1. Audits & Inspections
CRO Perspective

2. What is a CRO
 Contract Research Organization
 A person or an organization (commercial,
academic, or other) contracted by the
sponsor to perform one or more of a
sponsor's trial-related duties and
functions

3. CRO types
 Pharmacokinetic (BABE)
 Clinical Research – Phase I, II, III, IV
 Preclinical
 Discovery
 Analytical and Microbiological
 Hospitals, clinics, etc.
 Or any other

4. Our Focus
 Site
 Where actual work will get executed
 Clinical Trials
 Any investigation in human subjects intended to
discover or
 verify the clinical, pharmacological, and/or other
pharmacodynamic effects of an investigational
product(s), and/or
 to identify any adverse reactions to an
investigational product(s), and/or
 to study absorption, distribution, metabolism, and
excretion of an investigational product(s) with the
object of ascertaining its safety and/or efficacy.

5. Structured compliance plan
 CDSCO
 Slovac Republic
 WHO
 Brazil
 Zimbabwe
 Nigeria
 Thailand
 EU
 SA MCC
 USFDA
 TGA
CROs need to define their own Objectives and Goals
and Plans to execute according to the business needs

6. Compliance to
 GLP
 GCP
 GXP
 Applicable Rules, Regulations, Laws and
guidelines of the target regulatory agency
and those of the land

7. Controlled regulated environment
 US: CFR and guidelines
 ICH Guidelines, including E6: GCP
 GXPs: GCP, GLP, GMP
 EU: Clinical trials directive and guidelines
 CIOMS guidelines (council for international
organizations of medical sciences WHO Geneva)
 National regulations & guidelines

8. Why Compliance?
 Promote quality and validity of test data
 Help scientists to obtain Reliable,
Repeatable, Auditable, Acceptable results
 Necessary intrinsic scientific value
 Organizational requirement
 Management responsibility
 Mandatory
 Safety, Efficacy, Quality

9. Meeting Phenomenon
 We all are in a marathon meeting to
discuss why work is not being done
 We are conducting an Audit to check for
compliance to the remarks in the Audit
conducted to check compliance…….
 Vicious cycle?? Or routine and sincere
practice!!!

10. To ensure compliance
 Build Quality systems
 Execute Protocols using these quality
systems
 Quality Control and Assurance
 Monitoring
 Audit
 Review
 Inspection

11. Quality Control / Quality Assurance
 Quality Control / Operational Units
 Responsible for inspecting and certifying
predefined quality expected in a product or
process through Quality Control Systems
 Quality Assurance / Audit Group
 Assesses the Performance, Accuracy,
Reliability And Integrity Of Quality Systems
through Independent Auditing Activities

12. Monitoring (ICH-GCP)
 The act of overseeing the progress of a
clinical trial, and of ensuring that it is
 conducted, recorded, and reported in
accordance with
 the protocol,
 standard operating procedures (SOPs),
 GCP, and
 the applicable regulatory requirement(s)

13. Audit (ICH-GCP)
 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's standard operating procedures (SOPs),
 good clinical practice (GCP), and
 the applicable regulatory requirement(s).

14. Inspection (ICH-GCP)
 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
(CROs) facilities, or
 at other establishments deemed appropriate by
the regulatory authority(ies)

15. Time of Compliance Check
 Pre-study
 During Study
 After Study
 Sponsor Site Qualification
 CRO/ Site QA/ QC Unit
 Sponsor (monitoring)
 Sponsor (Audit of completed data)
 CRO/ Site QA/ QC Unit
 Sponsor (Audit of completed data)
 CRO/ Site QA/ QC Unit
 Inspection by RA

16. Ultimate Aim
 Pass Inspection by regulatory
authority(ies)
 Well this means compliance!!!!

17. Compliance Certification
 Audit certificate: A declaration of confirmation
by the auditor that an audit has taken place.
 Audit report: A written evaluation by the
sponsor's auditor of the results of the audit
 A written report from the monitor to the sponsor
after each site visit and/or other trial-related
communication according to the sponsor’s
SOPs.

