1. Preparing For A VA Compliance Audit Kimberly Summers, PharmD Assistant Chief for Clinical Research South Texas Veterans Health Care System, San Antonio, TX

2. An Active Monitoring and Auditing Program is Important for… Maintaining participant and staff safety Protecting the reputation of the PI, staff, sponsor, and institution Maintaining data quality Protecting funding Measuring compliance with regulatory requirements

3. Components of a Monitoring Program Investigators and their staffInvestigators and their staff Research Compliance OfficeResearch Compliance Office –STVHCS –UTHSCSA IRBIRB Research PharmacyResearch Pharmacy External MonitorsExternal Monitors R&D CommitteeR&D Committee

4. Layers of the Local Monitoring Program Research Subject PI Research staff IRB Compliance Office Research Pharmacy Specialized Monitoring Privacy Office Data Security Sponsor Monitors R&D Committee QA/QI Subcommittee

5. Components of a Local Monitoring Program The PI has primary responsibility for the proper conduct of the study; this includes appropriate monitoring by the research teamThe PI has primary responsibility for the proper conduct of the study; this includes appropriate monitoring by the research team Provides first and most important level of local research monitoringProvides first and most important level of local research monitoring Closest to the action; can respond to issues earlier and more quicklyClosest to the action; can respond to issues earlier and more quickly Can identify and correct problems before they harm participants or reach institutional visibilityCan identify and correct problems before they harm participants or reach institutional visibility Investigator Responsibilities

6. Role of External Monitors in local Monitoring Role of External Monitors in local Monitoring VHA Directive From Chief Research and Development Officer:VHA Directive From Chief Research and Development Officer: –Each research office must develop procedures that will ensure all serious findings and concerns are appropriately addressed and the appropriate facility officials and committees are notified Types of External monitoring visitorsTypes of External monitoring visitors –Pharmaceutical companies –Study sponsors –Contract Research Organizations (CROs) –VA Cooperative Studies Program –UTHSCSA Compliance Office

7. Auditing vs Monitoring Audits are in addition to the more detailed monitoring of studies by the research team and sponsor Audits are an independent evaluation by someone who is not directly associated with the research

8. ‘Research is concerned with discovering the right thing to do; audit with ensuring it is done right’ Smith, 1992; editor of the BMJ

9. VHA Directive 2008-064 Research Compliance Officers And The Auditing of VHA Human Subjects Research To Determine Compliance With Applicable Laws, Regulations, and PoliciesResearch Compliance Officers And The Auditing of VHA Human Subjects Research To Determine Compliance With Applicable Laws, Regulations, and Policies “An active auditing program should provide reasonable assurance of the integrity of the research program and that adequate protections for research subjects are in place.”“An active auditing program should provide reasonable assurance of the integrity of the research program and that adequate protections for research subjects are in place.” The Director must “ensure that the local HRPP conducts periodic audits of VA-approved research to assess compliance with all applicable laws, statutes, regulations...”The Director must “ensure that the local HRPP conducts periodic audits of VA-approved research to assess compliance with all applicable laws, statutes, regulations...”

10. Functions independently and objectively in the monitoring of research activitiesFunctions independently and objectively in the monitoring of research activities Reviews research activities from both a regulatory and human subject protection perspectiveReviews research activities from both a regulatory and human subject protection perspective Reports to the Medical Center DirectorReports to the Medical Center Director Findings reported to IRB and R&D Committee for appropriate actionFindings reported to IRB and R&D Committee for appropriate action Research Compliance Office

11. Investigator Site AuditsInvestigator Site Audits –Routine –For Cause Monitoring the Informed Consent ProcessMonitoring the Informed Consent Process Quality Assurance AuditsQuality Assurance Audits –IRB files and processes –R&D files and processes –Research Pharmacy files and processes How Does the Compliance Office Monitor Research

12. Problem identified by a bad outcomeProblem identified by a bad outcome Potential problem identified by a component of the HRPPPotential problem identified by a component of the HRPP –Clinical, pharmacy, or other institutional staff –IRB –R&D Office –Sponsor –Research subject Increased potential for research non-complianceIncreased potential for research non-compliance –Evidence of a poorly educated investigator –“Flying under the radar” investigator For-Cause or Targeted Audits

13. Routine Investigator Audits Check documents and procedures at the project level Each VA-approved human research protocol is completely audited at a minimum of once every 3 years Compliance with regulations for informed consent is audited at a minimum once a year

14. The audit process is designed to be support rather than punitive The process is meant to be useful in helping investigators and staff to achieve best practice in their research

15. Approach to Research Compliance Monitoring and Auditing VS.

16. Why Has My Study Been Chosen? Studies for routine auditing are chosen at random The STVHCS and UTHSCSA Compliance offices coordinate auditing visits to avoid duplication

