At a site closeout visit, the monitoring CRA’s closeout report explicitly confirms the ISF has been reconciled against the trial’s expected-document list and is complete before it is archived — the same completeness check performed on the sponsor’s TMF, scoped to that one site.

Counter-Example

A binder of a site’s IRB correspondence and signed consent forms that omits the delegation-of-authority log and staff training/license records is not a complete ISF, even if every document present is individually accurate and current — it is missing categories the ICH E6(R2) essential-documents framework requires the site to maintain.

Related Terms

• Trial Master File (TMF) — the sponsor-level counterpart the ISF parallels at the site.
• Electronic Trial Master File (eTMF) — the software category an electronic ISF mirrors at site level.
• Clinical Research Coordinator (CRC) — the role that typically maintains the ISF day-to-day.
• Clinical Research Associate (CRA) — reviews the ISF against the expected-document list during monitoring visits.
• IRB (Institutional Review Board) — the source of the site-specific ethics correspondence the ISF must contain.
• Informed Consent — the signed documentation every ISF must include for each enrolled subject.
• Inspection Readiness — the compliance outcome ISF completeness directly supports.

Frequently Asked Questions

Is the ISF the same as the TMF?

No. They apply the same essential-documents logic from ICH E6(R2) Section 8, but at different scopes: the TMF is the sponsor’s trial-wide record, and the ISF is each individual site’s own record. A trial has one TMF and as many ISFs as it has participating sites, and a complete trial record requires both — neither substitutes for the other.

Who is responsible for maintaining the ISF?

The site is responsible, typically through its Clinical Research Coordinator working under the Principal Investigator’s oversight, since the PI is accountable under ICH E6(R2) for the accuracy of the site’s own records — not the sponsor or CRO, whose responsibility is the central TMF.

What documents commonly appear in both the TMF and the ISF?

Documents describing the protocol itself, such as the signed protocol, its amendments, and the investigator’s brochure, are typically filed in both. Most other ISF content — the delegation log, site-specific IRB correspondence, local staff credentials — has no TMF equivalent, because it describes something specific to that one site.

Does a regulatory inspection review the ISF or the TMF?

An inspection of a specific investigator site typically starts with that site’s ISF, since it is the direct record of what happened locally. A sponsor-level inspection or audit focuses on the TMF instead. Large trials can face both.

See also: Clinical Research Administration, the broader CASRAI cluster this term sits within.