SOP-204
Essential Documents and the Investigator Site File
- Number
- SOP-204
- Category
- Start-up and Regulatory
- Edition
- Reference Edition 1.3
- Approx. pages
- 7
[YELLOW] the site fills in. [DEFAULT: green] a value the site may keep or change.
On this page
1. Purpose
This SOP describes how [SITE NAME] sets up, maintains, controls and closes the Investigator Site File (ISF) for each study, on paper or electronically, so that the site's essential records show how the study was conducted and can be produced on request to a monitor, auditor, IRB or FDA inspector. ICH E6(R3) Appendix C lists the essential records and expects them to be identifiable, version controlled where appropriate, filed in a timely manner, and retained so they stay complete, readable and directly accessible.
2. Scope
This SOP applies to every study at [SITE NAME] from start-up to archiving. It covers the content and structure of the ISF, paper and electronic ISF (eISF or eRegulatory system), filing, version control, notes to file, the record location map and the relationship between the site's ISF and the sponsor's trial master file (TMF).
Out of scope: participant source records and source documentation practice (SOP-306), validation and access control of electronic systems (SOP-401) and archiving after close-out (SOP-402). Where a sponsor, CRO or IRB requirement is stricter than this SOP, the site follows the stricter requirement.
3. Responsibilities
| Role | Responsibilities |
|---|---|
| Principal Investigator (PI) | Holds responsibility for the site's essential records and their control. Signs or approves records that require the investigator's signature. Makes records available for monitoring, audit and inspection. |
| Regulatory Coordinator | Sets up the ISF, files records, maintains the index (F-204-01), version control and record location map, and prepares the ISF for monitoring visits, audits, inspections and archiving. |
| Lead CRC / CRC | Gives the Regulatory Coordinator study records they create or receive (logs, training records, shipping records, correspondence). Maintains study logs kept in the clinic between filings. |
| Research Pharmacist or IP Manager | Maintains IP records (accountability, temperature logs, shipping records) and files or provides them for the ISF. |
| Quality Lead | Defines the site's standard ISF index, checks ISF completeness during QC (SOP-700) and approves the eISF system for use under SOP-401. |
| All Research Staff | File or hand over study records promptly and do not remove records from the ISF without recording it. |
4. Definitions
| Term | Definition |
|---|---|
| Essential records | Records that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced (ICH E6(R3) Appendix C). E6(R2) called these "essential documents". |
| Investigator Site File (ISF) | The repository held by the investigator/institution for the site's essential records. Also called the regulatory binder. |
| Trial Master File (TMF) | The repository held by the sponsor for the sponsor's essential records. |
| eISF / eRegulatory system | An electronic system used to hold the ISF, with access control, audit trail and electronic signatures where used. |
| Record location map | A record of where each category of essential record is kept when it is not in the ISF itself (for example EDC, IRT, sponsor portals, EHR, IRB portal, pharmacy). Part of F-204-01. |
| Certified copy | A copy of the original record, in any media, verified by dated signature or by a validated process to have the same information as the original, including relevant metadata. |
| Note to file (NTF) | A dated, signed record that explains a discrepancy, absence, or decision in the ISF. Recorded on F-306-01. |
| Superseded document | A version of a document replaced by a newer approved version. Retained, marked as superseded. |
5. Procedure
5.1 ISF format and system
5.1.1
Before the study starts, the Regulatory Coordinator decides with the sponsor whether the ISF is paper, electronic (site eISF or sponsor-provided eISF) or hybrid, and records the decision on F-204-01.
5.1.2
An eISF used for the ISF must meet 21 CFR 11 for records and signatures it holds, with validation or fitness-for-purpose assessment, unique user accounts, role-based access, audit trail and backup, as required by SOP-401. The Quality Lead confirms the system is listed on F-401-01 before use.
5.1.3
A sponsor-provided eISF is acceptable if the site has continuous access during the study and will receive a complete, readable copy (or continued access) for the full retention period. The Regulatory Coordinator confirms this with the sponsor in writing and files the confirmation.
5.1.4
In a hybrid ISF, the index (F-204-01) states for each section whether the paper or electronic copy is the original.
5.2 Setting up the ISF
5.2.1
The Regulatory Coordinator sets up the ISF using the site standard index F-204-01 before the site qualification visit or, at the latest, before the SIV. If the sponsor provides its own ISF index, the Regulatory Coordinator uses the sponsor index and maps it to F-204-01 so no site requirement is lost.
