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Audits Monitoring & Inspections
       CRO Perspective


        Dr.Prashant Bodhe

        prashant.bodhe@gmail.com
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
CRO types
   Pharmacokinetic (BABE)
   Clinical Research – Phase I, II, III, IV
   Preclinical
   Discovery
   Analytical and Microbiological
   Hospitals, clinics, etc.
   Or any other
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.
Structured compliance plan
   CDSCO                        Thailand
   Slovac Republic              EU
   WHO                          SA MCC
   Brazil                       USFDA
   Zimbabwe                     TGA
   Nigeria
CROs need to define their own Objectives and Goals
and Plans to execute according to the business needs
Compliance to
   GLP
   GCP
   GXP
   Applicable Rules, Regulations, Laws and
    guidelines of the target regulatory agency
    and those of the land
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
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 & Staff Responsibility
 Mandatory
 Safety, Efficacy, Quality
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!!!
To ensure compliance
 Infrastructure & Facilities
 Build Quality systems
 Execute Protocols using these quality
  systems
 Quality Control and Assurance
 Monitoring
 Audit
 Review
 Inspection
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
   Assessment and Analysis of the Performance,
    Accuracy, Reliability And Integrity Of Quality
    Systems through Independent Auditing Activities
   Defines new paradigms, systems, methods
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)
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).
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)
Time of Compliance Check
 Pre-study       Sponsor Site Qualification
                  CRO/ Site QA/ QC Unit


 During Study    Sponsor (monitoring)
                  Sponsor (Audit of completed data)
                  CRO/ Site QA/ QC Unit

                  Sponsor (Audit of completed data)
 After Study
                  CRO/ Site QA/ QC Unit
                  Inspection by RA
Ultimate Aim
 Pass Inspection by regulatory
  authority(ies)
 Well this means compliance!!!!
   Audit certification by Sponsor and other external agencies do not
    guarantee this, but takes the organization a step closer
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.
Who and What are Inspected?
Who?
   Sites
   Investigators (Doctors) and Site staff
   IRB, ethics committees
   Sponsor, if applicable (Industry)
   Contract Research Organization
   CPU
   Laboratories (Clinical, Bio-analytical)
   Pharmacy (e.g., Investigational Drug Services)
   Devices (e.g., ECG, Biomedical Engineering)
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)
What studies?
 Usual Emphasis: Bioequivalence studies
  for ANDA
   Clinical facilities, procedures, documentation
   Quality Systems
   Analytical facilities, procedures,
    documentation
   Clinical investigations laboratory
Impact factor
 Global Importance of data impact on the outcomes
  stated in the regulatory filing under consideration
 Suspected for Cause, suspiciously very good data
 Reported for Cause
 Multiple studies from same investigator(s) with
  huge no of patients from same or multiple sites
 Data incongruent with experience of RA
QC/ QA, Monitoring, Auditing,
Inspection check for compliance


   Purpose is same, Objectives and method
   can be different
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)
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
Reasons: “For Cause” Inspections
 Study of “singular    Investigator conducts
  importance” in         too many studies
  product approval      Investigator works
 Study has major        outside of specialty
                         area
  impact on medical
  practice              Safety or efficacy
                         findings are
 Sponsor reports        inconsistent with other
  concerns about         investigators
  investigator          Lab results are outside
                         range of biological
 Patient complaint      expectations
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)
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.
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
Preparation Tips for Site


 Notify all staff involved in AND/OR
  knowledgeable about the study:
    Key staff, “information providers” are on
     standby
    Industry sponsor
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
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
Documentation thumb rule
 If not documented means not done
 If documented does not mean that it is
  done
FDA Form 482
  FDA written notice of inspection presented
   by the investigator at the beginning of an
   inspection.
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
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
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
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
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
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.
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
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
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
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
Dos and Don’ts
 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
 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
 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
 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.
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
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.
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
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       Informational
  Indicated)
  OAI (Official Action        Warning
  Indicated)
FDA Inspection Process

     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)
QC/ QA, Monitoring, Auditing,
Inspection check for compliance


   Purpose is same, Objectives and method
   can be different
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
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?

