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									Clinical Trials Conference
      July 17, 2007

   Managing and Complying
       with Clinical Quality
                Obligations
       Bradley Merrill Thompson
     Epstein Becker & Green, PC
            Topics
1. Importance of quality assurance
2. Overview of risk management
   approach
3. Good Clinical Practices
4. GCP experience
5. Quality and risk management
   techniques
Importance of Quality Assurance

   • More studies; more sites; greater
     volume
   • Expansion and fluidity of clinical
     investigator pool
   • New players in new roles (CROs,
     SMOs)
   • New technologies (electronic
     recordkeeping)
   • More participation by vulnerable
     subjects
   • Global expansion (areas new to GCP)
Quality Requirements (ISO 9000)

   • A quality requirement is a
     characteristic that a product or
     service must have to satisfy needs
     and expectations of the customer


            requirements
The end product of clinical research


    • A product is an output from a
      process
    • The output from the clinical
      research process is information
                                pooling
         trial    collection    of data               trial
                                          analysis
       protocol    of data       in the              report
                               database
Quality in clinical research
may be defined as . . .

     • Reliability and credibility of
       information providing an answer to
       a scientific question
     • Compliance of the trial process with
       defined requirements

            A                                         An
                    Collection & analysis of data
         question                                   answer
Customers of clinical research

   •   Society / consumers
   •   Research subjects
   •   Sponsors
   •   Regulatory authorities worldwide
   •   Hospitals / institutions
   •   Ethics committees
Clinical research customers‘ requirements



                                 Law & Regulations:
                                    EU Directives
                                      US CFR
                                   local legislation

        Ethical Standards:
       Declaration of Helsinki       Good Practice Standards:
                                              GXPs:
                                   ICH GCP, ICH GMP, OECD GLP
           Topics
1. A quality assurance approach
2. Overview of risk management
   approach
3. Good Clinical Practices
4. GCP experience
5. Quality and risk management
   techniques
Risk Management

  • Product Risk
    – FDA does, and you should, consider the intrinsic risk
      of the product you are investigating, when deciding
      the level of sophistication and elegance of your
      quality system.
    – Product risk is a function of:
        • Technology
        • Disease or condition
        • Setting
        • User
    – Remember that the clinical trials quality system is a
      design input under device QSR, in addition to being
      subject to Good Clinical practices
    – Systems require very similar approach and
      philosophy
Risk Management

  • Commercial Risk
    – FDA does, and you should, consider the
      commercial complexity of the structure of the
      clinical trial you are organizing when
      deciding the level of sophistication and
      elegance of your quality system and the
      extent of training needed
        • Use of CROs, sub-investigators, and so
          forth
    – The more complexity, the greater the burden
      to manage it well
Risk Management

  • Drive it with data
    – Study your products
    – Study the commercial arrangements
      to identify risks and weaknesses
    – Study FDA experience inspecting
      clinical trials
    – Study litigation brought against
      sponsors
    – Study reports investigating clinical trial
      quality
Why? If you don‘t, you might …

   • Harm patients
   • Liability to patients
   • Data from expensive studies
     disqualified from use in FDA
     submissions
     – Or expensive fixes required
   • Civil and criminal liability to federal
     and state regulators
     – Such as OIG, FDA, and state
       agencies
FDA Regulatory Actions

   • Rejection of data   • IRB restrictions
   • Deficiency letter      – No new studies or
                              subjects
   • IDE, 510(k), or
                         • Application Integrity
     PMA withdrawal        Policy
   • Untitled letters    • Civil Money
   • Warning letters       Penalties
   • Consent Agreement   • Seizure / Detention
   • Disqualification    • Injunction
      – CI, IRB, GLP     • Criminal Prosecution
            Topics
1. Importance of quality assurance
2. Overview of risk management
   approach
3. Good Clinical Practices
     A. What are they?
     B. Where do you find them?
4. GCP experience
5. Quality and risk management
   techniques
What are Good Clinical Practices?

   • GCPs are the rules—and self-determined
     standards—governing clinical research
   • GCPs promote scientific and ethical quality in
     the conduct of clinical trials
   • For clinical trials, GCPs set standards for the:
                            Design
                            Conduct
                          Performance
                           Monitoring
                            Auditing
                           Recording
                            Analysis
                           Reporting
What are they?

