Audits

1
Audits InspectionsCRO Perspective

• Dr.Prashant Bodhe
• prashant.bodhe_at_gmail.com

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

• Thailand
• EU
• SA MCC
• USFDA
• TGA

• CDSCO
• Slovac Republic
• WHO
• Brazil
• Zimbabwe
• Nigeria

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
  organizations (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 sponsors 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 gt5 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., gt10 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 investigators 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

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
  ones expertise (seek expert), directly (remain
  within scope), without speculation or guesswork
• Avoid
• Unsolicited questions, hypothetical questions,
  long delays to requests, affidavits

39
Dos and Donts

• 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 inspectors 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
Dos and Donts

• 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

45
Dos and Donts

• 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.

46
Dos and Donts

• 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.

47
Dos and Donts

• 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.

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

52
FDA Inspection Process
FDA Office
Site Location
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 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

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
What to audit (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)

60
What to audit (Essential documents)

• 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

61
What to audit (Essential documents)

• 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)

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
What to audit (Essential documents)

• 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

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
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

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 Monitors 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!!

• ????
• prashant.bodhe_at_gmail.com
• Contact no 919371069226