SOP-13
Monitoring, Audits and Inspections
- Number
- SOP-13
- Category
- Core
- Edition
- Lean Edition 2.0
- 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] hosts and follows up on sponsor monitoring, sponsor and IRB audits, FDA inspections and FDA Remote Regulatory Assessments (RRAs), and tracks every finding to closure.
2. Scope
This SOP applies to every monitoring visit (on site, remote or centralized, including qualification and initiation visits), every audit by or for a sponsor, CRO or IRB, and every FDA Bioresearch Monitoring (BIMO) inspection or RRA of a study at [SITE NAME], routine or for-cause, including inspection of the site as a sponsor-investigator (SOP-M6, if adopted). Inspections by other agencies (for example DEA, state health department or CLIA surveyors) follow sections 5.5 to 5.8, with that agency's form and response timeline recorded on F-702-01.
Out of scope: internal QC and internal audits (SOP-14) and close-out visit content (SOP-15).
Where the protocol, clinical trial agreement (CTA), monitoring plan, sponsor or IRB sets a stricter requirement than this SOP, follow it.
3. Responsibilities
| Role | Responsibilities |
|---|---|
| Principal Investigator (PI) | Permits monitoring, audit and inspection and gives access to records (21 CFR 312.68; 21 CFR 812.145). Meets monitors, auditors and FDA, receives Form FDA 482 and Form FDA 483, and approves and signs responses. |
| Site Director | Provides space, system access and resources, decides on legal counsel and sponsor attendance at inspections, and resolves resource-related findings. |
| Quality Lead | Approves monitor and auditor system access, acts as audit and inspection liaison unless another person is named, keeps F-702-01, drafts audit, 483 and RRA responses and opens CAPAs (SOP-08). |
| Regulatory Coordinator | Prepares the Investigator Site File (ISF), sends sponsor and IRB notifications, makes and logs copies, and files correspondence. |
| Lead CRC / Clinical Research Coordinator (CRC) | Schedules and prepares monitoring visits, retrieves participant records, answers questions about their own work, and keeps F-600-01 and F-600-02 current. |
| Research Pharmacist or IP Manager | Presents IP storage, temperature and accountability records and resolves IP findings. |
| All Research Staff | Answer truthfully and only within their own knowledge, and never alter, destroy or hide records. |
4. Definitions
| Term | Definition |
|---|---|
| Monitoring | The sponsor's ongoing oversight of trial conduct, performed on site, remotely or centrally (ICH E6(R3) Annex 1, 3.11.4). |
| Centralized monitoring | The sponsor's evaluation of accumulated data (for example trend review) to find risks, anomalies or site performance issues. |
| Audit | A systematic and independent examination of trial activities and records against the protocol, SOPs, GCP and regulations (ICH E6(R3) Glossary). |
| Inspection | An official review by a regulatory authority of records, facilities and other resources related to the trial (ICH E6(R3) Glossary). |
| Form FDA 482 | Notice of Inspection, issued with FDA credentials at the start of an on-site inspection. |
| Form FDA 483 | Inspectional Observations, issued at the end of an inspection listing observed deviations from the regulations. |
| Remote Regulatory Assessment (RRA) | A wholly remote FDA examination of records. It is not an inspection. It is mandatory when FDA requests records under FD&C Act section 704(a)(4), and voluntary otherwise. |
| Liaison | The staff member who is the auditor's or FDA investigator's single point of contact and keeps F-702-01. |
| Follow-up letter | The sponsor's written summary of a monitoring visit, its findings and required actions. |
5. Procedure
5.1 Monitoring setup and access
5.1.1
At the site initiation visit, the Lead CRC files the sponsor's monitoring expectations (frequency, method) in the ISF.
5.1.2
The Lead CRC agrees with the sponsor a remote method the CTA permits and the consent and HIPAA authorization cover (Site decision below; SOP-12).
5.1.3
The Quality Lead approves each monitor, auditor or FDA account on site systems before use and logs it on F-401-01: one named account per person, read-only, limited where the system allows to the study's consented participants, time-limited, with a signed confidentiality or access agreement on file for monitors and auditors (not for FDA). Where the EHR cannot restrict access, no monitor account is issued.
5.2 Monitoring visits
5.2.1
The Lead CRC records each confirmed visit on F-600-01, asks for the agenda, confirms staff availability and, for remote visits, checks the monitor's access beforehand.
5.2.2
By [DEFAULT: 1 business day before the visit], the Lead CRC confirms that EDC entry and queries are current (SOP-07), SAEs are reported (SOP-09), deviations are on F-308-01 and prior F-600-02 actions have a status. The Regulatory Coordinator updates the ISF and the IP Manager reconciles IP records (SOP-06).
