Audits and Inspections in Clinical Trials

1. Overview of Inspections and Audits
Presented by Ashish A
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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
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3. Inspection
 An Audit conducted by a Regulatory Body
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4. Auditors and Inspectors
Auditors Inspectors
Independent of clinical trial project Are the members of particular
team 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.
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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.
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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 improvement
CAPA = Corrective And Preventive Action
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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)
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8. Audit Agencies
 Can be Sponsor
 Can be CRO
 Can be a contracted party
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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)
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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
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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.
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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
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13. When Inspector/Auditor Calls
HOW TO FACE …….
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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)
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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
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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 exhibits
File all the document asked by inspectors/auditors
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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
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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
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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)
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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) Warning
Auditors classify observations as; Minor, Major, Critical
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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 necessary
Minor: No significant deviations
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22. Inspection Classification
Voluntary 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 complete
Major: Significant deviations if not corrected can lead to rejection
of the data. CAPA required
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23. Inspection Classification
Official 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 and
unacceptability of the data
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24. Response to Form 483
Comments to Form 483 should be responded to:
 In writing
 Within 10 days
 Each response with corrective action and timeline
Audit response is required in written and with CAPA as per the
time lines agreed with auditor
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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
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26. To Get the Approval ……..
 Follow the Regulations/Protocol/SOP/GCP
 Document the activities
 Accept if done wrong and establish the CAPA
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27. Comparison between Audits and Inspections
Audits Inspections
Who conducts? Independent unit of the sponsor Regulatory authorities, IRB/IEC, Data
company Protection Agencies
Auditors Inspectors
What do they Trial conduct and compliance with
check? Protocol
ICH–GCP
Regulatory requirements
Data generated and reported is reliable, credible and acceptable
When do they Any time before, during, or after the trial
occur?
Why do they Randomly
take place? for cause
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28. Thank You
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