1. MONITORING AND
AUDITING IN CLINICAL
TRIALS
Presented By :
Jyotsna Kapoor
MSc Clinical Research
Sem III

2. Introduction
 QC systems are the operational techniques and activities
undertaken to verify the requirements for the quality of trial
related activities .
 Monitoring is a part of QC activity
 QC activities are undertaken by the trial members
themselves
 QA is the planned and systemic action that ensures that the
trial is performed and the data is generated , documented
, analyzed and reported in compliance with GCP and
applicable regulatory requirements.
 Audit and inspection are part of QA activities and are
undertaken by personnel independent of trial.

3. Monitoring
 Monitoring is the act of overseeing the
progress of a clinical trial , and ensuring
that it is conducted, recorded, and
reported in accordance with the
protocol, Standard Operating Procedures
(SOPs), Good Clinical Practice (GCP), and
the applicable regulatory
requirement(s).

4. Purpose of Monitoring
To verify that:
 The rights and well-being of human subjects are
protected.
 The reported trial data are accurate, complete, and
verifiable from source documents.
 The conduct of the trial is in compliance with the
currently approved protocol/amendment(s), with
GCP, and with the applicable regulatory
requirement(s).

5. Selection and Qualifications of
Monitors
 Monitors should be appointed by the sponsor.
 Monitors should be appropriately trained, and should
have the scientific and/or clinical knowledge needed
to monitor the trial adequately.
 Monitors should be thoroughly familiar with the
investigational product(s), the protocol, written informed
consent form and any other written information to be
provided to subjects, the sponsor's SOPs, GCP, and the
applicable regulatory requirement(s).

6. Responsibilities of Monitor
 Acting as the main line of communication
between the sponsor and the investigator.
 Verification of investigator’s qualifications
,expertise and resources and availability
throughout the study.
 Adequate & continued availability of institutional
facilities , sufficient IP’s with proper storage
facilities.
 To ensure that the IP’s are supplied to eligible
subjects at the specified doses and times and
with proper instructions for handling
 To Ensure documentation of receipt

7. Contd…
 To ensure investigator receives current IB
 To ensure compliance of protocol and
maintenance of essential documents by
investigator
 To ensure proper training of the trial team
 To ensure that any of the trial tasks are not
delegated to unauthorized individuals
 Informing sponsor in case of an unwarranted
deviation
 To follow predetermined written set of SOPs
 Observing and reporting subject recruitment rate
to sponsor
 To ensure that all CRFs are correctly filled , legible
, accurate , complete signed and dated

8. Contd…
 To submit a written report to sponsor after each
site visit and after all communications
 Ensuring the documentation of storage , handling
, dispensing and return IP as per protocol and
SOP

9. Monitoring Report
 Submitted to sponsor
 Reports should include :
I. Date
II. Site
III. Name of the monitor
IV. Name of the investigator or other individuals
contacted during study
V. Summary of monitor review , statements
concerning significant findings , deficiencies
, deviations , actions to be taken or taken or
actions recommended to secure compliance

10. Contd..

12. Audit
 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)

13. Purpose of Audit
 to evaluate the trial conduct and compliance
with:-
I. Quality Systems
II. SOPs
III. Protocol
IV. Good clinical practices &
V. other applicable regulatory requirements
 Auditors are independent of the clinical trial/
data collection system(s) Sponsor or CRO or
Site

14. What to audit ?
 Organization and personnel Responsibilities and
functions .
 Qualification, training and adequacy of staff List of
monitors , List of all investigators ,
 Drug supply agreement , clinical trial (site )agreement
, other services agreement and material transfer
agreement
 Quality management systems
 Investigational drug
 Manufacturing,
 packaging,
 labeling and coding of the IP(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

15. Contd…
 IRB/EC
 Responsibilities
 Composition,
 functions and
 operations
 Procedures
 Records

16.  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? )

17.  Subject Databank
 Subject screening log
 Subject identification code list
 Subject Enrollment log
 Case report forms
 Documentation of CRF corrections
 Serious adverse events reporting

18. What to audit (cntd..)
 Certifications or accreditation of labs
 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
 Records of retained body fluids/tissue samples (if
any)
 Monitoring visit reports
I. Pre trial
II. During trial
III. Post trial

19. What to audit ? (Contd)
 Bio-analytical Laboratories
 Computerized systems
 Statistical components

20. How to execute an audit ?
 The execution of audit process is divided into
three steps :
1. BEFORE THE AUDIT
2. DURING THE AUDIT
3. AFTER THE AUDIT

21. Before the audit process
 Auditor contacts the site to arrange for a mutually
acceptable date and time for an audit to be
conducted
 A detailed agenda of an audit is informed to the
CRC and also about the documents to be
checked during an audit
 Auditor previews the protocol , CRF , local
regulations and guidelines , project specific
guidelines , relevant SOPs to be aware of the trial.