5.2.3
Certified copies for remote review are prepared under SOP-07, redacted under the single redaction rule in SOP-12, and uploaded only to the sponsor-approved secure system.
5.2.4
Source records and the ISF stay on site. The monitor does not write in or sign site records except the visit log; corrections are made by the original author or a delegated staff member under SOP-07.
5.2.5
The PI or Sub-I meets the monitor when asked. If the PI cannot attend, the PI holds a call with the monitor within [DEFAULT: 5 business days] and the CRC records it on F-600-01.
5.2.6
At the exit meeting, the Lead CRC enters findings and actions on F-600-02 without waiting for the follow-up letter. Findings on safety, consent, eligibility or IP go to the PI the same day.
5.2.7
The CRC answers centralized monitoring queries within the sponsor's timeline, or [DEFAULT: 5 business days], and records findings that suggest a systemic issue on F-600-02.
5.3 Follow-up and escalation of monitoring findings
5.3.1
The Lead CRC checks each follow-up letter against the exit notes within [DEFAULT: 5 business days of receipt] and reports errors to the monitor in writing.
5.3.2
Each action goes on F-600-02 with owner and due date: the sponsor's date, or [DEFAULT: 30 calendar days or the next visit, whichever comes first]. Deviations go on F-308-01 (SOP-08); IRB-reportable items are handled under SOP-09.
5.3.3
The PI reviews open F-600-02 items for the study as part of the PI oversight note at each monitoring visit (SOP-02).
5.3.4
The Lead CRC escalates any overdue action, or a finding repeated in a second letter, to the PI and Quality Lead. The Quality Lead decides whether a CAPA is needed under the SOP-08 triggers and records the decision on F-600-02.
5.3.5
The PI raises unresolved disagreements in writing with the sponsor and files the outcome in the ISF. Monitor requests to change data without a source basis go to the Quality Lead; requests to falsify records go to SOP-M5 (if adopted) or SOP-08, 5.6.5.
5.3.6
Follow-up letters are filed in the ISF (SOP-03). Open actions across studies go to the quarterly quality review (SOP-14).
5.4 Sponsor and IRB audits
5.4.1
Any staff member who receives an audit request forwards it the same business day to the PI, Quality Lead and Site Director.
5.4.2
The Quality Lead confirms in writing the auditor and whom they represent, scope, dates, format, records and systems needed. The Site Director checks the CTA for audit rights and fees. For an auditor not employed by the sponsor, the Quality Lead obtains written confirmation that the sponsor authorized the audit and the auditor is bound by confidentiality.
5.4.3
The Quality Lead agrees a date when the PI and key staff can attend, names the liaison and a backup on F-702-01, and does not delay the audit to gain preparation time. For a sponsor audit, the Regulatory Coordinator tells the IRB only if IRB policy requires it. For an IRB audit, the Regulatory Coordinator tells the sponsor within [DEFAULT: 2 business days] unless the CTA says otherwise.
5.4.4
The Quality Lead runs a focused pre-audit check on F-700-01 and briefs staff on 5.6.3.
5.4.5
The audit is conducted under 5.6.1 to 5.6.6. Clear errors may be corrected during the audit under SOP-07 and noted on F-702-01.
5.4.6
The PI attends the closing meeting. The liaison records each finding, its grade and the requirement cited; the Quality Lead asks for written findings, the response deadline and an audit certificate.
5.4.7
The Quality Lead assesses each finding against the SOP-08 triggers. Findings graded major or critical go to a CAPA on F-703-01 and the CAPA log F-703-02; minor findings that meet no trigger are corrected and answered with a one-line cause.
5.4.8
The response is due by the auditor's deadline or, if none, within [DEFAULT: 30 calendar days of written findings]; any extension is requested in writing before the due date. For each finding it states the correction and date, the root cause scaled to severity, actions with owners and dates, and the effectiveness check. The Quality Lead drafts, the PI signs, the Regulatory Coordinator sends.
5.4.9
The PI assesses whether any finding is reportable to the IRB or sponsor (for example serious or continuing noncompliance) and reports it under SOP-08 and SOP-09.
5.5 FDA inspection: readiness and notification
5.5.1
The Quality Lead keeps an inspection readiness file at [INSPECTION READINESS FILE LOCATION]: organization chart, list of active and retained studies (sponsor, protocol, IND/IDE number, PI, IRB), SOP index F-100-03, blank F-702-01 and a contact list. The Regulatory Coordinator updates the study list when a study is activated or closed. Inspection conduct (5.6) is part of each staff member's SOP training under SOP-01.
