An investigator site file (ISF) is the set of essential records a trial site holds to show how the trial was run. ICH-GCP E6(R3) Appendix C defines that set. The file covers approvals, agreements, staff qualifications, consent, safety reports and accountability records, kept current from set-up through to archive.
The investigator holds the site copy of those records, on paper or in an electronic Investigator Site File (eISF). The sections below set out the full investigator site file index by document type, the investigator site file requirements under ICH-GCP, and what investigator site file maintenance involves once the study is open.
The list originates in Section 8 of ICH-GCP E6(R2), which grouped essential documents into three phases: before the trial begins, during the trial, and after it completes. It is the single most predictable thing an inspector asks to see, which is exactly why a site should be able to produce any item on demand, not reconstruct it before a visit.
- Essential documents fall into three phases: before, during, and after the trial.
- The investigator holds the site copy in the eISF; the sponsor holds its copy in the Trial Master File.
- ICH-GCP E6(R3) renames “essential documents” to “essential records” and moves to a risk-based approach rather than a fixed list.
- A checklist proves a document is present; it does not prove it is current or complete. Those are separate, ongoing checks.
What is an ISF in clinical research?
An ISF in research is the site’s own file of essential records for one study. It is the investigator’s counterpart to the sponsor’s Trial Master File. The two files hold overlapping records for different purposes: the sponsor evidences oversight of the whole trial, and the site evidences conduct at that location.
- Scope: one file per study, per site. A site running six studies maintains six files.
- Owner: the investigator, under ICH-GCP E6(R3) section 2.12.11, which places control of the essential records the site generates with the investigator and institution.
- Format: paper, electronic, or both. The format does not change the record set.
- Audience: monitors, auditors, the ethics committee and regulatory inspectors, who have direct access on request under section 2.12.14.
What are the essential documents in a clinical trial?
Essential documents are the evidence base of the trial. If the trial were questioned by a monitor, an auditor, or a regulatory inspector, these are the records that answer the question. ICH-GCP defines them as the documents that permit evaluation of both the conduct of the trial and the quality of the data produced.
They are not filed for their own sake. Each one demonstrates that the investigator and sponsor complied with GCP and the applicable regulatory requirements at the point the activity happened. A trial is only as defensible as the records that survive it.
Before the trial: the documents to have in place
These are collected during study set-up, before the first participant is enrolled. Most are approvals and agreements: the authority to run the trial at all.
| Document | What it evidences |
|---|---|
| Investigator’s Brochure | The investigator had current safety and efficacy information. |
| Signed protocol, amendments & sample CRF | Agreement on how the trial would be conducted and recorded. |
| Ethics committee (IRB/IEC) approval | Independent ethical review before enrolment. |
| Regulatory authority authorisation | The trial was approved by the competent authority (e.g. MHRA). |
| Approved consent form & participant information | The exact wording participants were consented against. |
| Investigator CVs & financial disclosure | The site team was qualified; conflicts were declared. |
| Lab certification & normal ranges | Test results could be interpreted against validated references. |
| Signed agreements & insurance | Responsibilities and indemnity were defined up front. |
During the trial: the documents that accumulate
These build continuously as the trial runs. This is where filing discipline slips first, because the volume is highest and the work is busiest.
| Document | What it evidences |
|---|---|
| Signed consent forms | Every participant consented before any trial procedure. |
| Delegation of authority log | Each task was performed by an authorised, trained person. |
| Monitoring visit reports & follow-up | The sponsor oversaw conduct and issues were resolved. |
| Updated approvals & amendments | Changes were approved before they took effect. |
| Source documents & signed CRFs | Data was recorded, attributable, and traceable to source. |
| Safety reports (SAEs / SUSARs) | Safety events were reported and handled correctly. |
| Screening, enrolment & ID logs | Participant accountability across the trial. |
The delegation of authority log deserves particular attention: it is checked at almost every inspection, and a task performed before its effective date is a finding regardless of a later signature.