5.2.2
The standard index groups records by section. Typical sections, adapted to the study:
- protocol and amendments, signed protocol signature pages
- Investigator's Brochure or product information and updates
- IRB: submissions, approvals, approved documents, correspondence, rosters or compliance statement, reliance agreement
- informed consent: approved forms (all versions and languages), consent version log (F-301-02)
- regulatory: Form FDA 1572 (drugs and biologics) or signed investigator agreement (devices), financial disclosure forms, investigator and staff CVs, licenses, GCP and human subjects training, trial-specific training records (F-103-01)
- delegation of authority log (F-302-01) and signature records
- agreements: CDA, CTA, budget, amendments, insurance statement (or a pointer to where financial records are held, see 5.2.4)
- laboratory: CLIA certificates, accreditation, normal ranges, laboratory director CV where required
- IP: pharmacy manual, shipping and receipt records, accountability logs (F-304-01), temperature records (F-304-02), destruction or return records, IRT instructions, emergency unblinding procedure
- specimens: processing and shipping records (F-311-01), shipping training records
- equipment: calibration and maintenance records for study equipment (F-312-01), or a pointer to the site equipment file
- safety: SAE reports (F-501-01), IND safety reports and sponsor safety letters, reportable event submissions
- monitoring: monitoring visit log (F-600-01), follow-up letters and action tracker (F-600-02), site qualification, initiation and close-out visit reports or letters
- deviations (F-308-01), notes to file (F-306-01), CAPA records relevant to the study
- logs: pre-screening (F-300-01), screening and enrollment (F-303-01), participant identification code list
- correspondence: sponsor, CRO and vendor communications that record decisions
- systems: user access records, system manuals, training for EDC, IRT, eCOA and portals
- coverage analysis and billing grid (SOP-202) or a pointer to where they are held
- the sponsor's feasibility questionnaire responses (F-200-01 stays in the site's business files, SOP-200 5.11.1) and activation checklist (F-205-01)
- close-out records
5.2.3
Records that are not specific to one study (SOPs, site staff CVs and licenses, site equipment files, master agreements) may be kept centrally. The ISF holds a pointer to them in the record location map, and the central location must still allow the study versions to be retrieved for the retention period.
5.2.4
Financial records that the sponsor does not need to see (for example internal budget calculations) may be kept in [CONTRACTS FOLDER] with a pointer in the ISF. The executed CTA and budget are essential records.
5.2.5
Signed consent forms, the participant identification code list and other records that identify participants are kept in a secure location separate from records shared with the sponsor, with a pointer in the ISF. These are never sent to the sponsor TMF unless the participant authorized it and the sponsor process allows it (SOP-400).
5.3 The record location map
5.3.1
The Regulatory Coordinator completes the record location map in F-204-01 at activation and updates it when a new system or location is added. For each record type held outside the ISF it lists: the system or location, who controls it (site or sponsor), how the site gets access, and how the site will keep a copy or access at close-out.
5.3.2
Typical external locations: EDC, IRT, eCOA, central laboratory portal, imaging portal, safety reporting portal, IRB portal, sponsor document portal, EHR, eConsent platform, temperature monitoring system.
5.3.3
Sponsor portals that hold site essential records (for example IND safety reports posted to a portal) are mapped. Before portal access ends, the Regulatory Coordinator obtains a copy of the records the site must retain (see 5.8).
5.4 Filing
5.4.1
Staff give new records to the Regulatory Coordinator, or file them directly if they are delegated to do so on F-302-01, within [DEFAULT: 10 business days of receipt or creation]. Safety reports and IRB approvals are filed within [DEFAULT: 5 business days].
5.4.2
Each filed record is complete, legible and identifiable: protocol number, document title, version and date where applicable, and signature and date where required.
5.4.3
Records are filed in the section shown in F-204-01, newest on top for paper files, with superseded versions retained behind the current version and marked "superseded" with the date.
5.4.4
Original wet-ink documents scanned into an eISF are retained as originals unless the scan is made as a certified copy under SOP-401 and the site's procedure permits destruction of the paper original. The Regulatory Coordinator does not destroy any original until the Quality Lead confirms the certified copy process is in place.
5.4.5
Emails that record decisions, instructions or approvals are saved in a readable format (PDF with header information) and filed in correspondence. Routine scheduling emails are not filed.
5.5 Version control
5.5.1
Only one version of each controlled document (protocol, IB, consent form, recruitment material, pharmacy manual, study plan, log template) is current at any time. The Regulatory Coordinator records the current version on F-204-01 or the consent version log (F-301-02).
5.5.2
When a new version is approved, the Regulatory Coordinator files it, marks the previous version superseded, removes superseded copies from working areas (5.4.3 and SOP-203, 5.4), and tells the study team.
5.5.3
Logs in use (delegation, screening, accountability) are not re-versioned when pages are added. Completed pages are numbered and filed in order.
5.6 Notes to file
5.6.1
A note to file (F-306-01) is used to explain something that would otherwise be unclear in the record: a missing record, a late filing, a discrepancy between records, a system issue, or a decision with no other record.
5.6.2
The note states the facts, the reason, any corrective action, and, where relevant, a pointer to the deviation (SOP-308) or CAPA (SOP-703) record. It is signed and dated by the author and, where it concerns investigator responsibilities, by the PI (SOP-306, 5.8.3).
5.6.3
A note to file does not replace a required record, does not correct a source record (SOP-306) and is not used to report a deviation that must be reported to the sponsor or IRB.