5.5.2
Any staff member contacted by FDA records on F-702-01 the caller's name and contact details, the study, proposed dates, records requested and whether FDA calls it an inspection or an RRA, commits to nothing else, and tells the PI, Quality Lead and Site Director immediately. The PI or Quality Lead calls back the same business day.
5.5.3
The Quality Lead verifies the caller through FDA contact details obtained independently from fda.gov.
5.5.4
The PI or Quality Lead confirms a start date, asking for a change only for genuine unavailability. Delay to gain preparation time may be treated as refusal of inspection (5.6.9).
5.5.5
The Regulatory Coordinator notifies the sponsor in writing within [DEFAULT: 1 business day of FDA contact] or the CTA time if shorter, and the IRB as its policy requires. The Site Director involves [LEGAL COUNSEL] for any for-cause inspection, and decides with the PI whether sponsor representatives attend; they do not answer for staff.
5.5.6
The Quality Lead holds a planning meeting, the study team gathers the F-204-01 records and source, and the Site Director arranges an inspection room, a back room and requested read-only accounts.
5.5.7
Errors found while preparing are corrected under SOP-07 with the current date and reason, or recorded on F-306-01. Backdating, re-creating or discarding records is prohibited.
5.5.8
Where the PI holds the IND or IDE (SOP-M6, if adopted), FDA may inspect sponsor and investigator records together (Compliance Programs 7348.810 and 7348.811); the readiness file also holds the sponsor file, and notices under 5.5.5 and 5.7.2 go to any product supplier the agreement names.
5.6 Conduct of an audit or inspection
5.6.1
The liaison greets the visitor and notifies the PI and Quality Lead. The FDA investigator presents credentials and issues Form FDA 482 to the PI or most responsible person present; the liaison records the name and credential number on F-702-01 without photocopying credentials, and files the original 482. FDA is not asked to sign confidentiality or sign-in terms.
5.6.2
At the opening meeting the PI describes the site, study and who did what (delegation log); the liaison asks for scope, interviews and schedule.
5.6.3
Staff answer the question asked, truthfully and from their own knowledge, using the records where possible. They say "I don't know" rather than guess, and tell the liaison before correcting an earlier answer.
5.6.4
The liaison logs every request on F-702-01. The back room checks each record is complete before hand-over. The site provides what is requested and volunteers nothing else; out-of-scope audit requests go to the Quality Lead.
5.6.5
For copies, the Regulatory Coordinator makes two identical sets, keeps one in the audit or inspection file, marks FDA copies "Copy" with the date and confidential commercial pages "Confidential", and logs each on F-702-01. Copies for auditors are redacted under SOP-12. Copies for FDA identify participants by participant ID unless FDA requires identified records (21 CFR 312.68; 21 CFR 812.145(c)); HIPAA permits that disclosure (45 CFR 164.512(b)(1)(i), (d)). The liaison logs any identified records provided.
5.6.6
The liaison or a delegate escorts the visitor on tours and interviews. Each day the liaison asks for concerns and next-day requests, then holds an internal wrap-up.
5.6.7
If FDA photographs would capture participant identifiers, the liaison asks the investigator to avoid it and records what was photographed on F-702-01; any further objection is a Site Director decision with [LEGAL COUNSEL].
5.6.8
Staff are not required to sign an affidavit (Form FDA 463a). A staff member asked to sign tells the liaison, may decline or consult [LEGAL COUNSEL] first, never signs an inaccurate or unread statement, and keeps a copy.
5.6.9
No one refuses entry or access to or copying of records FDA may inspect, delays unreasonably, or alters, destroys or hides records (FD&C Act section 301(f)).
5.7 Form FDA 483, response and outcomes
5.7.1
The PI attends the close-out meeting with the Quality Lead and Site Director, asks clarifying questions, corrects factual errors with evidence, promises nothing unagreed, and asks where to send the response. The liaison records every observation and discussion item, including those not listed on the 483.
5.7.2
The Regulatory Coordinator sends a copy of the 483 (or confirms none was issued) to the sponsor within [DEFAULT: 2 business days] or the CTA time if shorter, and notifies the IRB under its policy.
5.7.3
The site submits a written response within 15 business days of the date the 483 was issued (day 0; business days exclude weekends and US federal holidays) to the address given at close-out. For each observation the response gives the content in 5.4.8 with evidence attached and dates for promised updates. The Quality Lead drafts it with the PI, the PI signs it, and the Site Director arranges review by [LEGAL COUNSEL] where Official Action Indicated is possible. The response admits no violation that did not occur and marks confidential commercial information, because FDA may release it under FOIA.
5.7.4
The Quality Lead opens a CAPA for each observation on F-703-01 and F-703-02 and sends promised updates to FDA on time.
