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This content was written exclusively for the BDC

by Emily Fivekiller, MPH, CCRP

Preparing for a

FDA Audit

Before an Inspection

FDA Regulation and Site Selection

Assume any study overseen by the FDA has the potential to be audited

Bioresearch Monitoring Program

Comprehensive, agency-wide program of on-site inspections and data reviews designed to monitor all aspects of the conduct and reporting of FDA-regulated research

BIMO

BIMO Objectives

  • Protect the rights, safety and welfare of human research subjects
  • to verify the accuracy / reliability of clinical trial data
  • to assess compliance with FDA regulations

Site Selection

Site Selection

  • Enrollment Rate
  • Known Compliance Issues, complaints or a previous FDA 483 (finding)
  • Research Experience
  • Values different from other sites
  • Geographical Area
  • Media Attention

Starting an FDA Study

Starting an FDA Study

Preparation - begins before you start the study!

Preparation

  • Know your protocol
  • Reference the Code of Federal Regulations and FDA Guidance Documents
  • Understand Staff Roles and Responsiblities
  • Ensure you have the appropriate staff
  • Ensure proper training & documentation
  • Ensure proper delegation

Be in Compliance

Compliance

  • Assume all studies will be inspected
  • Facilitate transparent and open communications with staff and sponsor
  • Keep accurate records
  • Patient Study Binders
  • accurate records of study visits
  • detailed accouting of drug/device dispensation and return
  • AEs
  • Regulatory Binders
  • staff trainings, licenses
  • DOA log
  • IRB submissions and approvals
  • Essential communications

Resources

Resources

Know FDA BIMO Metrics

https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/bimo-inspection-metrics

Inspections Operation Manual

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/investigations-operations-manual

Chapter 5 covers site inspections

Focus of an Inspection

Inspection Focus

Focus

  • Regulatory
  • Qualifications and Training Records
  • DOA and Investigator Oversight
  • Protocol Compliance
  • IRB Review and Approval
  • Device/Drug Accountability
  • Document Maintenance and Retention
  • Fiancial Disclosures
  • Conflict of Interest
  • Sponsor Contact
  • Protocol Deviations
  • Note to Files

  • Patient Files
  • Consent/Assent
  • AEs and Reporting
  • Inclusion / Exclusion Criteria

Failure to Follow Protocol

Inadequate Records

Training

Case History

Study Records

Common Findings

Common Findings

Failure to Protect Subjects

Informed Consent Issues

Safety Reporting

Screening

Inclusion/Exclusion and Subject Enrollment

Preparation is Key

Preparation Is Key

Tools

Preparation

Inspection Announced

Know Your Policies

Review Study Documentation

SOPs Available

Typically Via Phone, Usually w/in 5 days of intended start

Clinical Trial Agreements & Financial Disclosures

Inspection Announced

Epic Access

Calls are Courtesy and Not Required

Key Study Dates, Enrollment timelines

IRB Approvals

Recorder - Uninvolved with the Study Under Inspection

Attempt to Accomodate Their Schedule

Determine Who Will Interact With the Inspector, Contact Should be Minimized

Consents and AEs / SAEs, Protocol Deviations and Notes or Memos to File

Keep a Record of All Documents Requested, and A Duplicate File For Your Records

Tools

1

List of all studies PI has been involved in as a PI or Sub-I over the last 5 years

Organizational Charts:

BDC & Team Specific

2

3

Detailed Study Timeline

During an Inspection

Inspector Arrival

  • Notify PI, Greet Inspector, Confirm Credentials
  • Form 482 Notice of Inspection Presented to PI
  • Escort Inspector to an empty conference room
  • Scope of Inspection and schedule determined
  • Introduction of PI and Study Staff
  • Do not keep any documents in the room
  • Inspections typically last 3-7 days
  • PI needs to be available
  • Inspection Initiation
  • Periodically throughout for questions
  • At Inspection conclusion

Inspection Process

Inspection Process

  • Assign a Scribe
  • Provide Only Requested Documentation
  • Keep a Record of Requested Documentation
  • Keep Inspector in a Secluded Conference Room
  • Escort the Inspector Within the Facility
  • Be Honest & Suscint in Responses - Never Guess
  • Request Issues Brought to Staff Attention as Noticed
  • Debrief at End of Each Day

