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Title: audit and inspection in clinical trial


1
Audit and Inspection in Clinical Trial
  • Dr. Ranjeet Prasad
  • (MBA,CCRP,BDS)

2
OBJECTIVE
  • WHAT IS AUDIT
  • PURPOSE OF AUDIT
  • WHAT IS INSPECTION
  • DIFFERENCES BETWEEN AUDIT AND INSPECTION
  • WHO IS RESPONSIBLE FOR AUDIT AND INSPECTION
  • TYPES OF AUDIT AND INSPECTION
  • REASON FOR AUDIT AND INSPECTION
  • WHEN AND WHAT GET AUDITED

3
OBJECTIVE (Conti)
  • AUDIT PROCEDURES RULE
  • PREPRATION FOR AUDIT
  • MULTIPLE CHOICE QUESTION

4
What is 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
    sops, GCP, and Applicable regulatory
    requirements.
  • (ICH-GCP Sec. 1.6)

5
Purpose of Audit
  • The purpose of a sponsors audit is to evaluate
    the trial conduct and compliance with-
  • Quality Systems and SOPs
  • Protocol
  • Good clinical practices other applicable
    regulatory requirements
  • Auditors are independent of the clinical trial/
    data collection system(s)
  • Sponsor or CRO or Site

6
What to audit
  • Organization and personnel
  • Responsibilities and functions - Ensure clear
    responsibilities exist so as to minimize
    ambiguity between-
  • Investigator and sub-investigator
  • Sponsors and contractors
  • Contractors/suppliers (CROs, Labs, IRBs) audit
    suppliers!
  • Qualification, training and adequacy of staff
  • List of monitors
  • List of all investigators

7
What to audit (Cont)
  • Quality management systems
  • Management responsibilities
  • Procedures and their adequacy
  • Training
  • Documentation control
  • Change control
  • Deviations and non conformities management
  • QC, QA
  • Internal Monitoring Program
  • Internal Auditing Program

8
What to audit (Cont)
  • Investigational drug
  • Manufacturing, packaging, labeling and coding of
    the investigational product (including placebo
    and active comparator where applicable) in
    accordance with applicable GMP standards
  • Labeling requirements, For Clinical Trial Use
    Only to protect blinding where applicable
  • Drug Product Accountability
  • Control Quantity

9
What to audit (Cont)
  • IRB/EC
  • Responsibilities
  • Composition, functions and operations
  • Procedures
  • Records
  • Investigators and sub-investigators
  • Qualifications and agreements
  • Essential documents

10
What to audit (Cont)
  • Essential documents
  • Investigators brochure
  • Has all current info been provided to the
    investigator?
  • Signed protocol and amendments
  • How are changes and deviations to the protocol
    handled?
  • Advertisements for subject recruitment
  • Informed consent forms
  • Approved by IRB/IEC?
  • All been signed off according to requirements?
  • Financial aspects of the trial
  • Approved by IRB/IEC?
  • Insurance statement (where required)

11
What to audit (Cont)
  • Essential Document
  • Subject Databank
  • Subject screening log
  • Subject identification code list
  • Subject Enrollment log
  • Case report forms
  • Documentation of CRF corrections
  • Serious adverse events reporting
  • Signature sheet
  • Signed agreements between parties
  • IRB/IEC approval/favorable opinion
  • IRB/IEC composition

12
What to audit (Cont)
  • Essential Document
  • Regulatory authorities authorization/approval/
    notification of the protocol
  • Normal value(s)/ranges for medical/laboratory
    tests
  • Certifications or accreditation of labs (or other
    means that establishes competency of lab)

13
What to audit (Cont)
  • Essential Document
  • At the clinical site- investigational product
    and trial related materials
  • Instructions for handling
  • Shipping records
  • Certificates of analysis of product shipped
  • Accountability at the trial site
  • Decoding procedures for blinded trials
  • Master randomization list and method

14
What to audit (Cont)
  • Essential Document
  • Records of retained body fluids/tissue samples
    (if any)
  • Monitoring visit reports
  • Pre trial
  • During trial
  • Post trial
  • Final report by investigatory
  • Clinical study report
  • Archiving

15
What to audit (Cont)
  • Bio-analytical Laboratories
  • Documentation control including archiving
  • Qualification of instruments
  • Qualifications and Training of staff
  • Bio-analytical method validation
  • Receipt and storage of samples
  • Handling of reagents and solution
  • Testing conducted as outlined in protocol
  • CFR 11 compliance

