How to Handle FDA Audits 9/11/2018 How to Handle FDA Audits Kate Dalton, MS, RD Clinical Manager Center for Interventional Vascular Therapy Columbia University TCT 2008 - DRAFT

I/we have no real or apparent conflicts of interest to report. Kate E. Dalton, MS, RD I/we have no real or apparent conflicts of interest to report.

9/11/2018 FDA Inspection The FDA may inspect a study at any time-always be prepared Utilize institution and sponsor support FDA inspector checklist Become familiar with the FDA BIMO manual for clinical investigators (7348.811) Audits are an expected part of clinical research. IF the study involved an IND or IDE, the FDA may conduct an inspection on site. 80% are routine Near the end of study and usually associated with PMA or NDA submission. BiMo=Bioresearch Monitoring Inspection The BiMo program is a comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA regulated research. The BiMo Program was established to assure the quality and integrity of data submitted to the agency, as well as to provide for protection of the rights and welfare of the thousands of human subjects involved in FDA regulated research. TCT 2008 - DRAFT

9/11/2018 FDA Inspection The FDA may inspect a study at any time-always be prepared Utilize institution and sponsor support FDA inspector checklist Become familiar with the FDA BIMO manual for clinical investigators (7348.811) Audits are an expected part of clinical research. IF the study involved an IND or IDE, the FDA may conduct an inspection on site. Near the end of study and usually associated with PMA submission. BiMo=Bioresearch Monitoring Inspection The BiMo program is a comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA regulated research. The BiMo Program was established to assure the quality and integrity of data submitted to the agency, as well as to provide for protection of the rights and welfare of the thousands of human subjects involved in FDA regulated research. TCT 2008 - DRAFT

FDA Audit Site Selection 9/11/2018 FDA Audit Site Selection High enrollment High drop-out/withdrawal rate Investigator or site new to research Unusually high or low SAE rate Unusually high or low protocol deviation rate Location Previous inspection history TCT 2008 - DRAFT

9/11/2018 Know the Regulations In order to increase compliance have a strong knowledge of: FDA regulations Good Clinical Practice (GCP) State regulations Institutional Standard Operating Procedures (SOP) Department guidance documents Protocol requirements 21 CFR parts X-X Code of Federal Regulations (CFR) title 21: Food & Drugs TCT 2008 - DRAFT

Always Be Prepared! Ongoing completion of source documents 9/11/2018 Always Be Prepared! Ongoing completion of source documents Regulatory binder maintenance Encourage frequent monitoring visits Ensure previous action items are addressed Conduct internal audits RC should complete source documents and data entry on an ongoing basis to prevent huge amount of work prior to monitoring visit and to avoid forgetting the details of the visit. TCT 2008 - DRAFT

9/11/2018 Anticlamactic TCT 2008 - DRAFT

What to Expect When You are Inspecting? 9/11/2018 What to Expect When You are Inspecting? Entrance interview Facility tour Quiet, spacious environment Regulatory and subject records Easy to read logs Check in with the Inspector Make copies of everything the Inspector takes PI can respond to the 483 verbally during the exit interview and/or in writing within 30 days Less is More TCT 2008 - DRAFT

9/11/2018 Regulatory Binder All protocols and consents with evidence of FDA and IRB approval FDA Form 1572 or Investigator Agreements Delegation of Authority CVs, License, Training Certificate, Financial Disclosures The 1572 is a binding contract between the investigator and the FDA, whereby the investigator makes certain commitments. TCT 2008 - DRAFT

Regulatory Binder Continued… 9/11/2018 Regulatory Binder Continued… FDA, IRB, Lab documentation Device/Drug Accountability Monitoring log and correspondence Sponsor correspondence TCT 2008 - DRAFT

Subject Charts Review all informed consents Documentation of: 9/11/2018 Subject Charts Review all informed consents Documentation of: Consent process Inclusion/Exclusion criteria Randomization Endpoints correctly reported Adverse Events/Serious Adverse Events (AE/SAE) captured in Case Report Forms (CRFs) TCT 2008 - DRAFT

Subject Charts Continued… 9/11/2018 Subject Charts Continued… Source data (labs, EKG) reviewed by the investigator Indicate clinical significance Cross check MR, source and CRF Address issues using NTF Device/drug accountability NTF Source data-show review by signing and dating. Make sure indicate clinical significance Research Tips-Any medications for treatment that the subject is on at baseline should correlate to medical history -If a subject starts a new med it should raise flags as an AE. Have someone screen the census for rehospitalizations thus flag SAE to sponsor Con Med Log-Make point about differences between MR and source docs TCT 2008 - DRAFT

Timeliness of Reporting 9/11/2018 Timeliness of Reporting Timely reporting Protocol deviations AEs/SAEs Unanticipated Problems TCT 2008 - DRAFT

What to Expect When Your Inspecting? 9/11/2018 What to Expect When Your Inspecting? Exit interview Deficiencies noted on form 483 Establishment Inspection Report (EIR) Post inspection letters No Action Indicated (NAI) Voluntary Action Indicated (VAI) Official Action Indicated (OAI) Warning letter Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) TCT 2008 - DRAFT

No Action Indicated (NAI) Voluntary Action Indicated (VAI) 9/11/2018 No Action Indicated (NAI) Voluntary Action Indicated (VAI) Official Action Indicated (OAI) http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm261409.htm TCT 2008 - DRAFT

2011 Most Common Deficiencies 9/11/2018 2011 Most Common Deficiencies Failure to follow the investigational plan and/or regulations Inadequate record-keeping Inadequate accountability for the IP Inadequate communication with IRB Inadequate subject protection-including informed consent issues Unorganized source Discrepancies in MR and source Protocol Deviations/Violations Create Corrective Action Plan Report to IRB Implement the plan http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm261409.htm TCT 2008 - DRAFT

In Summary… Ongoing preparation Know the scope 9/11/2018 In Summary… Ongoing preparation Know the scope Documentation, documentation, documentation Issues arise-it’s how you handle them Clean, Concise, Calm TCT 2008 - DRAFT

Things Not to Say Of course I allocated patients randomly: I let them choose. Well, I ran out of placebo, so I gave them this instead… Here are the staff I’ve delegated the key tasks to: Matt, Lauren and… um… what was your name again? Did I say I had data from thirteen patients? OK, wait a minute…I thought we had twelve You’re much nicer than the auditors who did that for-cause inspection last month.