After the trial: close-out and archive
| Document | What it evidences |
|---|---|
| IP accountability & destruction records | Investigational product was reconciled and disposed of correctly. |
| Completed participant ID code list | Final participant accountability, retained securely. |
| Final close-out monitoring report | The site was formally closed by the sponsor. |
| Treatment allocation & decoding records | Blinding and randomisation were handled correctly. |
| Final report to ethics / authority | The trial’s end was reported as required. |
After close-out, the file is archived and must remain readable and retrievable for the full retention period, which in the UK is at least 25 years.
The investigator site file index, section by section
The phase view answers when a record arrives. A site also needs the document-type view, because that is how the file is actually structured and how an inspector navigates it. The investigator site file index below groups the same records into twelve sections. Each row names the records to file and where ICH-GCP E6(R3) places them.
| ISF section | Records to file | E6(R3) reference |
|---|---|---|
| 1. Protocol and amendments | Signed current protocol, every approved amendment, superseded versions marked as such, sample case report form. | Appendix C |
| 2. Product information | Investigator’s Brochure and its updates, or the summary of product characteristics where one applies. | Appendix C |
| 3. Approvals and authorisations | Ethics committee favourable opinion, committee membership or constitution, regulatory authorisation, amendment approvals. | Appendix C |
| 4. Agreements and insurance | Clinical trial agreement, confidentiality agreement, financial agreement, insurance or indemnity certificate. | Appendix C |
| 5. Staff and delegation | Signed and dated CVs, GCP and protocol training records, the delegation of authority log, signature and initials log. | Appendix C |
| 6. Participant documentation | Approved participant information sheet and consent form by version, signed consent forms, screening log, enrolment log, participant identification code list. | Appendix C |
| 7. Source data and CRFs | Source documents, the source data location agreement, completed and signed case report forms, data queries and their resolution. | Section 2.12.2 |
| 8. Safety reporting | Serious adverse event reports, SUSAR notifications, safety letters from the sponsor, evidence the site acted on each one. | Appendix C |
| 9. Laboratory and technical | Laboratory accreditation or certification, normal ranges by version, equipment calibration and maintenance records. | Appendix C |
| 10. IMP and accountability | Shipment and receipt records, the accountability log, temperature records, returns, reconciliation and destruction records. | Appendix C |
| 11. Oversight and correspondence | Monitoring visit reports and follow-up letters, audit certificates, deviation log, note-to-file register, study correspondence. | Appendix C |
| 12. Close-out and archive | Final close-out report, treatment allocation and decoding records, end-of-trial notifications, the archive index and retention record. | Sections 2.12.12, 3.16.3 |
Section numbering is a local decision. A consistent index across every study in a portfolio is worth more than any particular numbering scheme, because it lets a monitor or inspector find the same record in the same place at every site.
Keeping this index complete by hand, across every study, is where most site files fall behind. See how AQ eISF keeps every essential document filed against it, or book a 30-minute demo on a live study.
What are the investigator site file requirements under ICH-GCP?
The investigator site file requirements sit in the investigator records duties of ICH-GCP E6(R3), adopted at Step 4 on 6 January 2025. Five duties shape how the file is built and kept.
- Keep the defined set: file the trial records specified in Appendix C and in the applicable regulatory requirements (section 2.12.11).
- Keep source records sound: source records should be attributable, legible, contemporaneous, original, accurate and complete (section 2.12.2).
- Retain for the full period: retain essential records for the required period, or until the sponsor confirms they are no longer needed, whichever is longer (section 2.12.12).
- Name the custodian: tell the sponsor who is responsible for the records, including where a site closes or the investigator leaves (section 2.12.13).
- Allow direct access: make records available on request to monitors, auditors, the ethics committee and regulators (section 2.12.14).
Compliance with the ICH E6 GCP principles became a legal requirement in the UK on 28 April 2026 under Regulation 28 of the amended UK Clinical Trials Regulations, as MHRA guidance of 28 April 2026 sets out. An ISF checklist in an NHS trust therefore has to satisfy ICH-GCP, the UK regulations, and the trust’s own record-keeping and information governance policies at the same time.
How is an investigator site file maintained?