5.7.5
If the narrative Establishment Inspection Report has not arrived within [DEFAULT: 6 months of the inspection], the Regulatory Coordinator requests it from FDA through a FOIA request. The 482, 483, response, EIR, classification letter and all FDA correspondence are filed in the ISF and inspection file and copied to the sponsor and IRB as required.
5.7.6
Any Warning Letter, Untitled Letter or disqualification notice (21 CFR 312.70; 21 CFR 812.119) goes immediately to the Site Director and [LEGAL COUNSEL]. The PI responds within the time stated, and the Site Director informs the sponsors of all the PI's active studies as the CTAs require.
5.8 Remote Regulatory Assessments
5.8.1
An RRA request is handled as in 5.5.2; the Site Director and Quality Lead decide the response.
5.8.2
Mandatory RRA. For a records request under FD&C Act section 704(a)(4), the site provides the records within the time FDA states. If it cannot, the Quality Lead contacts FDA before the due date.
5.8.3
Voluntary RRA. Only the Site Director or PI may consent, after agreeing scope and technology with FDA, and records the decision on F-702-01. Declining may lead FDA to inspect instead.
5.8.4
During an RRA, records go only by the secure method FDA specifies, each file sent is logged on F-702-01 with an identical copy kept, and the liaison closes all other records before any screen share.
5.8.5
FDA may present a written list of RRA observations. The site responds in writing within 15 business days, following 5.7.3, and opens CAPAs under 5.7.4.
5.9 Records and lessons learned
5.9.1
The Regulatory Coordinator files audit and inspection correspondence and certificates in the ISF. The Quality Lead keeps F-702-01, the duplicate copy set and meeting notes in the quality file.
5.9.2
Within [DEFAULT: 30 calendar days] of an inspection or RRA close-out, the Quality Lead holds a lessons-learned review with the study team and records the actions, with any CAPA on F-703-02. Audit and inspection results go to the annual management review (SOP-14).
6. Related Forms and SOPs
- F-600-01 Monitoring Visit Log
- F-600-02 Monitoring Follow-Up Action Tracker
- F-702-01 Inspection Request and Document Log
- F-703-01 CAPA Record
- F-703-02 CAPA Log
- F-700-01 Internal QC Review Checklist
- F-100-03 SOP Master Index and Review Schedule
- F-304-01 Investigational Product Accountability Log
- F-304-02 Temperature Monitoring Log
- F-306-01 Note to File
- F-204-01 Investigator Site File Index
- F-308-01 Protocol Deviation Log
- F-401-01 Computerized System Inventory and Access Log
- SOP-01 SOP Control, Training and Qualification
- SOP-02 Roles, PI Oversight, Delegation and Conflicts of Interest
- SOP-03 IRB Oversight, Essential Records and Study Activation
- SOP-07 Source Documentation and EDC
- SOP-08 Protocol Deviations and CAPA
- SOP-09 Safety Reporting (AEs, SAEs, IRB-Reportable Events, Pregnancy)
- SOP-12 Privacy, Electronic Systems and Record Retention
- SOP-14 Quality Control and Quality Review
- SOP-15 Study Closeout
- SOP-M5 Research Integrity and Misconduct Reporting (if adopted)
- SOP-M6 Sponsor-Investigator Studies (IND/IDE Holder) (if adopted)
7. References
| Reference | Title |
|---|---|
| FD&C Act section 704 (21 U.S.C. 374) | Inspection, including 704(a)(4) records requests |
| FD&C Act section 301(f) (21 U.S.C. 331(f)) | Prohibited acts: refusal to permit inspection |
| 21 CFR 312.68; 21 CFR 812.145 | Inspection of investigator records |
| 21 CFR 312.70; 21 CFR 812.119 | Disqualification of a clinical investigator |
| 21 CFR 312.56(a); 21 CFR 812.46 | Sponsor monitoring |
| 45 CFR 164.512(b) and (d) | HIPAA: public health and health oversight disclosures |
| ICH E6(R3) Annex 1, 2.3.5 and 2.12.14 | Investigator permits monitoring, audit and inspection; direct access |
| ICH E6(R3) Annex 1, 3.11.2 and 3.11.4 | Audit; monitoring |
| FDA Compliance Program 7348.811 | Bioresearch Monitoring: Clinical Investigators and Sponsor-Investigators |
| FDA Compliance Program 7348.810 | Bioresearch Monitoring: Sponsors, Contract Research Organizations and Monitors (sponsor-investigators) |
| 74 FR 40211 (August 11, 2009) | Review of Post-Inspection Responses |
| FDA Guidance | Conducting Remote Regulatory Assessments: Questions and Answers |
| FDA Guidance (2013) | Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring |
| Reference Edition SOP-600, SOP-701, SOP-702 | Full text and background |
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