Navigating Investigator Site File Audits: A Guide to Clinical Trial Compliance
Clinical trial audits are a crucial part of ensuring that research is conducted according to regulatory standards and Good Clinical Practice (GCP). However, preparing for an audit can be a daunting task. With so many documents to manage and multiple stakeholders involved, it’s easy to overlook key details. In this blog, we’ll explore the most critical components that auditors will focus on when reviewing your Investigator Site File (ISF) and offer practical advice to ensure your trial remains in compliance.
What Is the Investigator Site File (ISF)?
The Investigator Site File is a comprehensive collection of essential documents that help demonstrate how a clinical trial is being conducted. These documents ensure that all activities adhere to regulatory requirements and GCP standards. During an audit, the auditor’s goal is to “reconstruct” the trial based on the available documentation at the site. Any missing or incomplete records can result in findings that may delay or hinder the progress of your trial.
To ensure a smooth audit process, it’s essential to focus on key documents that auditors typically review.
Key Documents Auditors Look for in Your ISF
1. Delegation Log
The Delegation Log (also known as the Site Responsibility Log or SRL) is one of the most scrutinized documents during an audit. It helps ensure that the Principal Investigator (PI) is delegating study-related tasks to qualified staff members.
What Auditors Will Look For:
- PI’s Responsibility: The PI must ensure that tasks are delegated to qualified individuals and that the log reflects this clearly.
- Staff Qualifications: The PI should cross-check qualifications (such as CVs and medical licenses) to ensure staff are properly trained and qualified.
- Regular Updates: The log should be regularly updated to reflect any changes in staff, along with their roles and involvement in the trial.
- Training Confirmation: Auditors will verify that all delegated staff members received the necessary training for their roles.
2. Form FDA 1572
For trials conducted in the U.S., some sponsors may request the PI to sign the FDA Form 1572, confirming adherence to Title 21 of the Code of Federal Regulations (CFR). However, for sites outside of the U.S. (e.g., in the EU), this form should not be signed, as it conflicts with local legislation.
What You Need to Know:
Ensure that your site is using the correct forms for regulatory compliance in your region.
3. IRB Communications and Approvals
The Institutional Review Board (IRB) plays a key role in ethical oversight, and auditors will closely examine all IRB-related documentation.
What Auditors Will Review:
- Complete Documentation: Make sure all protocol submissions, amendments, investigator brochures, and informed consent forms (ICFs) are filed and up to date.
- IRB Assurance Letter: Ensure the IRB list or assurance letter is included to confirm your site’s oversight by an accredited IRB.
- Continuing Review: Auditors will check for evidence of ongoing IRB reviews to maintain ethical oversight throughout the trial.
- Adverse Event Reporting: Confirm that any deviations, serious adverse events (SAEs), or suspected unexpected serious adverse reactions (SUSARs) have been reported to the IRB.
4. Staff Qualifications and Training Records
Maintaining up-to-date records for staff qualifications and training is essential for demonstrating compliance.
What Auditors Will Expect to See:
- Current CVs: Ensure that all staff CVs are signed, dated, and include complete information about their education, experience, and current qualifications.
- Valid Licenses: Medical and nursing licenses should be current and valid throughout the trial period.
- Training Records: Documentation of training in GCP, study protocols, and relevant amendments should be readily available. Ensure that training is documented for all relevant personnel before they participate in study activities.
5. Investigational New Drug (IND) Safety Reports
If applicable, ensure that all safety reports from the sponsor are included in the ISF and have been reviewed by the PI. These reports must also be submitted to the IRB for ethical oversight.
What Auditors Will Check:
- Sponsor Reports: Ensure that sponsor safety reports are filed and reviewed by the PI. Auditors will look for evidence of proper evaluation.
- Lab Accreditation: If lab results are part of the trial, ensure that both central and local laboratories are accredited and maintain valid certifications.
- Reference Ranges: Confirm that updated reference ranges are used and documented in accordance with lab findings.
6. Communications and Site Visit Logs
Proper documentation of communications is critical, even though it might not be reviewed in great detail.
What to Include:
- Correspondence: Include communications related to safety, protocol deviations, IRB submissions, and other key decisions.
- Site Visit Logs: Ensure that site visits are logged accurately, and records of monitoring visits align with documentation. Any site-specific procedures requiring auditor signatures should be followed.
7. Pharmacy File
Auditors will also review your pharmacy documentation to ensure compliance with investigational product (IP) handling.
What to Have in Order:
- Inventory Records: Keep updated records of IP inventory.
- Dispensing/Return/Destruction: Ensure that all documentation of IP dispensing, returns, or destruction is present.
- Temperature Logs: Maintain accurate temperature records, especially for temperature-sensitive medications.
- Delegation Log: Confirm that the pharmacy delegation log is available and complete.
Final Tips for a Successful Audit
Preparation is key to a smooth audit process. Here are a few final tips to keep in mind:
- Stay Organized: Ensure all documents are filed chronologically and are easy to locate during an audit.
- Maintain Accuracy: Regularly update the ISF to reflect the most current and accurate information.
- Be Proactive: Rather than waiting for an audit, routinely review your ISF to identify and correct any potential issues before the auditor arrives.
By focusing on these essential areas and staying organized, you’ll be in a great position to ensure a successful audit and maintain compliance throughout the duration of your clinical trial.
Keywords: Clinical Trials, Audit, Investigator Site Files, GCP, Compliance, Pharmacy Files, IRB, Delegation Log, Site Training, IND Safety Reports
References
- Lazar, E. L., Schwartz, T. A., & Zuckerbraun, B. S. (2023). Practical Guide to Budgeting and Funding a Clinical Trial in Surgery. JAMA Surgery, 158(2), 206-207.
🔗 https://jamanetwork.com/journals/jamasurgery/article-abstract/2797680 - Neugebauer, E. A. M., Rath, A., Antoine, S. L., et al. (2017). Specific barriers to the conduct of randomised clinical trials on medical devices. Trials, 18, 427.
🔗 https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-017-2168-0 - Faris, O., & Shuren, J. (2017). An FDA Viewpoint on Unique Considerations for Medical-Device Clinical Trials. New England Journal of Medicine, 376(14), 1350-1357.
🔗 https://www.nejm.org/doi/full/10.1056/NEJMra1512592 - Kramer, D. B., & Cutlip, D. E. (2015). Trust and transparency in clinical trials of medical devices. Nature Reviews Cardiology, 12(9), 503-504.
🔗 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698975 - Aycock, K. I., Battisti, T., Peterson, T. E., et al. (2024). Toward trustworthy medical device in silico clinical trials: a hierarchical framework. Frontiers in Medicine, 11, 1433372.
🔗 https://www.frontiersin.org/articles/10.3389/fmed.2024.1433372/full - Lübbeke, A., Combescure, C., Barea, C., et al. (2023). Clinical investigations to evaluate high-risk orthopaedic devices: systematic review. medRxiv.
🔗 https://www.medrxiv.org/content/10.1101/2023.08.24.23294479v1 - U.S. Food and Drug Administration (FDA). (2018). Code of Federal Regulations Title 21, Part 312 – Investigational New Drug Application.
🔗 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312 - European Medicines Agency (EMA). (2020). Clinical Trials Regulation (EU) No 536/2014.
🔗 https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/clinical-trials-regulation
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