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

The ISF contains essential documents that permit evaluation of the conduct of the clinical trial. In addition to checking that the minimum requirements stated in ICH E6 (R2) section 8 are met, auditors also check the presence and content of a variety of documents. 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 specifically what auditors/inspectors are looking for during an audit.

  1. Site responsibility log (SRL) or delegation log
    • The delegation log is one of the most common sources of issues during an audit. Staff turnover can often impact the completeness of this log. Remember: It is the principal investigator’s (PI’s) responsibility to ensure study-related activities have been delegated appropriately.
    • Review and confirm the staff are qualified to carry out delegated duties. E.g., 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.
    • Validate that delegated duties are signed and dated by the PI before involving staff in the study.
    • Confirm that the log is up to date, reflecting additions and deletions in staff, using good documentation practices.
    • Certify that staff are trained on the study before performing study-related duties (cross-check against site initiation visit attendance and subsequent training logs).
  2. Form FDA 1572
    • Note that the Form FDA 1572 is unique to US-based sites. Ex-US sites do not use Form FDA 1572s, so sponsors may need to request these sites sign a different document. For more information on completing the Form FDA 1572, see FDA Information Sheet Frequently Asked Questions – Statement of Investigator (Form FDA 1572).
    • The Form FDA 1572, CV, financial disclosure form, and medical license should all show consistency regarding the PI’s name.
    • Validate that the PI’s affiliation on the CV is consistent with the site address on the Form FDA 1572.
    • Check that all investigators and other pertinent study staff are recorded in section 6.
      1. As a rule, you should 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).
      2. Note: It is the sponsor or contract research organization’s (CRO’s) decision whether to list supporting personnel, such as study coordinators, on the Form FDA 1572.
    • Verify names, address(es), and other relevant information are correct for the following:
      1. All investigator sites where the participants are seen for trial procedures and the investigational product (IP) shipment address(es) recorded in section 3.
      2. All laboratory facilities (central and local) and diagnostics laboratories utilized in the study recorded in section 4.
      3. All institutional review boards (IRBs) consistent with other IRB documents (e.g., the name/address on the IRB letterhead) 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 Form FDA 1572 must be signed and dated by the PI (original), and any changes to the form must be initialed and dated by the PI.
  3. Financial disclosure forms
    • This form must be present, original, signed, and dated for all staff detailed on the Form FDA 1572.
  4. 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.
  5. Protocol and amendments
    • Confirm that these are all on file and signed/dated by the PI. In some countries, these should also be signed by the sub-investigators as required by local regulations.
  6. IRB communications, including submissions and approvals
    • Ensure this documentation is complete (e.g., for protocol; 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 and serious adverse events (SAEs)/suspected unexpected serious adverse reactions (SUSARs) has 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.
    • Confirm that informed consent forms (ICFs) have been stamped for approval, if required.
  7. 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 should cover the duration for when staff are involved in the study. Make sure licenses are valid for the state (US) in which the site is located.
    • Document that relevant staff are trained on study/study materials (initial and subsequent), electronic case report form (eCRF), and Good Clinical Practice (GCP). E.g., if a protocol amendment is issued and approved, study staff are expected to have been trained on the changes prior to implementing the amendment.
  8. Investigational New Drug (IND) safety reports
    • Attest that all reports submitted by the sponsor are present, have been submitted to the IRB, and that there is documentation of PI review.
  9. Lab accreditation and reference ranges for central, as well as local, laboratories (if used)
    • Check to see if accreditation is valid for the duration of the study, 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.
  10. 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 that actions are resolved in a timely manner. Other communication that should be filed includes communications with medical monitors related to safety questions, inclusion/exclusion criteria, and newsletters.
  11. Site visit log
    • Confirm all visits are recorded and consistent with monitoring visit documentation.
  12. Pharmacy file
    • Make sure inventory records are up to date.
    • Documentation of IP dispensing, return, or destruction must be present.
    • Confirm that 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, such as Forte eReg, can help to keep your documentation organized and up to date. Electronic documentation should be made 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.

Looking for additional help? Get expert support on virtual audits, document QC/QA, regulatory inspections, and more.

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