1. Audits and Inspections in Clinical Research Jobin Kunjumon Vilapurathu

2. What is an Audit: A Systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted and the data were recorded, analyzed and accurately reported according to the: Protocol Sponsor’s SOP Good Clinical Practice and Applicable Regulatory requirement (ICH-GCP Sec 1.6)

3. What is an Inspection: “The act by a regulatory authority, of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority to be related to the clinical trial and that may be located at the: Site of the trial, Sponsor’s and/or CRO’s facilities, Other establishments deemed appropriate by the regulatory authority” (ICH-GCP Sec 1.29)

4. Difference between Audit & Inspection: In Audit, Inspectors are employed of the company who work for a active clinical quality assurance (CQA) function (i.e. Sponsor/CRO) An Audit is done to ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements. In Inspection, Inspectors are employed by government, through the agency of the regulatory or competent Authority (i.e. FDA/DCGI) An Inspection is done to ensure that trial related obligations and acceptability of resultant clinical data is in support of a new drug approval

5. Who can Audit a Clinical Trail: The following entities have rights to conduct the Audit/Inspection at site based on regulation FDA: OHRP: ( Department of health and Human Services) The Sponsor of the clinical trial: Cooperative Groups/Grant-Funded Research; (Cancer and leukemia Group B handbook) IRBs and Institutions:

6. What triggers an Audit/ Inspection: In connection with a clinical study, An inspection may be undertaken if there are Concerns about its safety, data or ethics Monitor standards of clinical research When there is suspicion of fraud or scientific misconduct When there is serious quality systems breakdown

7. What all can be Audited/ Inspected: Site Investigators and Study Team IRB/IEC Sponsor CRO, if involved Laboratories Pharmacy (e.g. Investigational Drug Services) Devices (e.g. ECG, Biomedical, Engineering)

8. Why sites are Audited: Routine: (Study-oriented Inspection): To ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements. This is referred as “ROUTINE AUDIT” For-Cause:(Investigator – oriented Inspection) If the site is out of compliance and the sponsors want to either verify the problem or be reassured that no problem exists. This is referred as “FOR-CAUSE AUDIT”

9. Routine Audit: FDA: To evaluate data supporting a new drug or device application Sponsor: To verify site data and conduct To verify how the study was monitored Inhouse (CRO): To evaluate quality of research ongoing at the institution. Cooperative Groups/Grant Funded Research: To Justify placing a grant Continuous Funding To Verify data

10. For Cause Audit: FDA / Sponsor/In-house (CRO)/ IRB: Allegation/Suspicion of non-compliance. Safety or efficacy data is inconsistent with other study sites. PI conducting research outside area of specialty. Accrual is abnormally high for geographical or ethnicity/race location.

11. When can a Site be Audit: At anytime during the study After the study is completed prior to regulatory approval for the product At anytime after regulatory approval (15 years) if a safety concern with the product (rare)

12. On what basis the sites are selected for an Audit: Study oriented audits: Patient Enrollment: Highest enrolling sites Patient Retention: Large number of screen failures, unusually high patient drop-out rates Adverse Events: Large number of severe adverse events at only one or two sites Trial Importance: Pivotal studies. Investigator oriented audits Generally occur when the drug regulatory authority has cause to suspect particular research’s conduct i.e. “For- cause audit

13. Pre- Audit Procedures: CRC Preparation: Notify all staff involved in study about the audit with date, time & duration of the audit. Ensure the Investigator’s attendance during the Audit. Reservation/Arrangement for quiet, comfortable place to work and to assemble the necessary documents for Auditor Defined SOP/Agenda should be present and properly reviewed by all staff involved in trial before audit about interaction of auditor with site, from his welcome to exit Assemble all study documents in one place, they should be complete and well organized Assure accessible photocopier, provide a backup if necessary (to provide document when requested by them) Confirm / Verify about the CRA’s presence during the Audit and Review all the essential documents or any other problem which is found during this review so that the situation may be able to be remedied before audit

14. CRA’s Preparation: 1. Review and verification of every essential document should be complete and properly placed 2. Ensure resolution of unresolved queries before audit 3. Notify confirmation of audit agenda to site for conduct of audit at selected site

15. Auditor’s Preparation: Auditor should have an Audit plan/Agenda Auditor may also prepare working documents for use during audit, sometimes it becomes necessary to generate Audit-specific working Notify conduct of audit to CRA and Site

16. What happens during Audit : Auditors present their credentials (photo ID) & a Notice of Inspections Form to the Clinical Investigator Conduct Introductory Meeting Auditor will start auditing by reviewing specific data related to trial study and regulatory requirements. They will document all their findings Auditor also interview site staff directly involved in trial activities and process

17. What happens during Audit : Auditor’ s common observations for study 1. Protocol Non-adherence 2. Inadequate & inaccurate records 3. Failure to report adverse events 4. Failure to report concomitant therapy 5. Inadequate drug accountability 6. IRB/IEC problems 7. Informed Consent issues

18. What happens during Audit : Closing meeting (exit interview): At site visit completion, Auditor conducts “exit interview” with all responsible site personnel to: Review findings Clarify misunderstandings Describe any deviations from current regulations Suggest corrective action, if appropriate Auditor (FDA) may issue a Form FDA 483 (Notice of Observation) to the Investigator. This form will detail the findings from the audit that may constitute compliance violation

19. What happens after Audit : After the Audit is complete, the Auditor prepares an: Audit certificate: A declaration of confirmation by the auditor that an audit has taken place. Audit report / Establishment Inspection Report (EIR): A written evaluation by the sponsor's auditor of the results of the audit EIR Classification: Classification & Type of Letter NAI (No Action Indicated) : Notice of no significant deviations VAI (Voluntary Action Indicated) : Informational OAI (Official Action Indicated) : Warning

20. What gets Audited : 1. Regulatory and protocol compliance 2. Subject Records 3. Investigational Product 4. Adverse events, SAEs or complications 5. Documentation

21. Some Do’s : Inspector should present a Form FDA 482 “Notice of Inspection.” Have all subject records organized and available. Give the inspected only those records specifically requested. Make scrupulous notes of comments/ concerns/ deficiencies pointed out by the inspected Question entries in the inspector’s notes regarding adverse findings. Clarify or attempt to resolve issues as they are made known. (remember 3-5 rule)

22. Some Do’s: If the questions seems vague, ask for clarification before answering. Make sure the inspector understands your response. Be courteous, professional and available. Object to requests for unreasonable information (e.g. Financial records and Home addresses of subjects). In this case, the investigator may ask for a written request from the FDA Let the sponsor know of the outcome as soon as possible Answer- Politely, co-operate, understanding them factfully, without speculation or guess work

23. But Please Don’t even think of… Giving more information than asked for. Offering to change data unless it can be verified with the sponsor and supported by source documents. Discussing other studies. Discussing financial arrangement between you and sponsor Hiding information or volunteer information Signing affidavits. Allowing pictures Leaving the inspector alone Putting initials/signing any errors.