16
What to audit (Cont)
  • Computerized systems (used to create, modify,
  • maintain, archive, retrieve or transmit data)
  • Identify software and hardware used, when and
    where?
  • Check security of the system (individual Login,
    secure passwords)
  • Check traceability
  • Check audit trail capabilities where applicable-
  • Who made the changes?
  • When and
  • Why, Certification of changes by appropriate
    authorities
  • Check validation status where applicable
  • Check record retention capabilities

17
What to audit (Cont)
  • Computerized systems (used to create, modify,
  • maintain, archive, retrieve or transmit data)
  • Adequate procedures that need to be in place-
  • System setup/installation
  • Data collection and handling
  • System maintenance
  • Data backup, recovery and contingency plans
  • Security
  • Change control
  • Alternative recording methods
  • Personnel training

18
What to audit (Cont)
  • Statistical component
  • Check statistical procedures and methods used are
    according to protocol
  • Check statistical package used has been validated
  • Review statistical analysis and results
  • Check integrity of data and timely locking of
    database

19
What is Inspection
  • The act by a regulatory of conducting and
    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,
  • Sponsors and/or CROs facilities,
  • Other establishments deemed appropriate by the
    regulatory
  • authority

  • (ICH-GCP Sec 1.29)

20
Steps in FDA Inspection Process
Site Location
FDA Office
  1. Select Site
  2. Contact Site
  3. Schedule Site

7. Present Findings 8. Depart (483)
21
FDA Form 483 (Notice of Observation)
  • A summary report of inspectional observations.
  • It is a list of objectionable conditions or
    practices observed during the inspection,
    prepared by the FDA investigator and presented to
    the auditee at the conclusion of an inspection.

22
Difference between Audit and Inspection
AUDIT INSPECTION
Inspectors are employed of the company who work for a active clinical quality assurance (CQA) function (i.e. Sponsor/CRO) Inspector are employed by government, through the agency of the regulatory or competent Authority (i.e. FDA/DCGI)
To ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements. To ensure that trial related obligations and acceptability of resultant clinical data is in support of a new drug approval.
23
Who is responsible for Audit and Inspection
  • The following entities have rights to conduct the
    Audit/Inspection at site based on regulation
  • FDA/CDSCO
  • OHRP ( Department of health and Human Services)
  • The Sponsor of the clinical trial
  • CRO/ Cooperative Groups/Grant-Funded Research
  • IRBs and Institutions

24
Reason to Audit and Inspection
  • In connection with a clinical study, An
    Audit/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

25
Types of studies Audit/Inspection
Routine For-Cause
To ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements. This is referred as ROUTINE AUDIT 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
Study-oriented Audit Investigator oriented Audit
26
Routine Audit/Inspection
  • 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
  • In-house (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

27
For-Cause Audit/Inspection
  • Done by FDA / Sponsor/In-house (CRO)/ IRB
  • Cause
  • 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.

28
When is Study Audited
  • At anytime during the study
  • After the study is completed prior to regulatory
    approval for the product
  • At any time after regulatory approval (15 years)
    if a safety concern with the product (rare)

29
What Gets Audited
  • 5 Categories
  • Regulatory and protocol compliance
  • Subject Records
  • Investigational Product
  • Adverse events, SAEs or complications
  • Documentation

30
How Auditor select the sites
Study oriented audits Investigator 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. It generally occur when the drug regulatory authority has cause to suspect particular researchs conduct i.e. For-cause Audit
31
Audit Procedure-rule
  • 3 to 5 minutes rule
  • To provide documents requested by Inspector
  • If not available be truthful
  • Beyond five minutes inspector may assume that it
    has been fabricated
  • Documentation thumb rule
  • If not documented means not done
  • If documented does not mean that it is done

32
Tips on Document Requests
  • Do not provide or copy these information for
    FDA/Auditor
  • Financial data (salary information, budgets)
  • (except financial disclosure of clinical
    investigators)
  • Personnel data (performance appraisals)
  • (except qualifications job descriptions and
    training records)
  • Remember 3-5 minute rule

33
Audit Procedures
  • Pre Audit Procedure
  • During Audit Procedure
  • After Audit Procedure

34
Pre-Audit preparation
  • 1) CRC Preparation
  • Notify all staff involved in study about the
    audit with date, time duration of the audit.
  • Ensure the Investigators 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

35
Pre-Audit preparation Cont.
  • 1) CRC Preparation (Continue)
  • 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 CRAs 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