Potential Requests

Potential Requests

Inspectors May Ask For A Variety of Study Documents to:

Verify Protocol Compliance

Compare Source and Submitted CRFs

Review Device and Drug Accountability Records

Review Other Study Related Documents

Review Medical Records to Ensure AE/SAE Reporting

Inspection Close

Inspection Close

Request a Closure Meeting

Clarify Any Confusing Remarks and Determine Next Steps

Potential Outcomes

No Action Indicated

Voluntary Action Indicated

Official Action Indicated

Hear Inspector Observations

Following an Insepection

Following an Inspection

No Findings

No Action Indicated: There were no findings and no response is indicated

Voluntary Action Indicated: Some objectionable conditions but not at threshold to take action

For either of these a formal response is not required. Consider any notes or corrective actions and policies that you can implement in future studies

Form 483 Issued

483 Issued

A Written Response in the Form of A Corrective Action, Preventative Action (CAPA) Plan Should be Prepared

  • Recap Observations
  • Provide Explanations
  • Describe Corrective and Preventative Actions That Will be Implemented
  • 4 Cs
  • Clear
  • Concise
  • Compelling
  • Complete
  • Must be Submitted Within 15 Days of Inspection Close

Questions

What kind of help can we expect from sponsors in an FDA Audit?

This depends on the sponsor, for some studies we have had sponsors come out and do a pre-study internal audit

For our most recent they did not come out but were available via email in case we needed a copy of anything but were mostly there to receive report on how the audit was going

1st thing after audit announced

What to do on the first day you find out an audit is happening?

Gather your team and initiate a plan of action

Retrieve binders - Iron Mountain / Storage

Review Critical Data - Complete Study Timeline

Subject Binders

What Prep Needs to be done with subject binders before an FDA Audit

Review:

Consents

AEs/SAEs

Inclusion/Exclusion Criteria

Visit CRFs

Order of things to review

What is the 1st thing you'd recommend reviewing in your site files prior to an FDA audit?

Consents

AEs/SAEs

IRB documents

Trainings/Certifications/CVs

Device/Drug Accountability

Calibration logs

DOA log

Screening and Enrollment Log

Top 3 Tips

Share you top three tips for facing an FDA audit!

Know your protocol

Be aware of all AEs/SAEs that occurred, when/how they were reported and be able to speak to these

Review your consents and be able to speak to any discrepancies or deviations.

Lessons Learned

What is something you learned from the audit that will prepare you better for another audit later?

Create a detailed study timeline - I can share an example if this is helpful

Keep an evolving record of Investigator trial involvement - this is easier to do ongoing as opposed to retrospective.

Pitfalls

What are some pitfalls in preparing for an FDA audit?

Becoming overwhelmed. The best thing you can do is remain calm and institute a plan for how to review the documents before inspectors come.

Sometimes there are many patient and regulatory binders, focus on the items discussed that are commonly reviewed by inspectors, then if there's time, proceed to other less critical study portions.

Resources

Are there resources that are useful for thinking about this not for FDA audits, but for other monitoring and study activities?

Know FDA BIMO Metrics

https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/bimo-inspection-metrics

Inspections Operation Manual

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/investigations-operations-manual

Chapter 5 covers site inspections

483 Consequences

What are the consequences for the study if you don't pass an FDA audit?

The 483 is not a final determination, but is a notice that the inspector found pieces of the audit objectionable and require a written CAPA w/in 15 days. This is then reviewed by the FDA and a determination is made

FDA 483 FAQs available here: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/fda-form-483-frequently-asked-questions

Non-compliance and missed calibrations

Please address resolving non-compliance from personnel that are no longer at the BDC or missing calibration records etc.

Unfortunately this is a common cause for a 483.

Best practice is know whats missing and be able to answer with a clear and concise 'why' should the investigator ask

For former workers, there is not much to be done either. You can see if they may have another similar training in your files that could be used: i.e. skillsoft in place of CITI or a study specific training

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