Audit and Inspection in

Clinical Trial

Dr. Ranjeet Prasad

(MBA,CCRP,BDS)
 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
 OBJECTIVE (Conti…)
• AUDIT PROCEDURES RULE
• PREPRATION FOR AUDIT
• MULTIPLE CHOICE QUESTION
 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 sop’s, GCP, and Applicable
regulatory requirements.

(ICH-GCP Sec. 1.6)

 Purpose of Audit
• 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
 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
 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
 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
 What to audit (Cont…)
• IRB/EC
– Responsibilities
– Composition, functions and operations
– Procedures
– Records
• Investigators and sub-investigators
– Qualifications and agreements
• Essential documents
 What to audit (Cont…)
Essential documents:
– Investigator’s 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)
 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
 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)
 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
 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
 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
 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
 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
 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
 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,
• Sponsor’s and/or CRO’s facilities,
• Other establishments deemed appropriate by the regulatory
authority”

(ICH-GCP Sec 1.29)

 Steps in FDA Inspection Process
FDA Office Site Location

1. Select Site
2. Contact Site
3. Schedule Site

9. Write Report (EIR) 7. Present Findings

10. Classify Inspection 8. Depart (483)

 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.
 Difference between Audit and Inspection
AUDIT
Inspectors are employed of the
company who work for a active
clinical quality assurance (CQA)
function (i.e. Sponsor/CRO)
To ensure that a site is complying
with Protocol, SOP, GCP and
Applicable regulatory
requirements.
INSPECTION
Inspector are employed by
government, through the agency
of the regulatory or competent
Authority (i.e. FDA/DCGI)
To ensure that trial related
obligations and acceptability of
resultant clinical data is in support
of a new drug approval.
 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
 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
 Types of studies Audit/Inspection
Routine: For-Cause:
To ensure that a site is complying If the site is out of compliance and
with Protocol, SOP, GCP and the sponsors want to either verify
Applicable regulatory the problem or be reassured that
requirements. no problem exists.
This is referred as “ROUTINE This is referred as “FOR-CAUSE
AUDIT” AUDIT”
“Study-oriented Audit” “Investigator – oriented Audit”
 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
 For-Cause Audit/Inspection
• Done by FDA / Sponsor/In-house (CRO)/ IRB
• Cause:
1. Allegation/Suspicion of non-compliance.
2. Safety or efficacy data is inconsistent with other study sites.
3. PI conducting research outside area of specialty.
4. Accrual is abnormally high for geographical or ethnicity/race
location.
 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)
 What Gets Audited
5 Categories :
1. Regulatory and protocol compliance
2. Subject Records
3. Investigational Product
4. Adverse events, SAEs or complications
5. Documentation
 How Auditor select the sites
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
It generally occur when the
drug regulatory authority
has cause to suspect
particular research’s
conduct i.e. “For-cause
Audit
 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
 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
 Audit Procedures
• Pre Audit Procedure
• During Audit Procedure
• After Audit Procedure
 Pre-Audit preparation
1) 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
 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 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
 Pre-Audit preparation Cont…..
2) CRA’s 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
 Pre-Audit preparation
3) Auditor’s 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
 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
 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
 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
 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
 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:
 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.
 Do’s (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.
 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
 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
 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.
 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
 Multiple choice questions
1) Audit is:
a) Systemic examination of trial
b) Independent examination of trial
c) Both of above
d) None of above

2) Purpose of audit : trial conduct and compliance with

a) GCP and regulatory authorities
b) Protocol and Sponsor SOP
c) Quality System
d) All of the above
 Multiple choice questions
3) Manufacturing, packaging, labeling and coding of the
investigational product must be compliance with
a) GCP
b) GMP
c) Both of the above
d) None of the above

4) What documents not to be show during audit/inspection

a) Certifications or accreditation of labs
b) Normal value(s)/ranges for medical/laboratory tests
c) Monitor and CRC appraisal letter
d) All of the above
 Multiple choice questions
5) What to be audited from following
a) Decoding procedures for blinded trials
b) Financial disclosure of Investigator
c) Salary structure of CRC and CRA
d) Both (a) & (b)
e) Both (a) & (c)
6) Inspection is done by:
a) Sponsor
b) Regulatory authority
c) CRO
d) Pharmaceutical Industries
e) All of the above
 Multiple choice questions
7) A summary report of inspectional observations is done on:
a) Form 482
b) Form 483
c) Form 1571
d) Form 1572
 
8) Inspectors are employed by Sponsor/CRO for the purpose of:
a) Audit
b) Inspection
c) Both of the above
d) None of the above
 Multiple choice questions
9) “Notice of Inspection” is to be report on:
a) Form 482
b) Form 483
c) Form 1571
d) Form 1572
 
10) Inspectors are employed by government/Regulatory authority
for the purpose of:
a) Audit
b) Inspection
c) Both of the above
d) None of the above
 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:
a) For cause audit
b) For cause inspection
c) Routine audit
d) Routine inspection

12) Sponsor want to ensure that a site is complying with Protocol, SOP,
GCP and applicable regulatory requirements, Procedure referred as:
a) For cause audit
b) For cause inspection
c) Routine audit
d) Routine inspection
 Multiple choice questions
13) “For Cause Audit” is:
a) “Investigator – oriented Audit”
b) “Study-oriented Audit”
c) None of the above
d) All of the above

14) When is Study Audited:

a) At anytime during the study
b) After the study is completed prior to regulatory approval for the product
c) At any time after regulatory approval
d) None of the above
e) All of the above
 Multiple choice questions
15) During audit, auditor must be present :
a) Photo ID and Form 483
b) Photo ID
c) Form 482
d) Photo ID and Form 482