Investigator site file maintenance is a running task, not a set-up task. A file is built once and maintained for the life of the study plus the retention period. Four routines carry most of the load.
| Routine | Frequency | What it protects |
|---|---|---|
| File on receipt | Same week the record is created or received | Contemporaneous filing, which is what section 2.12.2 asks of source records. |
| Supersede on amendment | Every approval or version change | The current version is the filed version, and the superseded one is marked rather than discarded. |
| Reconcile against the index | Monthly, and before every monitoring visit | Gaps surface as operational work instead of inspection findings. |
| Review delegation and training | On every team change | Each task was performed by an authorised, trained person on the date it happened. |
Close-out moves the file to archive. It must stay readable and retrievable for the whole retention period, which is where a format decision taken at set-up has consequences 20 years later. A file that cannot be read is a file that was never kept.
Also Read: eISF vs Paper Site Files and CTMS vs eTMF vs EDC vs eISF: Which System Do You Actually Need?
What changes under ICH-GCP E6(R3)?
The 2025 revision, ICH-GCP E6(R3), changes the language and the philosophy. “Essential documents” becomes “essential records“, reflecting that evidence is increasingly data rather than paper. The prescriptive Section 8 list moves to Appendix C, titled Essential Records for the Conduct of a Clinical Trial, which covers an introduction, the management of essential records and the essentiality of trial records. The emphasis shifts to a risk-based approach: teams determine which records are essential for their specific trial rather than filing against one fixed checklist.
The checklist in this guide remains the right starting point. The core records are unchanged. What E6(R3) asks is that you justify the set for your trial, keep it current, and treat completeness as an ongoing judgement, not a one-off tick-box. The principle reflected in MHRA good clinical practice inspections guidance, updated 22 September 2026, is the same: the file must let someone reconstruct the trial.
Why does a checklist alone not make a file inspection-ready?
A checklist answers one question: is the document present? An inspection asks three:
- Complete: is every expected record actually there?
- Current: is the filed version the right one (the current protocol, not a superseded amendment)?
- Timely: was it filed close to when it was created, not reconstructed the week before the visit?
A ticked box can hide a superseded version, a missing signature, or a document filed six months late. This is the gap between a file that looks complete and one that is genuinely inspection-ready.
How does AQ eISF keep essential documents complete?
The AQ eISF starts each study from an expected-document list built on the ICH-GCP essential set, structured to mirror the sponsor’s Trial Master File. Filed, missing, and expected records are visible against that list in real time, so a gap surfaces in daily operations rather than during inspection preparation.
Version control keeps the current record current; the audit trail records who filed what and when, which is where timeliness is proven. The system tracks presence, version, and completeness. Confirming a record is genuinely the right one remains a human review. The eISF makes that review fast and evidenced rather than a manual reconstruction.
Frequently Asked Questions
What documents go in an investigator site file?
An investigator site file holds the essential records listed in ICH-GCP E6(R3) Appendix C. These include the protocol and amendments, the Investigator’s Brochure, ethics and regulatory approvals, the approved consent documents, staff CVs and training records, the delegation log, signed consent forms, source documents, safety reports, IMP accountability records and the close-out and archive records.
What should an ISF checklist include?
An ISF checklist should list every record the trial expects, grouped by document type, with the holder of each one and the point in the trial at which it is due. A usable checklist also records the filed version and the filing date, because presence alone does not show that the record is current or that it was filed contemporaneously.
What are essential records under ICH E6(R3)?
ICH-GCP E6(R3) replaces the term essential documents with essential records, and describes them in Appendix C, Essential Records for the Conduct of a Clinical Trial. Appendix C covers the introduction, the management of essential records and the essentiality of trial records. The set is justified for each trial rather than filed against one fixed list.
Who is responsible for maintaining the ISF?
The investigator holds responsibility for the site’s essential records. ICH-GCP E6(R3) section 2.12.11 places control of the essential records the site generates with the investigator and institution, and section 2.12.13 requires the sponsor to be told who keeps those records if the site closes or the investigator leaves. Day to day filing is usually delegated through the delegation log.
Read also: What is eISF: Electronic Investigator Site File in Clinical Research, The CDISC TMF Reference Model: A Practical Guide to the 11 Zones, and Clinical Research Audits: Types, Process, Checklist and Audit Readiness.
Book a live demo to see how AQ tracks the essential documents against a defined expected set across every site.
