1. Planning and Surviving An Audit/Monitoring visit Carmen B. Jacobs, BS, RN,OCN, CCRP U.T. MD Anderson Cancer Center Houston, Texas U.S.A

2. Objectives Sponsor’s role or responsibilities Difference between monitoring and auditing Preparing for monitor/audit visits Consequences of an audit with poor results Suggestions to prevent non-compliance

3. Sponsor’s Role According to 21CFR Part 312.50) – Select investigators and sites – Inform investigators of increased subject risk – Ensure proper monitoring – Ensure the investigation is conducted per the protocol – Maintain and retain records – Ensure the return or disposition of unused investigational drug supplies

4. Monitoring and Auditing Necessary to assure: 1.Rights and safety of patients are protected. 2.Reported trial data are accurate, complete, and verifiable from source documents. 3.Conduct of trial is in compliance with protocol, good clinical practice (GCP) and applicable regulatory requirements.

5. MONITORING

6. Monitoring Monitoring: act of overseeing the progress of a clinical trial, of ensuring that is conducted, recorded and reported in accordance with the protocol, standard operating procedures (SOPs), GCP, and all applicable regulatory requirements.  Data safety and monitoring plan  DSMB/DSMC Visits are routine and expected. May be conducted by the sponsor or CRO. Key to success visit: Preparation and Planning

7. Preparation and Planning  General Considerations:  Request medical records to be reviewed  Inform pharmacy of visit and schedule appointment  Check availability of PI, CTN, others  Arrange for a quiet room

8. Preparing for a Regulatory Review  All protocol versions and approvals  All Investigator Brochure versions  Lab certifications and normal ranges  All versions of Form 1572  CVs, licenses and Financial Disclosures for all investigators  All IRB correspondence  All Sponsor correspondence  Signature and Delegation of Responsibilities Log

9. Preparing for a Source Document Review Assure medical records contain (obtain missing information or document why unobtainable):  All laboratory and radiology reports  Progress notes (physician’s notes, nursing notes)  All AEs reviewed and attribution assigned by the investigator  Drug compliance/administration notes including stop and start times/dates  Procedures documenting study parameters  All original signed and dated consents  Informed consent process documentation

10. Preparing for a Source Document Review  Make sure laboratory reports and procedure reports are reviewed and signed by PI (if required per sponsor SOP).  Review research/shadow chart to make sure that documents not allowed in the medical record (e.g., QOL survey, PK worksheets) are available.

11. Preparing for a Case Report Form (CRF) Review Assure CRFs are complete, accurate, up to date. Focus on:  Adverse events  Concomitant medications  Study drug administration

12. Preparing for a Pharmacy/Drug Dispensing Review  Pharmacy or responsible individual should review drug dispensing records prior to visit to assure drug count is accurate  Will help if able to check the Drug Accountability Record Form (DARF) and actual drug count before visit  Inform PI of discrepancies

13. Common deficiencies found at a monitoring visit  Failure to follow the protocol  Failure to keep adequate and accurate records  Problems with the informed consent form  Failure to report adverse events  Failure to account for the disposition of study drugs  Source document to support eligibility criteria is not located  Source documents are not signed/dated  Corrections are not initialed /dated

14. Important factors to keep in mind  If the Investigator fails to comply with the protocol, prompt action is necessary to secure compliance.  When attempts to reach compliance remain an issue, the Sponsor may terminate the contractual agreement.  Completion of CRFs and query resolution may be tied to financial payment for the clinical trial  Successful monitoring visit:  Adequate preparation  Organization  Staying on top of documentation, CRFs completion, answering queries in a timely manner and documentation of circumstances for non-adherence to the protocol.

15. AUDITING

16. Auditing Auditing: systematic and independent examination of the trial related activities and documents to determine whether the evaluated trial related activities were conducted, the data recorded accurately, analyzed and appropriately reported, according to the protocol, sponsor’s SOPs, GCP, and all applicable regulatory requirements. Audits may be conducted during or after a study is completed.

17. Audit Goals  Review, inspect and verify:  The ethical conduct of human subject research  Integrity of previously reported data  Adherence to the study protocol  Applicable institutional, state and federal regulations and guidance

18. Audit Types  Federal audits  Sponsor audits  Cooperative group audits  Internal site audits  IRB audits  Routine  For-cause

19. Audits Routine inspections  sites with high subject enrollment  sites with data that significantly differs from others  representative “sample” For-cause inspections  issues with the quality or/and integrity of the data  rights of subjects may have been infringed  “complaint” from someone

20. Opening Interview  Who should be present  principal investigator  to determine his/her oversight of study activities  other individuals directly involved in the study  to answer questions, especially if the P.I. was not closely involved in study activities  Others that the inspector may ask to speak to:  sub-investigators, study coordinators, pharmacist, lab personnel, regulatory personnel

21. Source Documents  Documents to be inspected should be:  accurate  up to date  readily available  organized SHOULD BE ABLE TO RECONSTRUCT THE TRIAL

22. Most often reviewed  informed consent forms  documentation of the informed consent process  reported data  adverse events  regulatory records  source documentation to ensure protocol compliance  drug shipping records  drug dispensing records

23. Most often reviewed Auditors may also request to review the site’s internal SOPs for conducting human subjects research, the research team credentials and documentation of training.

24. Answering the inspector questions  make sure you understand the question before responding, ask for clarification if necessary.  answer honestly, succinctly.  do not be evasive.  do not interpret questions (i.e., “Do you mean……?”).  do not give false or misleading information.  do not trust your memory. Refer to documentation if necessary.

25. Exit meeting inspector will present the results of the inspection and discuss them with you.

26. Consequences of an audit with poor results  investigator may be prevented from conducting further studies.  investigator may be penalized in other ways.  agency (i.e., FDA) may require the sponsor to remove the data from the marketing application

27. Suggestions to prevent non-compliance  create standard operating procedures for the research being conducted at your site  document delegation of responsibilities  develop plan for organizing records  promptly report protocol violations to IRB and sponsor  work with monitors  correct small problems before they grow

28. Ensure Quality Data AA AAttributable - Is it obvious who wrote it? LL LLegible - Can it be read? CC CContemporaneous - Is the information current and in the correct time frame? OO OOriginal - Is it a copy? Has it been altered? AA AAccurate - Are conflicting data recorded elsewhere?

29. Points to remember Most importantly:  preparation for an audit should begin before the study starts  organize  create SOPs  educate  collect  ensure quality data

30. wisdom after “There is no wisdom equal to that which comes after the event.” - Geraldine Jewsbury