   1. Ethics: Clinical trials should be conducted in
      accordance with the ethical principles that
      have their origin in the Declaration of Helsinki,
      and that are consistent with GCP and the
      applicable regulatory requirement(s).
   2. Risk/Benefit: Before a trial is initiated,
      foreseeable risks and inconveniences should
      be weighed against the anticipated benefit for
      the individual trial subject and society. A trial
      should be initiated and continued only if the
      anticipated benefits justify the risks.
What are they?

   3.   Protection: The rights, safety, and well-
        being of the trial subjects are the most
        important considerations and should prevail
        over interests of science and society.
   4.   Well-Supported: The available nonclinical
        and clinical information on an investigational
        product should be adequate to support the
        proposed clinical trial.
   5.   Scientifically sound: Clinical trials should
        be scientifically sound, and described in a
        clear, detailed protocol.
What are they?

   6.   IRB Review: A trial should be conducted in
        compliance with the protocol that has
        received prior intuitional review board
        (IRB)/independent ethics committee (IEC)
        approval/favorable opinion.
   7.   Doctor Managed: The medical care given
        to, and medical decisions made on behalf of,
        subjects should always be the responsibility
        of a qualified physician, or, when appropriate,
        of a qualified dentist.
What are they?

   8.   Well-staffed: Each individual involved in
        conducting a trial should be qualified by
        education, training, and experience to perform
        his or her respective task(s).
   9.   Informed Consent: Freely given informed
        consent should be obtained from every
        subject prior to clinical trial participation.
   10. Record keeping: All clinical trial information
       should be recorded, handled, and stored in a
       way that allows its accurate reporting,
       interpretation, and verification.
What are they?

   11. Confidentiality: The confidentiality of
       records that could identify subjects should be
       protected, respecting the privacy and
       confidentiality rules in accordance with the
       applicable regulatory requirement(s).
   12. Products: Investigational products should be
       manufactured, handled, and stored in
       accordance with applicable good
       manufacturing practice (GMP). They should
       be used in accordance with the approved
       protocol.
What are they?

   13.   SOP Driven: Systems with procedures
         that assure the quality of every aspect of
         the trial should be implemented.
   14.   Others: Country specific requirements
         also must be factored in, such as financial
         conflict of interest and investigator payment
         rules
Basic US sponsor obligations

   • Select qualified investigators
   • Provide sufficient information to
     investigators to conduct the trial
   • Oversee the trial and enforce compliance
   • Monitor trial progress
   • Conduct safety analyses, provide
     notification, and submit reports (when
     appropriate)
   • Keep appropriate records
   • Review and evaluate safety and
     effectiveness
Basic US investigator obligations

   • Ensure IRB review
   • Protect the rights and welfare of trial
     subjects
   • Obtain informed consent
   • Follow the protocol
   • Personally supervise the study and clinical
     staff
   • Report adverse events
   • Submit appropriate financial disclosures
   • Keep appropriate records
Where do you find them in US?

             A Tale of Two Systems
   • In the US, the standards actually vary
     depending on the purpose of the
     clinical trial.
     – FDA rules for trials that will be conducted
       on articles subject to regulation by FDA
       and for possible submission to FDA
     – HHS (common rule) for research
       conducted or supported by HHS and
       those who voluntarily agree to be bound
       (federal-wide assurance)
     – Both sets of standards can apply
Clinical research customers‘ requirements




                                                         US FDA
                              Both           •   FDA IRB
     Common Rule     • Fraud and abuse,      •   FDA informed consent
   • HHS IRB           antikickback, false   •   FDA Part 812 investigator
                       claims                    and sponsor obligations
   • HHS informed    • HIPAA                 •   FDA Part 312 investigator
     consent                                     and sponsor obligations
   • HHS reporting   • Industry standards
     obligations       (e.g., PhRMA          •   Investigator financial conflict
   • HHS guidance
                       Principles)           •   Drug and device quality
                     • State law privacy         system requirements
                     • Other state law       •   FDA Part 11 electronic
                                                 records
                                             •   FDA guidance
International Conference on Harmonization
(ICH) Tripartite Guideline for GCP (1996)