22. During the audit process
 Opening meeting
 An introductory meeting between the auditor
and the site team
 Auditor briefs the scope and procedures to be
followed during the audit
 An opportunity for trial team members
including the investigator to communicate with
the auditor
 Reviewing documents and collating
information
 Audit observations ( documents all
observations)

23. After the audit process
 Auditor should issue the audit report (an internal and
confidential document) within 28 days of the final
audit activity
 He makes clinical research personnel aware of the
findings relevant to their activities , and findings are
classified as critical , major and minor
 Prevention/ corrective action list should accompany
the report
 A formal audit response should be prepared and
submitted by the trial team to the concerned
personnel after the corrective measures have
been taken
 Following the satisfactory responses to the audit
, auditor issues an audit certificate confirming that
audit has taken place and filed in clinical trial report
and also submitted to regulatory authorities

24. 6 Types of audit
 Sponsor audit of investigative site
a. Routine Audit
b. For Cause Audit
 IRB audit of investigative site
 System audit of sponsor / CROs
 Clinical laboratory Audit
 Clinical study report audit
 Validation of computer system

25. 1. Sponsor audit of investigative
site
 Aim To assess whether :
• the subject’s rights and safety have been
maintained
• Company procedures satisfactorily
implemented
• Accurate , reliable and verifiable data has been
obtained from the trial
 Provides assurance to both the sponsor and
investigator that if a regulatory inspection occurs ,
no major problems have remained undetected
and unresolved

26. Routine audit and For cause
audit
Routine: For-Cause:
To ensure that a site is If the site is out of compliance
complying with Protocol, SOP, and
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”

27. 2. IRB audit of investigative
site
 To ensure ethical conduct of the trial
 Ensure subjects enrolled are well informed
about the trial and enrolled through a proper
informed consent procedure
 To ensure IRB plan is followed , proper
documents are made .

28. 3. System audits
 To assess the quality and efficiency of the QC
systems employed by the sponsor or CRO
 Policies and procedures audited :
 SOPs
 Document access control
 Security and validation of computers used
 Personnel record
 Interviewing of the staff about their job
responsibility and description

29. 4. Clinical laboratory audit
 Involves evaluation of –
 Contracts , financial agreements and
delegation
 Facilities and environmental conditions
 Analytical plan , report and results
 Equipments
 QC procedures
 Raw data
 Labeling and storage
 Documentation , filing and archiving
 Methodology , specific tests
 Reference ranges , alerts for out of range

30. 5. Clinical study report audit
 To check for :
1. Compliance with ICH requirements,
2. Consistency of data,
3. Accuracy of data ( verifying with the
source data )

31. 6. Validation of computer
system
 Audit of following is done –
 System setup / installation
 Data collection and handling
 System maintenance
 Data backup , recovery and contingency plans
 Security
 Electronic signatures
 Date/ time stamps
 Basically done to ensure the authenticity ,
integrity and confidentiality of the electronic
records

32. Comparison between monitoring
and auditing
 Monitoring  Auditing
I. Continuous process I. Done either during
trial or after the
completion of trial
II. It controls quality of
trial II. It assures quality of
trial
III. It is done by monitor
who is a part of trial III. It is done by an
. independent
personnel of trial
, e.g. IRB
IV. Appointed by the , regulatory
sponsor authorities
IV. Appointed by the

33. Inspection
 The act by a regulatory authority(ies) of
conducting an official review of
documents, facilities, records, and any other
resources that are deemed by the
authority(ies) to be related to the clinical trial
and that may be located at the site of the
trial, at the sponsor's and/or contract research
organization’s (CRO’s) facilities, or at other
establishments deemed appropriate by the
regulatory authority(ies).
( ICH GCP sec 1.29)

34. Inspection program
determines
 Degree to which sponsor , monitors , clinical
investigators , site staff , IRB’s and CRO's
have fullfilled their trial related obligations
 The acceptability of resultant clinical data

35. Difference between Audit and
Inspection
AUDIT INSPECTION
Inspectors are employed of the Inspector are employed by
company who work for a active government, through the agency
clinical quality assurance (CQA) of the regulatory or competent
function (i.e. Sponsor/CRO) Authority (i.e. FDA/DCGI)
To ensure that a site is complying To ensure that trial related
with Protocol, SOP, GCP and obligations and acceptability of
Applicable regulatory resultant clinical data is in support
requirements. of a new drug approval.