17. What Will Happen at the Auditing Visit? The auditor will use an auditing tool consisting of a checklist for determining compliance with GCP and local policies and procedures STVHCS and UTHSCSA use the same auditing tool The auditors will visit the study staff work area to review study documents –A study staff member must be on hand to facilitate the review

18. Elements of the Auditing Tool Regulatory documents IRB submissions Informed consent Subject and/or data use Banking of specimens Inclusion / exclusion elements Serious adverse events Investigational drug Study site Confidentiality / data security

19. Additional Elements of the Auditing Tool Participant review –Consent form –Inclusion / exclusion criteria –CRF / source documents –UPIRSO reporting –Exceptions / deviations –VA documentation Investigational devices Principal investigator initiated / sponsored trials

20. Participant and Regulatory File Reviews – Your Record Keeping Purpose of record keeping –To keep an orderly account of progress –To facilitate the detection of errors –To meet legal requirements –To supply information required for taking certain actions Deviations, exemptions, etc. Notes to file

21. Participant Review Portion of Audit Research records and source documentation Adherence to IRB-approved research protocol –Inclusion/exclusion criteria –Screening procedures –Study procedures –Follow-up procedures Documentation of informed consent –Consent enrollment note in CPRS –Informed consent document scanned in CPRS

22. Preparing For The Participant Review Portion of the Audit Treat each patient as if he/she will be audited Make the research interventions an obvious portion of the patient’s chart Use documentation templates for enrollment, progress notes, and termination Provide complete documentation of clinical care and the rationale for protocol deviations or exemptions Document assessment of AEs and reporting of UPIRSOs

23. Components of the Regulatory File

24. Audit of Regulatory Files IRB correspondence –Initial and continuing review approval letters –Waivers and authorizations R&D correspondence –Initial and continuing review approval letters –Clinical impact statements –Data security checklist –Research protocol safety survey Sponsor correspondence –Exemptions –Queries –Changes in conduct of the study List in not intended to be all inclusive

25. Audit of Regulatory Files (cont) Protocol –Approved versions of the protocol –Protocol amendments –Investigator brochures Continuing review –Progress reports –DSMB minutes and reports Informed consent –All versions of IRB approved informed consent documents List in not intended to be all inclusive

26. Audit of Regulatory Files (cont) Participant enrollment –Screening log Reason not enrolled if screen failure –Enrollment log Name Last four Assigned study number Date informed consent was signed Enrollment date Termination date –Must be able to account for each signed informed consent List in not intended to be all inclusive

27. Audit of Regulatory Files (cont) Patient safety and monitoring –Data Safety and Monitoring Plan Adverse event monitoring and summaries Notes to file –Reported UPIRSOs –IND safety reports –PBM alerts Note to file for the PIs assessment and actions List in not intended to be all inclusive

28. Audit of Regulatory Files (cont) Drug/device accountability –All versions of 1572 if applicable –Shipment receipts –Inventory logs –Dispensing log if not maintained by pharmacy –10-9012 Investigational Drug Information forms –Contract if drugs are stored outside research pharmacy (rare instances) Laboratory –Certifications –Normal values –Lab director CVs List in not intended to be all inclusive

29. Audit of Regulatory Files (cont) Investigators and study staff –CVs signed and updated within 2 years –Medical / professional licenses –Certificates of training –Scopes of practice –Responsibility and signature logs –COI disclosure forms Monitoring –Monitor sign in log –External monitor reports List in not intended to be all inclusive

30. Hierarchy of Audit Problems I-words –Informed consent –Ineligibility –IRB –IND D-words –Drugs –Documentation –Diagnostic studies F-words –Follow-up –Forms –pro Forma (practices that seek to satisfy the minimum requirements )

31. Standard Operating Procedures (SOPs) Informed consent process Handling of body fluids / tissue samples Protocol coverage when PI is unavailable Maintaining participant confidentiality Handling participants’ comments, complaints, or concerns Unblinding procedures List in not intended to be all inclusive

32. Investigator Audit Report Summary of visit –Recommendations for improving practice –Action plan if necessary –Timelines for achieving compliance –Follow-up if required

33. A process for Principal Investigators to respondA process for Principal Investigators to respond Communication with responsible administratorCommunication with responsible administrator ConfidentialityConfidentiality Triggering of educational process as neededTriggering of educational process as needed Appropriate committee reporting, review and action if neededAppropriate committee reporting, review and action if needed Audit Reports Should Provide

34. Following The Audit Re-examine strengths and weaknesses in your individual program Address any issues in a written response to the audit findings –Including findings that may have been erroneous or require clarification Use this as a time to improve your research program

35. VA Compliance Office –Kari Williams, Research Compliance Officer –Pam Cervantez, Research Compliance Coordinator –Joanne Gonzales, Research Compliance Auditor UTHSCSA Compliance Office –Gayle Knight, Assistant Vice President for Regulatory Affairs and Compliance –Anna Taranova, Manager of Clinical Study Monitors 35

36. Questions and Comments?