18. Who and What are Inspected?

19. Who?
 Sites
 Investigators (Doctors) and Study Coordinators
 IRB (IRBMED)
 Sponsor, if applicable (Industry)
 Contract Research Organization, if involved
 Laboratories
 Pharmacy (e.g., Investigational Drug Services)
 Devices (e.g., ECG, Biomedical Engineering)

20. What studies?
 Usual Emphasis: Phase 3
 Adequate and well controlled
 Blinded
 Safety and Efficacy
 Multi-site
 High patient enrolling sites
 Recent marketing application (e.g. New Drug
Application) filed to an Investigational New
Drug (IND)

21. What studies?
 Usual Emphasis: Bioequivalence studies
for ANDA
 Clinical facilities, procedures, documentation
 Quality Systems
 Analytical facilities, procedures,
documentation
 Clinical investigations laboratory

22. QC/ QA, Monitoring, Auditing,
Inspection check for compliance
Purpose is same, Objectives and method
can be different

23. When will inspection Occur?
 At any time during the study
 After the study is complete prior to
regulatory approval for the product
 At any time after regulatory approval (15
years) if a safety concern with the product
(rare)

24. FDA selects Site(s)
• FDA selects site for inspection:
• Usually within 6 months of marketing
application [NDA] (Data Audit) or ANDA
• Selects 3 sites (average) per study, if multi-
site
• May concurrently inspect the associated IRB:
• If no previous inspection; or
• Last inspection >5 years
OR
• May conduct a “For Cause” Audit

25. Reasons: “For Cause” Inspections
 Study of “singular
importance” in
product approval
 Study has major
impact on medical
practice
 Sponsor reports
concerns about
investigator
 Patient complaint
 Investigator conducts
too many studies
 Investigator works
outside of specialty
area
 Safety or efficacy
findings are
inconsistent with other
investigators
 Lab results are outside
range of biological
expectations

26. FDA Inspection
• May give sufficient or very short advance
notice or no notice of visit
• Becomes suspicious on attempts to delay
visit (e.g., >10 days without valid reason)
• Previews internally following subject
related data:
• Number of total subjects, dropouts and evaluable
subjects
• List of AEs and deaths (with description and cause)

27. Objectives of Inspecting In-vivo BE
 To verify the quality and integrity of
scientific data from bioequivalence
studies submitted
 To ensure that the rights and welfare of
human subjects participating in drug
testing are protected; and
 To ensure compliance with the
regulations (21 CFR 312, 320, 50, and 56)
and promptly follow-up on significant
problems, such as research misconduct or
fraud.

28. Objectives of Inspecting In-vivo BE
 Clinical laboratories are usually certified
under programs based on the Clinical
Laboratories Improvement Act (42 USC
263a), and are not routinely inspected by
the FDA.
 A clinical laboratory may be visited
during a bioequivalence study audit to
confirm that reported screening or
diagnostic laboratory work was indeed
performed

29. Preparation Tips for Site
 Notify all staff involved in AND/OR
knowledgeable about the study:
 Key staff, “information providers” are on
standby
 Industry sponsor

30. Preparation Tips for Site
 Assign a site escort/facilitator
 Define “SOP” for Interacting with inspectors
from welcome to exit and do not underplay or
overplay
 Assemble all study documents in One place
 Include list of staff responsibilities and training
 Request all patient charts
 Prepare a list of investigator’s studies
 Reserve adequate work space for field
investigator for entire inspection
 Assure accessible photocopier provide a back up
if necessary

31. You have 3 to 5 minutes
 To provide documents requested by
Inspector
 If not available be truthful
 Beyond five minutes inspector may
assume that it has been fabricated

32. Documentation thumb rule
 If not documented means not done
 If documented does not mean that it is
done

33. FDA Form 482
 FDA written notice of inspection presented
by the investigator at the beginning of an
inspection.

34. Tips on Document Requests
 Do not provide or copy these information
for FDA:
 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

35. FDA interviews Site Staff
• FDA investigator interviews site staff
directly involved in trial activities and
processes
• May question any staff member during
inspection
• May use Compliance Program Guidance
Manual as interview guide

36. Tips for Anticipating FDA Questions
 Compliance Program Guidance Manuals
(CPGMs)
http://www.fda.gov/ora/cpgm/default.htm
In Vivo Bioequivalence 7348.001
IRBs 7348.809
Sponsors, CROs and Monitors 7348.810
Clinical Investigators 7348.811

37. FDA investigative techniques for
Gathering evidence
 Questioning employees at home at night
or on the weekend, permitted under
FDCA Sec. 704
 Can go through trash, obtain grand jury
subpoenas and search warrants for
telephone and business records
 Collaboration with FBI

38. Tips for Handling FDA Questions
 Answer
 Politely, cooperatively, understanding them
(ask for clarification), factually, briefly, within
one’s expertise (seek expert), directly (remain
within scope), without speculation or
guesswork
 Avoid
 Unsolicited questions, hypothetical questions,
long delays to requests, affidavits

39. Dos and Don’ts
 Effective inspection preparation requires
a multi-faceted approach.
 But communication issues can be just as
critical, as these dos and don'ts suggest.