36
Pre-Audit preparation Cont..
  • 2) CRAs Preparation
  • Review and verification of every essential
    document should be complete and properly placed
  • Ensure resolution of unresolved queries before
    audit
  • Notify confirmation of audit agenda to site for
    conduct of audit at selected site

37
Pre-Audit preparation
  • 3) Auditors Preparation
  • Auditor should have 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

38
Audit Procedure (During)
  • Auditors present their credentials (photo ID) a
    Notice of Inspections (Form 482) 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

39
Audit Procedure (During) cont.
  • 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

40
Audit Procedure (During) cont.
  • 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

41
Audit Procedure (During) cont.
  • 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

42
After Audit Procedure
  • 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

43
Dos
  • 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 inspectors notes
    regarding adverse findings.

44
Dos (Cont)
  • Clarify or attempt to resolve issues as they are
    made known. (remember 3-5 rule)
  • If the questions seems vague, ask for
    clarification before answering. Make sure the
    inspection understands your response.
  • Be courteous, professional and available.

45
Dos (Cont)
  • 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

46
Do Not
  • Do not give more information than asked for.
  • Do not offer to change data unless it can be
    verified with the sponsor and supported by source
    documents.
  • Do not discuss other studies.
  • Do not discuss financial arrangement between you
    and sponsor

47
Do Not (cont)
  • Do not hide information or volunteer information
  • Do not sign affidavits.
  • Do not allow pictures
  • Do not leave the inspector alone
  • Do not initial/sign any errors.

48
Key to Success
  • Compliance is Organizational responsibility
    mandatory act
  • Compliance is not a individual responsibility
  • Integrity as a culture
  • Document properly what you do
  • Do not document what you do not do
  • Do it right at for the first time, at right time,
    in right manner

49
Multiple choice questions
  • 1) Audit is
  • Systemic examination of trial
  • Independent examination of trial
  • Both of above
  • None of above
  • 2) Purpose of audit trial conduct and
    compliance with
  • GCP and regulatory authorities
  • Protocol and Sponsor SOP
  • Quality System
  • All of the above

50
Multiple choice questions
  • 3) Manufacturing, packaging, labeling and coding
    of the investigational product must be compliance
    with
  • GCP
  • GMP
  • Both of the above
  • None of the above
  • 4) What documents not to be show during
    audit/inspection
  • Certifications or accreditation of labs
  • Normal value(s)/ranges for medical/laboratory
    tests
  • Monitor and CRC appraisal letter
  • All of the above

51
Multiple choice questions
  • 5) What to be audited from following
  • Decoding procedures for blinded trials
  • Financial disclosure of Investigator
  • Salary structure of CRC and CRA
  • Both (a) (b)
  • Both (a) (c)
  • 6) Inspection is done by
  • Sponsor
  • Regulatory authority
  • CRO
  • Pharmaceutical Industries
  • All of the above

52
Multiple choice questions
  • 7) A summary report of inspectional observations
    is done on
  • Form 482
  • Form 483
  • Form 1571
  • Form 1572
  •  
  • 8) Inspectors are employed by Sponsor/CRO for the
    purpose of
  • Audit
  • Inspection
  • Both of the above
  • None of the above

53
Multiple choice questions
  • 9) Notice of Inspection is to be report on
  • Form 482
  • Form 483
  • Form 1571
  • Form 1572
  •  
  • 10) Inspectors are employed by government/Regulato
    ry authority for the purpose of
  • Audit
  • Inspection
  • Both of the above
  • None of the above

54
Multiple choice questions
  • 11) If the site is out of compliance and the
    sponsors want to either verify the problem or be
    reassured that no problem exists, referred as
  • For cause audit
  • For cause inspection
  • Routine audit
  • Routine inspection
  • 12) Sponsor want to ensure that a site is
    complying with Protocol, SOP, GCP and applicable
    regulatory requirements, Procedure referred as
  • For cause audit
  • For cause inspection
  • Routine audit
  • Routine inspection

55
Multiple choice questions
  • 13) For Cause Audit is
  • Investigator oriented Audit
  • Study-oriented Audit
  • None of the above
  • All of the above
  • 14) When is Study Audited
  • At anytime during the study
  • After the study is completed prior to regulatory
    approval for the product
  • At any time after regulatory approval
  • None of the above
  • All of the above

56
Multiple choice questions
  • 15) During audit, auditor must be present
  • Photo ID and Form 483
  • Photo ID
  • Form 482
  • Photo ID and Form 482

57
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