36. Various global monitoring
programs
1. US FDA’S CDER’S BIORESEARCH
MONITORING PROGRAM ( BIMO)
2. EMEA’S CHMP ,THE GCP INSPECTION
PROGRAM
3. MHRA GCP COMPLIANCE PROGRAM ( UK
)
4. PHARMACEUTICAL AND MEDICAL
DEVICES AGENCY

37. BIMO Program Overview
 Established in 1977 and expanded in 1992
 Comprehensive program of on-site inspections and data
audits to monitor all aspects of the conduct and
reporting of FDA regulated research
 Each FDA Center has its own BIMO program staff with
overall coordination by the Office of Regulatory Affairs
 Implemented domestically and internationally resulting
in over 1000 inspections annually
 Inspections are Conducted before the approval of drug
to be marketed , also called as Pre approval Inspection
by FDA

38. BIMO’S COMPLIANCE
INSPECTION PROGRAM
1. CLINICAL INVESTIGATOR INSPECTION PROGRAM (
mostly done , provides an indication how well sponsors and
IRBs are performing their roles)
2. SPONSOR/ MONITOR/ CRO INSPECTION PROGRAM
(done mostly in case of suspicion of non compliance with
regulations , not done regularly )
3. IRB INSPECTION PROGRAM :
 Conducts routine inspection of 150 IRB’s annually
 reviews those IRBs with highest volumes of studies or
complex studies
 periodically done ,
 IRB’S with full compliance or minor deficiences are
reinspected in 5 years and with major deficiencies within a
year
 Documents auditted : IRB procedures , IRB roster , copies
of IRB minutes , records of tracked studies
 Reveal significant regulatory deviations , which may lead to

39. Contd..
4. NON - CLINICAL INSPECTION PROGRAM ( not done often
, inspects GLP are followed or not )
5 .IN- VIVO BIOEQUIVALENCE INSPECTION PROGRAM (
inspects both clinical and analytical facilities to ensure
safety and quality of generic drugs and safety of subjects
participating in BE studies)

40. Most Common Investigator
inspection Deficiencies
 Failure to follow the investigational plan
 Protocol deviations
 Inadequate recordkeeping
 Inadequate accountability for the
investigational product
 Inadequate subject protection – including
informed consent issues

41. EIR – establishment inspected
report
 After inspection, FDA field inspector writes an
establishment inspection report (EIR)
 After district office review, the completed EIR
package is sent to the FDA
 Once the EIR is received, it is assessed and
classified by FDA

42. Classification of inspection by
FDA
 No Action Indicated (NAI) = the FDA
field inspector did not identify
objectionable practices or identified
only minor issues that did not justify
further action
 Voluntary Action Indicated (VAI) =
indicates that objectionable
practices were uncovered during the
inspection, but were not significant
 Official Action Indicated (OAI) =
inspection uncovered significant
objectionable practices, which could
affect data reliability or compromise
human subject protection. Generally
results in the issuance of a Warning
Letter or some other higher-level
compliance action

43. FDA Form – 483 f 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.

44. EMEA’s CHMP GCP inspection
program
 Focusses largely on clinical trials and clinical
data used to support marketing applications.
 Conducts inspection only at the request of
scientific committee of CHMP , to confirm the
information provided in the application for
marketing authorization

45. MHRA GCP compliance
program
 Assess compliance with requirements of
applicable GCP regulations and guidelines , by
conducting inspections at sites of sponsor
, CRO , trial sites , clinical laboratories , and
other facilities involved in clinical research
 Does not inspect IRB , but assures that related
documents are approved by IRB

46. PMDA
 Founded in April 2004 , comprises 13 offices
 Responsible for reviewing and approving new
drugs and medical devices , monitoring the
reliability of clinical trial data
 It inspects the site , IRB , sponsor , and
laboratories before approving the marketing
authorization only when they feel its necessary
.

47. Consequences of Inspection
 Study may be invalidated ( if there are significant
protocol deviations or underreporting of AEs )
 Could delay the new drug approval or disapproval of
application
 Investigator may be disqualified or restricted from
conducting CTs in future.

48. Reference
 ICH GCP guidelines E6
 www.fda.gov.in
 Basic principles of clinical Research and
Methodolgy , S.K. Gupta , vol 1