 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? 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
What to audit

   IRB/EC
        Responsibilities
        Composition, functions and operations
        Procedures
        Records
   Investigators and sub-investigators
      Qualifications and agreements
   Essential documents
What to audit (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 (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
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)
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
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
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
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
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
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
QC/ QA, Monitoring, Auditing,
Inspection check for compliance


   Purpose is same, Objectives and method
   can be different
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
Participants in compliance
   Sponsors
   CROs
   Management of all the organizations
   All the employees, contractors,
    subcontractors
Key to Success for all - 01
 Compliance is Organizational responsibility & mandatory act
Key to Success for all -02
 Compliance is not a individual responsibility
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
Some Lessons through Humor
Training Bunta


Master        Bunta, how much did you spend on the groceries today?
Bunta         I spent Rs.99 and 50 paise.
Master         Why don't you round it off to Rs.100. Rounding off figures is very
              convenient
              Then one day-
Master         Bunta, go and get me a ticket to Mumbai.
              Bunta Buys tickets and When he came back
Master        What time does the train leave tomorrow?
Bunta         4 p.m.
              Then the next day- Mater reaches station at 3:55 with Bunta
Master        Its 4 p.m., and the train to Mumbai hasn't arrived, I think it is late.
A passer by   No sir, the train left at 3.45.
Master        Bunta, you told me the train is leaving at 4.00 p.m
Bunta         The time was 3. 45 but I rounded it off to 4p.m.
Lessons
   Appropriate training is essential
   Scope of the training should be defined
   Continuous training is essential
   Instructions should be clear non-ambiguous
Urgency


Master    Bunta, why are you holding the receiver of
         the phone to your ear? Did it ring?


Bunta    No, I am expecting an urgent call from my
         brother.
Lessons
 Do not react to things not happened
 But be aware of options and possibilities
Guidelines, Rules and Regulations: Interpretation and Compliance



Bunta starts working as a guard in Bank
Bank manager            Bunta, you will watch and frisk if necessary all the people coming
                       inside branch. Do not allow any person with arms inside the branch
Bunta                  Yes Sir
Branch manager is happy that he has obedient guard. After an hour after opening a branch
manager does not see any customer inside branch but there is lot of noise outside branch.
Manager comes out of the branch and sees many customers arguing with Bunta
Customer to Manager Sir, this new guard is not allowing us to go in
Manager angrily        Bunta, why are you not allowing customers to go in
Bunta                   Yes Sir, I am complying to your orders
Manager                 Bunta, I did not tell you not to let customers in
Bunta                   Yes Sir, but you told me anyone with arms should not be allowed
                       to come in. See everyone here has two arms and that is why I am
                       not allowing them to come in
Lessons
 Interpretation is not just to letter but to
  letter and spirit
 Compliance should be to Spirit and Letter
 Common sense prevails all the time
Thank you!!

???? Any Questions ???
prashant.bodhe@gmail.com
Contact no: +919371069226

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Audit monitoring and inspections cro perspectives