5.6.4
Notes to file are written when the issue is identified, not before a visit to fill gaps. A note to file written long after the event states the date it was written and the date of the event.
5.7 Access, maintenance and review
5.7.1
The paper ISF is kept in a locked cabinet or room with access limited to study staff, and is protected from fire and water damage as far as practical. eISF access follows SOP-401.
5.7.2
Monitors, auditors, IRB representatives and inspectors are given direct access to the ISF on request (SOP-600, SOP-701, SOP-702). For an eISF, the Regulatory Coordinator sets up read-only accounts or supervised access.
5.7.3
Removal of any paper record from the ISF (for example for copying) is recorded and the record is returned the same day.
5.7.4
The Regulatory Coordinator reviews each active ISF against F-204-01 at least [DEFAULT: quarterly] and before each monitoring visit, and records the review date on F-204-01. The Quality Lead includes the ISF in QC reviews (SOP-700).
5.8 Sponsor TMF and site ISF
5.8.1
The ISF belongs to the investigator/institution and stays under the site's control. Copies of site records that the sponsor needs for the TMF are provided to the sponsor (usually collected by the monitor or uploaded to a sponsor portal). Originals stay at the site.
5.8.2
Sponsor-generated records the site must hold (for example IND safety reports, sponsor letters, monitoring visit follow-up letters, the IB) are filed in the ISF or retained by the site through the record location map.
5.8.3
Records that identify participants are not shared with the sponsor except as allowed by the consent and HIPAA authorization and the protocol, for example during on-site source review.
5.8.4
In blinded studies, records that would unblind site staff (for example unblinded pharmacy records) are filed separately with access limited per the protocol and SOP-305.
5.9 Close-out and retention
5.9.1
At close-out the Regulatory Coordinator reconciles the ISF against F-204-01, the sponsor's close-out list and the record location map, and records gaps and their resolution on F-601-01.
5.9.2
Before access to any external system ends, the Regulatory Coordinator obtains and files the site's records from it. Examples: EDC data and audit trail for the site's participants (usually a sponsor-provided archive on durable media or file), IRT reports, eCOA data, portal documents, eConsent records with audit trail. Receipt is recorded on F-601-01.
5.9.3
The ISF is archived and retained under SOP-402 for the longest of: 21 CFR 312.62(c) or 812.140(d), the period in the CTA, applicable state law (Appendix A), and until the sponsor confirms in writing that records are no longer needed. The site keeps the sponsor informed of the person responsible for the records during the retention period.
6. Related Forms and SOPs
- F-204-01 Investigator Site File Index
- F-306-01 Note to File
- F-401-01 Computerized System Inventory and Access Log
- F-601-01 Study Closeout Checklist
- F-301-02 Consent Form Version Control Log
- F-302-01 Delegation of Authority Log
- F-905-01 Cross-Entity Data Flow Register (Model N only)
- Appendix A State Law Worksheet
- Appendix B Central and Site Responsibility Matrix (Model N only)
- SOP-105 Oversight of Service Providers and Vendors
- SOP-203 IRB Submissions, Approval and Continuing Oversight
- SOP-205 Site Qualification, Initiation and Study Activation
- SOP-305 Randomization, Blinding and Emergency Unblinding
- SOP-306 Source Documentation and Data Integrity (ALCOA+)
- SOP-308 Protocol Deviations and Noncompliance
- SOP-400 Participant Privacy and HIPAA in Research
- SOP-401 Computerized Systems and Electronic Records
- SOP-402 Record Retention, Archiving and Destruction
- SOP-600 Sponsor Monitoring Visits
- SOP-601 Study Closeout
- SOP-700 Internal Quality Control and Quality Assurance Audits
- SOP-701 Sponsor and IRB Audits
- SOP-702 FDA Inspections and Remote Regulatory Assessments
- SOP-703 Corrective and Preventive Action (CAPA)
- SOP-901 Member Site Onboarding, Integration and Exit (Model N only)
- SOP-904 Shared Staff, Cross-Site Coverage and Central Services (Model N only)
- SOP-905 Network Data, Systems, Privacy and Records Across Sites (Model N only)
7. References
| Reference | Title |
|---|---|
| ICH E6(R3) Annex 1, 2.12 | Records |
| ICH E6(R3) Appendix C | Essential Records for the Conduct of a Clinical Trial |
| ICH E6(R3) Annex 1, 4.3 | Computerised Systems |
| 21 CFR 11 | Electronic Records; Electronic Signatures |
| 21 CFR 312.62 | Investigator Recordkeeping and Record Retention |
| 21 CFR 812.140 | Records (devices) |
| FDA Guidance (Oct 2024) | Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers |
Independent Site SOP Library. Licensed CC BY-NC 4.0 by the American Institute for Medical Research (AIMR), with added permission for any site's internal use (license terms). Not legal advice: each adopting site confirms state law, IRB and sponsor requirements with its own counsel and owns every step it approves.