40. What should you do for preparation?
 Review regulatory site files
 Confirm audit dates with all site staff
 Ensure all patient notes and other source
data are in good order.
 Ensure familiarity with the protocol and
the conduct of the study

41. Preparing for an inspection
 Have a written corporate policy for
regulatory inspections
 Conduct independent audits and internal
audits
 Establish attitude of the company
 Designate an inspection coordinator have
back up

42. Training personnel for inspections
 Every employee must know his/her job function
and regulatory obligations
 Document employee credentials, training and
knowledge
 Study related documents
 FDA program and inspection guidance
documents

43. Personnel interacting with inspector (s)
 confirm that they are at correct name and
institution, record inspector’s badge number
 Never leave investigator unattended
 List of inspection team members and alternate
persons:
 Clinical Director/Study Coordinator/Principal
Investigator
 Production V.P./Quality Control Manager
 Executive V.P./ President
 Legal Counsel

44.  Do be professional and confident
 Don't become argumentative or at worst
hostile
 Attitudes are important
 If management is seen as "uncooperative,"
the investigator may well become
suspicious and more zealous
Dos and Don’ts

45.  Don't tell the investigator that an
inspection isn't possible that day because
the owner is on vacation, and suggest
they return next week.
Dos and Don’ts

46.  Do balance cooperation with wariness.
 initial presentation about the facility's operations
and a tour can be useful in setting a positive tone
 wait for the investigator to make specific requests
before providing records, samples, labels and the
like.
 Respond to requests appropriately
 do not offer other materials that might relate to
another matter pending with FDA but are
unrelated to the request.
Dos and Don’ts

47.  Do provide timely and carefully prepared
written responses to 483s, and to any
letters issued by FDA regarding
violations identified as a result of the
inspection. Often, it is appropriate to
include a plan for corrective action.
 FDA wants to see that management is
taking these issues seriously.
Dos and Don’ts

48. FDA conducts “Exit Interview”
• [Review findings with FDA investigator at
end of each inspection day]
• At site visit completion, FDA investigator
conducts “exit interview” with responsible
site personnel to:
• Review findings
• Clarify misunderstandings
• Describe any deviations from current regulations
• Suggest corrective action, if appropriate

49. FDA Form 483
 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.

50. Most Common Observations
(for Investigators)
 Protocol non-adherence
 Inadequate and inaccurate records
 Failure to report adverse events
 Failure to report concomitant therapy
 Inadequate drug accountability
 IRB/IEC problems
 Informed consent issues

51. FDA classifies Inspection
• When evaluation is completed, FDA
classifies inspection and sends a letter to
site
Classification Type of Letter
NAI (No Action Indicated) Notice of no significant
deviations
VAI (Voluntary Action
Indicated)
Informational
OAI (Official Action
Indicated)
Warning

52. 1. Select Site
2. Contact Site
3. Schedule Site
4. Arrive (482)
5. Review Records
6. Interview Staff
7. Present Findings
8. Depart (483)
9. Write Report (EIR)
10. Classify Inspection
FDA Office Site Location
FDA Inspection Process

53. QC/ QA, Monitoring, Auditing,
Inspection check for compliance
Purpose is same, Objectives and method
can be different

54. Audit : purpose
 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

55. 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

56. What to audit?
 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

57. What to audit? Investigational drug
 Manufacturing, packaging, labeling and coding of the
investigational product (including placebo and active
comparator where applicable)
 In accordance with applicable GMP standards
 Labelling requirments, “For Clinical Trial Use Only”
 to protect blinding where applicable
 Drug Product Accountability
 Control Quantity

58. What to audit
 IRB/EC
 Responsibilities
 Composition, functions and operations
 Procedures
 Records
 Investigators and sub-investigators
 Qualifications and agreements
 Essential documents

59.  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 (Essential documents)

60.  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 (Essential documents)

61.  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 (Essential documents)

62. What to audit (Essential documents)
 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

63.  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 (Essential documents)

64. 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

65. 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 authorites
 Check validation status where applicable
 Check record retention capabilities

66.  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
Computerized systems (used to create, modify,
maintain, archive, retrieve or transmit data)

67. 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

68. QC/ QA, Monitoring, Auditing,
Inspection check for compliance
Purpose is same, Objectives and method
can be different

69. Temperature Reading
 Display is one digit -67.8
 In log book entries are -67.80, -70.50 etc
 Subsequently recording style changed to
single digit -56.7, etc.
 Sponsors Monitor’s View
 Sponsors Auditors View
 Inspectors View

70. Participants in compliance
 Sponsors
 CROs
 Management of all the organizations
 All the employees, contractors,
subcontractors

71. Key to Success for all - 01
 Compliance is Organizational
responsibility & mandatory act

72. Key to Success for all -02
 Compliance is not a individual responsibility

73. Key to Success for all -03
 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

74. Thank you!!