  • 1. Audits Monitoring & Inspections CRO Perspective Dr.Prashant Bodhe prashant.bodhe@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  CDSCO  Thailand  Slovac Republic  EU  WHO  SA MCC  Brazil  USFDA  Zimbabwe  TGA  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 & Staff 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  Infrastructure & Facilities  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  Assessment and Analysis of the Performance, Accuracy, Reliability And Integrity Of Quality Systems through Independent Auditing Activities  Defines new paradigms, systems, methods
  • 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  Sponsor Site Qualification  CRO/ Site QA/ QC Unit  During Study  Sponsor (monitoring)  Sponsor (Audit of completed data)  CRO/ Site QA/ QC Unit  Sponsor (Audit of completed data)  After Study  CRO/ Site QA/ QC Unit  Inspection by RA
  • 16. Ultimate Aim  Pass Inspection by regulatory authority(ies)  Well this means compliance!!!!  Audit certification by Sponsor and other external agencies do not guarantee this, but takes the organization a step closer
  • 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 Site staff  IRB, ethics committees  Sponsor, if applicable (Industry)  Contract Research Organization  CPU  Laboratories (Clinical, Bio-analytical)  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. Impact factor  Global Importance of data impact on the outcomes stated in the regulatory filing under consideration  Suspected for Cause, suspiciously very good data  Reported for Cause  Multiple studies from same investigator(s) with huge no of patients from same or multiple sites  Data incongruent with experience of RA
  • 23. QC/ QA, Monitoring, Auditing, Inspection check for compliance Purpose is same, Objectives and method can be different
  • 24. 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)
  • 25. 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
  • 26. Reasons: “For Cause” Inspections  Study of “singular  Investigator conducts importance” in too many studies product approval  Investigator works  Study has major outside of specialty area impact on medical practice  Safety or efficacy findings are  Sponsor reports inconsistent with other concerns about investigators investigator  Lab results are outside range of biological  Patient complaint expectations
  • 27. 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)
  • 28. 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.
  • 29. 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
  • 30. Preparation Tips for Site  Notify all staff involved in AND/OR knowledgeable about the study:  Key staff, “information providers” are on standby  Industry sponsor
  • 31. 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
  • 32. 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
  • 33. Documentation thumb rule  If not documented means not done  If documented does not mean that it is done
  • 34. FDA Form 482  FDA written notice of inspection presented by the investigator at the beginning of an inspection.
  • 35. 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
  • 36. 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
  • 37. 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
  • 38. 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
  • 39. 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
  • 40. 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.
  • 41. 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
  • 42. 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
  • 43. 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
  • 44. 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
  • 45. Dos and Don’ts  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
  • 46. Dos and Don’ts  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.
  • 47. Dos and Don’ts  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.
  • 48. Dos and Don’ts  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.
  • 49. 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
  • 50. 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.
  • 51. 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
  • 52. 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 Informational Indicated) OAI (Official Action Warning Indicated)
  • 53. FDA Inspection Process 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)
  • 54. QC/ QA, Monitoring, Auditing, Inspection check for compliance Purpose is same, Objectives and method can be different
  • 55. 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
  • 56. 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
  • 57. 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
  • 58. 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
  • 59. What to audit  IRB/EC  Responsibilities  Composition, functions and operations  Procedures  Records  Investigators and sub-investigators  Qualifications and agreements  Essential documents
  • 60. What to audit (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)
  • 61. 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
  • 62. 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)
  • 63. 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
  • 64. 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
  • 65. 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
  • 66. 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
  • 67. 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
  • 68. 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
  • 69. QC/ QA, Monitoring, Auditing, Inspection check for compliance Purpose is same, Objectives and method can be different
  • 70. 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
  • 71. Participants in compliance  Sponsors  CROs  Management of all the organizations  All the employees, contractors, subcontractors
  • 72. Key to Success for all - 01  Compliance is Organizational responsibility & mandatory act
  • 73. Key to Success for all -02  Compliance is not a individual responsibility
  • 74. 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
  • 76. Training Bunta Master Bunta, how much did you spend on the groceries today? Bunta I spent Rs.99 and 50 paise. Master Why don't you round it off to Rs.100. Rounding off figures is very convenient Then one day- Master Bunta, go and get me a ticket to Mumbai. Bunta Buys tickets and When he came back Master What time does the train leave tomorrow? Bunta 4 p.m. Then the next day- Mater reaches station at 3:55 with Bunta Master Its 4 p.m., and the train to Mumbai hasn't arrived, I think it is late. A passer by No sir, the train left at 3.45. Master Bunta, you told me the train is leaving at 4.00 p.m Bunta The time was 3. 45 but I rounded it off to 4p.m.
  • 77. Lessons  Appropriate training is essential  Scope of the training should be defined  Continuous training is essential  Instructions should be clear non-ambiguous
  • 78. Urgency Master Bunta, why are you holding the receiver of the phone to your ear? Did it ring? Bunta No, I am expecting an urgent call from my brother.
  • 79. Lessons  Do not react to things not happened  But be aware of options and possibilities
  • 80. Guidelines, Rules and Regulations: Interpretation and Compliance Bunta starts working as a guard in Bank Bank manager Bunta, you will watch and frisk if necessary all the people coming inside branch. Do not allow any person with arms inside the branch Bunta Yes Sir Branch manager is happy that he has obedient guard. After an hour after opening a branch manager does not see any customer inside branch but there is lot of noise outside branch. Manager comes out of the branch and sees many customers arguing with Bunta Customer to Manager Sir, this new guard is not allowing us to go in Manager angrily Bunta, why are you not allowing customers to go in Bunta Yes Sir, I am complying to your orders Manager Bunta, I did not tell you not to let customers in Bunta Yes Sir, but you told me anyone with arms should not be allowed to come in. See everyone here has two arms and that is why I am not allowing them to come in
  • 81. Lessons  Interpretation is not just to letter but to letter and spirit  Compliance should be to Spirit and Letter  Common sense prevails all the time
  • 82. Thank you!! ???? Any Questions ??? prashant.bodhe@gmail.com Contact no: +919371069226