Key Items Auditors Look for When Reviewing an Investigator Site File

Maintaining complete and compliant documentation while managing the complex processes and interactions of clinical trial conduct is complicated. This blog outlines what to look out for when preparing your investigator site files (ISF) for an audit.

Investigator Site Files

The ISF contains essential documents permitting evaluation of a clinical trial’s conduct. In addition to checking the minimum requirements stated in ICH E6 (R2) section 8 are met, auditors also check document presence and content. Essentially, the auditor should be able to “reconstruct” the trial based on the documentation in place at the site. If documentation is incomplete, sites run the risk of regulatory inspection findings such as a Form FDA 483. Below are examples of key items auditors/inspectors look for during an audit.

Delegation Log

The delegation log, also known as the site responsibility log (SRL), is one of the most common sources of issues during an audit. Staff turnover often impacts this log.

Remember: It is the principal investigator’s (PI’s) responsibility to ensure study-related activities are appropriately delegated.

It is also critical to review and confirm relevant staff are qualified to carry out delegated duties. For example, non-medical personnel should not assess adverse event causality or confirm the clinical significance of lab results. A cross-check ensures curriculum vitae (CVs), and medical licenses (if appropriate) are on file and current.

Before involving staff in the study, the PI must validate, sign and date duties delegated to staff.  They must confirm the log is up to date, reflecting additions and deletions in staff including their end dates for working on the trial, using good documentation practices.

Confirm all relevant staff are trained on the study before performing study-related duties (cross-check against site initiation visit attendance and subsequent training logs). Remember, some staff may not need protocol-specific training. For example, most hospital radiology technicians are trained to perform scans for the hospital and/or PI for clinical trials based on the information in the test requisitions.

Form FDA 1572

The Form FDA 1572 is unique to U.S.-based sites. Sites outside of the U.S. do not use Form FDA 1572s, so sponsors may need to request these sites sign a different document. The FDA 1572 Form, CV, financial disclosure form, and medical license should all show consistency regarding the PI’s name.

Checklist

• Validate the PI’s affiliation on the CV is consistent with the site address on the Form FDA 1572.
• Check all investigators and other pertinent study staff are recorded in section 6.
• List any individual member of the clinical trial physician team who is designated and supervised by the PI to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows).
  • Note: It is the sponsor or contract research organization’s (CRO’s) decision whether to list supporting personnel, such as study coordinators, on the FDA 1572 Form.
• Verify names, address(es), and other relevant information are correct for the following:
  • All investigator sites where the participants are seen for trial procedures and the investigational product (IP) shipment address(es) are recorded in section 3.
  • All laboratory facilities (central and local) and diagnostics laboratories utilized in the study are recorded in section 4.
  • All institutional review boards (IRBs) consistent with other IRB documents (e.g., the name/address on the IRB letterhead) are recorded in section 5.
• Keep names consistent with any certification and normal reference range documents
• Confirm the protocol number and title are listed correctly.
• The FDA 1572 Form must be signed and dated by the PI (original), and any changes to the form must be initialed and dated by the PI.
  • Financial disclosure forms: This form must be present, original, signed, and dated for all staff detailed on the Form FDA 1572.
  • Screening/enrollment log: Confirm all screened participants are present on the log and the reason for screen failure or date of randomization recorded. Keep data consistent with the source.
  • Protocol and amendments: Ensure these are all on file and signed/dated by the PI. In some countries, local regulations may indicate the sub-investigators need to sign as well.

IRB Communications, Including Submissions and Approvals

Ensure this documentation is complete (e.g., for protocol and any subsequent amendments; investigator’s brochure [IB]; consent documents, questionnaires, diaries, and other participant-facing documentation, etc.).

• The IRB list or assurance letter must be on file.
• Confirm evidence of continuing review is included.
• Confirm notification of protocol deviations, serious adverse events (SAEs), and/or suspected unexpected serious adverse reactions (SUSARs) have been reported as required by the IRB.
• All IRB-approved documents must be filed in the ISF.
• Assess whether the approved/current versions of each document are in use by the site.
• If required, confirm informed consent forms (ICFs) have been stamped for approval.

Training and Qualification Documentation

Current CVs must contain name, education and qualification, current position, affiliation(s), and experience (work history, research experience). Make sure they are signed and dated.

Both the medical licenses and nurse licenses need to be up to date. These licenses should cover the entire duration of staff involvement in the study. Make sure licenses are valid for the location in which the site is located.

Documents should be on file indicating relevant staff are trained on all study/study materials (initial and subsequent), electronic case report form (eCRF), and good clinical practice (GCP). For example, if a protocol amendment is issued and approved, study staff is expected to have been trained on the changes prior to implementing the amendment.

Investigational New Drug (IND) Safety Reports

Attest all reports submitted by the sponsor are present, have been submitted to the IRB, and there is documentation of PI review. Lab accreditation and reference ranges for central, as well as local, laboratories (if used).

Ensure accreditation is valid for the study’s duration, and reference ranges are on file and current; any revisions to these ranges during the study are to be filed. Cross-check against a current lab report to ensure consistency.

Communications

Although this section isn’t usually reviewed in detail, the auditor will check for correspondence pertaining to safety, protocol deviations, IRB notifications, and key study decisions. Minimally, monitoring visit confirmation letters and follow-up letters should be filed.

The auditor will also check to see documented evidence actions are resolved in a timely manner. Other communication to file includes communications with medical monitors related to safety questions, inclusion/exclusion criteria, and newsletters.

Site Visit Log

Confirm all visits are recorded and consistent with monitoring visit documentation. Check if site or study procedures stipulate to have auditors sign the log.

Pharmacy File

• Ensure inventory records are up to date.
• Documentation of IP dispensing, return, or destruction must be present.
• Confirm temperature records are available and excursions, if any, are documented.
• Determine if there is a separate delegation log in pharmacy or included in ISF.

If parts of the site files are kept electronically or in other locations (e.g., pharmacy), reference should be made to where the documentation is kept. Using an electronic regulatory system can help to keep your documentation organized and up to date. Electronic documentation should be available for the auditor/inspector for review, just like a paper file. In the case of an FDA inspection, the inspector will focus on a document review of 21 CFR parts 50, 54, 56, and 312, so it’s strongly recommended the site files (including the site regulatory binder and pharmacy files) are complete, easily accessible, and available at all times. For ease of review, file the documents chronologically.

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