    • Provides a unified standard for the
      conduct of clinical trials in Japan,
      US, and EU
    • Facilitates the mutual acceptance
      of clinical data by regulatory
      authorities in Japan, US, and EU
    • Assures the safety and protection
      of clinical trial subjects
    • Ensures the credibility of data
      collected in clinical trials
             Topics
1. Importance of quality assurance
2. Overview of risk management approach
3. Good Clinical Practices
4. GCP experience
    A. FDA‘s experience enforcing them
    B. Sponsor‘s experience defending them
    C. Studies examining weaknesses
5. Quality and risk management techniques
Clinical investigator inspections

   What does FDA look for during the
    inspection?

   The FDA Inspection (Audit) compares

        • Source Medical Record Data
              vs
        • Case Report Forms
              vs
        • Data Listing Submitted to NDA
Clinical investigator inspections

   • Clinical Investigator inspection
     determines
      – Source of subjects
      – Did subjects exist?
      – Did they have the disease/condition
        under study?
      – Did they meet inclusion/exclusion
        criteria?
      – Consent obtained?
      – IRB review and approval obtained?
Clinical investigator inspections

   • Clinical Investigator inspection
     determines
      – Did the subjects receive the assigned
        study drug in the dose, route and
        frequency specified by the protocol?
      – Are the case report forms complete and
        in agreement with source data?
        Compare with NDA data listing.
      – Are adverse experiences reported to
        sponsor and IRB?
      – Was the protocol followed?
      – Adequacy and completeness of records?
Investigator inspections: all centers - 2006




               183
                                          CDER: 379
                                          CBER: 66
                            379           CDRH: 183
              66
Clinical investigator deficiencies
CDER inspections - FY 2006

     30%


     25%


     20%

                                                                  Foreign
     15%
                                                                  Domestic


     10%


      5%


      0%
           Protocol   Record   AEs   Consent        Drug Acct

                                               Foreign n = 89
                                               Domestic n = 290
Prevalence of OAI inspections (DSI Data)


  Total number of FDA
    inspections

   FY04 – FY06* = 1175

  Total OAI cases = 31
                                Total Inspected

  Percent OAI = 3%              Total OAI



                              *FY06 to date
Prevalence of OAI inspections (DSI Data)


Routine FDA inspections
   FY04 – FY06* = 936
   Total OAI cases = 2
                           Routine Inspections        Total OAI
    Percent OAI = .6%

Directed FDA inspections
    FY04 – FY06* - 239
   Total OAI cases = 25
    Percent OAI = 11%      Directed Inspections       Total OAI



                                      *FY06 to date
Complaints to the Division of Scientific
Investigations (DSI)

    • The number of complaints about
      clinical investigators and clinical
      trials continues to increase
    • DSI encourages such reporting
      (new Electronic Complaint Form)
    • Follow-up on complaints is of vital
      strategic importance
       – Real-time follow-up
       – Public protection
       – Public confidence
What are they complaining about?

   • Informed Consent        •   Drug accountability
     Issues                  •   Recruitment Practices
   • Falsification
                             •   Poor Supervision
   • Failure to report
     adverse events          •   No active IND
   • Failure to follow the   •   Violations of GLP
     protocol                    regs
   • Inadequate Records      •   Monitoring practices
   • Qualifications of       •   Blinding
     persons performing
     physicals               •   Charging for the test
   • Failure to get IRB          article
     approval, report        •   Misleading
     changes in research         advertisements
   • Failure to follow FDA
     regulations
Complaints received: 1992-2006
                                 1992
  400
                                 1993
  350                            1994
                                 1995
  300                            1996
                                 1997
  250
                                 1998
  200                            1999
                                 2000
  150                            2001
  100                            2002
                                 2003
   50                            2004
                                 2005
    0
                                 2006
CI ―for cause‖ inspection assignments
(CDER, FY 1992 – 2005*)
 120                                               92
                                                   93
 100                                               94
                                                   95
 80                                                96
                                                   97
                                                   98
 60
                                                   99
                                                   FY00
 40
                                                   FY01
                                                   FY02
 20                                                FY03
                                                   FY04
   0                                               FY05

