Overview of Audits and Inspections in Clinical Research


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Audits and Inspections in Clinical Trials

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Overview of Audits and Inspections in Clinical Research

  1. 1. Overview of Inspections and Audits Presented by Ashish A 1
  2. 2. Audits A systemic 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, GCP and the applicable regulatory requirements. (ICH-GCP; E6 1.6) Audits are part of Quality Assurance 2
  3. 3. Inspection An Audit conducted by a Regulatory Body 3
  4. 4. Auditors and InspectorsAuditors InspectorsIndependent of clinical trial project Are the members of particularteam regulatory agencyQualified by training and experience Are appointed by regulatory agenciesQualifications should be documented on the basis of their own defined criteria of qualification, experience and (ICH-GCP 5.19.2) training. 4
  5. 5. Objective of Inspection and Audits is to ….. Determine compliance of IRB, sponsors, clinical investigators and CROs with Protocol, GCP guidelines and applicable regulations Determine whether data generated and submitted to the regulatory authority are credible and acceptable. Assure the stake holders and public health agencies that the product is safe and not compromising with the public health. 5
  6. 6. Objective of Inspection and Audits is 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, GCP and the applicable regulatory requirements. Determine whether systems and processes are in place to perform the trial related activities. Provide recommendation and (CAPA) to the sponsor/site, for quality improvementCAPA = Corrective And Preventive Action 6
  7. 7. Major Regulatory Agencies DCGI, (Drug Controller General of India) USFDA, (US Food and Drug Administration) MCC, (Medicine Control Council of South Africa) MHRA, (Medicines and Healthcare products Regulatory Agency UK) EMEA, (European Agency for the Evaluation of Medical Products) TGA, (Therapeutic Goods Administration), Australia) 7
  8. 8. Audit Agencies Can be Sponsor Can be CRO Can be a contracted party 8
  9. 9. Inspection and Audits: An Overview FDA has (under FD&C Act), the authority to inspect any unit that provided source data in support of an IND/NDA/ANDA. Applicable to; drugs, biological products, devices, veterinary medicine, food/color additives Sponsor responsible for QA/QC, as defined in the MSA, has rights to conduct systems/study audits. (ICH-GCP; E6 - 5.1) 9
  10. 10. Types of FDA Inspections The “Bioresearch Monitoring Program” covers two types of inspections:  “Study –Oriented Inspections”  “Investigator – Oriented Inspection”Audits can be Study and/or system and processes audits 10
  11. 11. Study – Oriented Inspection These cover the majority of inspections conducted for a specific application of a drug, device, biological. To assess compliance of data and procedures with FDA regulations. 11
  12. 12. Investigator – Oriented Inspection Initiated when questions arise from problems with previous inspections Questions from the reviewing center during its review of study data Complaint from a study subject, study monitoring staff or sponsor 12
  13. 13. When Inspector/Auditor Calls HOW TO FACE ……. 13
  14. 14. Preparation Immediately notify all relevant personals and parties Assign a site escort / facilitator Assemble all study documents in 1 place  Include list of staff responsibilities and training  Keep all study related documents ready & up to date  Request all patient data (source / hospital notes) 14
  15. 15. Preparation Train the staff to current procedures Perform adequate QC and be ready with CAPA Reserve adequate work space at the site for entire inspection Assure accessible photocopier 15
  16. 16. When inspector/auditors arrives…….  Upon arrival displays credentials (e.g., photo ID) and Notice of Inspection (482) or Agenda  Requests related trial data and documents during site visit  May need copies of documents as exhibitsFile all the document asked by inspectors/auditors 16
  17. 17. Conduct of Inspection/Audit includes Opening interviews with key persons to discuss the agenda Inspection of Facilities and Equipments used/going to be used for the study and generation of data SDV (source data verification) and IP accountability Review of all essential documents like IRB notifications, Protocol, IB, ICD, FDA 1572, safety notifications etc. Interviews of site staff directly involved in trial activities and processes. Exit interview to discuss the observations and clarifications 17
  18. 18. Exit Interview After completion, investigator/auditor conducts “exit interview" with responsible site personnel to: Review findings Clarify misunderstandings Describe any deviations from current regulations Suggest corrective action, if appropriate If deviations, FDA inspector leaves a Form 483, (Notice of Inspectional Observations)Auditors send Audit report 18
  19. 19. Outcome of FDA Inspection After an inspection the investigator writes ..  Establishment Inspection Report (EIR) to Bioresearch Monitoring Division, where it receives a “final classification”  The EIR is an internal agency document, not provided to the sponsor  Unless requested through the Freedom of Information Act (FOI) 19
  20. 20. Inspection Classification Establishment Inspection Repot classifies the observations as Classification Type of Letter NAI (No Action Indicated) Notice of no significant deviations VAI (Voluntary Action Indicated) Informational OAI (Official Action Indicated) WarningAuditors classify observations as; Minor, Major, Critical 20
  21. 21. Inspection Classification No Action Indicated (NAI)  No objectionable conditions or practices found during the inspection  A letter may be issued but no response is necessaryMinor: No significant deviations 21
  22. 22. Inspection ClassificationVoluntary Action Indicated (VAI) Objectionable practices that representing departure from regulations Letter may be issued, Written response by the investigator is warranted, even if the response to the 483 is completeMajor: Significant deviations if not corrected can lead to rejectionof the data. CAPA required 22
  23. 23. Inspection ClassificationOfficial Action Indicated (OAI) Objectionable practices that represent significant departures from regulations FDA issues a Warning Letter Must respond to Warning Letters in writing within 15 days Must indicate corrective action and time period for completion May result in rejection of the data, black listing and regulatory action against investigator, withdrawal of marketing approval.Critical : presence of exhibits of significant deviation andunacceptability of the data 23
  24. 24. Response to Form 483Comments to Form 483 should be responded to:  In writing  Within 10 days  Each response with corrective action and timelineAudit response is required in written and with CAPA as per thetime lines agreed with auditor 24
  25. 25. Common Inspection/Audit findings Problems with consent procedure Non-adherence to protocol/SOPs/Regulations Inadequate or in accurate records Improper drug accountability Problems with EC approval Failure to record Adverse Events and concomitant medications Problems in reconstruction 25
  26. 26. To Get the Approval …….. Follow the Regulations/Protocol/SOP/GCP Document the activities Accept if done wrong and establish the CAPA 26
  27. 27. Comparison between Audits and Inspections Audits InspectionsWho conducts? Independent unit of the sponsor Regulatory authorities, IRB/IEC, Data company Protection Agencies Auditors InspectorsWhat do they Trial conduct and compliance withcheck? Protocol ICH–GCP Regulatory requirements Data generated and reported is reliable, credible and acceptableWhen do they Any time before, during, or after the trialoccur?Why do they Randomlytake place? for cause 27
  28. 28. Thank You 28
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