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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
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AUDIT PROCEDURES RULE
PREPRATION FOR AUDIT
MULTIPLE CHOICE QUESTION
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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 sop’s, GCP,
and Applicable regulatory requirements.
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(ICH-GCP Sec. 1.6)
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The purpose of a sponsor’s 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
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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!
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Qualification, training and adequacy of staff
List of monitors
List of all investigators
What to audit (Cont…)
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Quality management systems
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Management responsibilities
Procedures and their adequacy
Training
Documentation control
Change control
Deviations and non conformities management
QC, QA
Internal Monitoring Program
Internal Auditing Program
What to audit (Cont…)
Investigational drug
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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
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IRB/EC
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Responsibilities
Composition, functions and operations
Procedures
Records
Investigators and sub-investigators
› Qualifications and agreements
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Essential documents
Essential documents:
› Investigator’s brochure
 Has all current info been provided to the investigator?
› Signed protocol and amendments
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 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)
What to audit (Cont…)
Essential Document :
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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
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)
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
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Decoding procedures for blinded trials
Master randomization list and method
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
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What to audit (Cont…)
Bio-analytical Laboratories :
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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
What to audit (Cont…)
Computerized systems (used to create, modify,
maintain, archive, retrieve or transmit data):
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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:•
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Who made the changes?
When and
Why, Certification of changes by appropriate authorities
Check validation status where applicable
Check record retention capabilities
What to audit (Cont…)
Computerized systems (used to create, modify,
maintain, archive, retrieve or transmit data) :
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Adequate procedures that need to be in
place:•
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System setup/installation
Data collection and handling
System maintenance
Data backup, recovery and contingency plans
Security
Change control
Alternative recording methods
Personnel training
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
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“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
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Site of the trial,
Sponsor’s and/or CRO’s facilities,
Other establishments deemed appropriate by the
regulatory
authority”
(ICH-GCP Sec 1.29)
FDA Office
Site Location
1. Select Site
4. Arrive (482)
2. Contact Site
5. Review Records
3. Schedule Site
6. Interview Staff
9. Write Report (EIR)
7. Present Findings
10. Classify Inspection
8. Depart (483)
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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.
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.
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The following entities have rights to conduct the
Audit/Inspection at site based on regulation
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FDA/CDSCO
OHRP: ( Department of health and Human Services)
The Sponsor of the clinical trial
CRO/ Cooperative Groups/Grant-Funded Research
IRBs and Institutions
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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
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”
• FDA:
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To evaluate data supporting a new drug or device
application
• Sponsor:
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To verify site data and conduct
To verify how the study was monitored
• In-house (CRO):
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To evaluate quality of research ongoing at the institution.
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To Justify placing a grant
Continuous Funding
To Verify data
• Cooperative Groups/Grant Funded Research:
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Done by FDA / Sponsor/In-house (CRO)/ IRB
Cause:
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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.
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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)
5 Categories :
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Regulatory and protocol compliance
Subject Records
Investigational Product
Adverse events, SAEs or complications
Documentation
Study oriented audits
Investigator oriented audits
Patient Enrollment: Highest
It generally occur when the
drug regulatory authority
has cause to suspect
particular research’s
conduct i.e. “For-cause
Audit
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.
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
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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)
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Remember 3-5 minute rule
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Pre Audit Procedure
During Audit Procedure
After Audit Procedure
1) CRC Preparation:
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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
1) CRC Preparation (Continue):
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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
2) CRA’s Preparation:
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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
3) Auditor’s Preparation:
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Auditor should have Audit plan/Agenda
Auditor may also prepare working documents for use during
audit, sometimes it becomes necessary to generate Auditspecific working
Notify conduct of audit to CRA and Site
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
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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
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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
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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
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:
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.
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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.
Do’s (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
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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
Do Not (cont…)
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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.
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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