                             *FY05 through 10/05
BIMO inspects more than just clinical
investigators

    •   Sponsors and monitors
    •   IRBs
    •   GLP
    •   Bio-equivalence
BIMO inspections completed



  800               683   690               723    692
              678                                        657
  700   627                                                    580
                                      556
  600                           549
                                                                     S-M
  500
                                                                     CI
  400
                                                                     IRB
  300                                                                BIOEQ
  200                                                                GLP
  100
    0




                                       *FY06 to date
BIMO warning letters by year
and type


   25

   20

   15                                      CI
                                           Sponsor
   10                                      IRB
                                           GLP
    5

    0
        2001   2002   2003   2004   2005
All GCP warning letters by year
(2004 – May 2007)


   45
   40
                                                2004-41
   35
   30
                                                2005-36
   25
   20                                           2006-28
   15
   10                                           2007-16

    5
    0
        2004   2005   2006   *2007


                                     *Thru May 2007
Warning letter observations for investigators, including
sponsor-investigators (Total 2004 – May 2007)


                   Misc

             Monitoring

             False Data

   Sponsor Deficiences

    Invest. Deficiencies

       Adverse Events

      Records / Reports

    Protocol Deviations

      Informed Consent

Human Subj (not incl IC)

   Regulatory Approval



                           0   50        100           150
Sponsor FDA warning letters

   • Sponsors are more likely to have
     problems with monitoring, which makes
     sense
   • Records and reports still a frequent
     observation (and an easy target for FDA)
   • Not surprisingly, FDA more likely to
     target investigators with human subject
     violations, such as IRB and IC violations,
     because these are investigator
     responsibilities
Warning letter observations for sponsors (Total 2004 –
May 2007)


                   Misc

             Monitoring

             False Data

   Sponsor Deficiences

    Invest. Deficiencies

       Adverse Events

      Records / Reports

    Protocol Deviations

      Informed Consent

Human Subj (not incl IC)

   Regulatory Approval



                           0   10       20               30
Total warning letters for drugs, devices, and
biologics (Total 2004 – May 2007)


       100
        90
        80
        70
        60
        50
        40
        30
        20
        10
         0
                Drug         Biologic       Device
FDA warning letters as focused on
drugs vs. devices. vs. biologics

   • Many, many more device letters
   • Wide difference in number of letters
     makes it difficult to make apple-to-
     apple comparisons.
   • However, relatively more
     observations in device warning
     letters relating to:
     – Sponsor deficiencies
     – Monitoring
Warning letter observations for drugs, devices, and
biologics (Total 2004 – May 2007)


160
                                                      Regulatory Approval

140                                                   Human Subj(not incl IC)

                                                      Informed Consent
120
                                                      Protocol Deviations
100                                                   Records/Reports

 80                                                   Adverse Events

                                                      Investigator Deficiencies
 60
                                                      Sponsor Deficiencies

 40                                                   False Data

                                                      Monitoring
 20
                                                      Misc.

  0
       Biologic       Device         Drug
Sponsor‘s experience defending
studies in litigation

    • University of Pennsylvania Study (1999)
      – Death of 18 year-old Jesse Gelsinger in a
        gene therapy trial for the treatment of an
        inherited liver disease resulted in an
        undisclosed settlement and U.S. Senate
        hearings
      – Study approval required termination of the
        trial if patients suffered serious side effects
      – Researchers failed to alert FDA to reports of
        earlier patients whose liver damage
        warranted termination
      – The level of ammonia in Gelsinger‘s liver
        should have excluded him from participating
        in the trial
Sponsor‘s experience defending
studies in litigation

    Johns Hopkins University (2001)
      – Death of 24 year-old Ellen Roche in a
        federally funded lung physiology study
        on asthma treatment resulted in an
        undisclosed settlement
      – FDA alleged inadequate oversight by
        the IRB
      – Supervising physician failed to
        perform a sufficient literature search
        on the dangers of the chemical under
        investigation.
Studies examining weaknesses

   • 1996 GAO study suggesting that Federal
     oversight is lax
   • 1999 NYT ―Research for Hire. A Doctor‘s
     Drug Studies Turn into Fraud.‖
   • 2000 Washington Post ―The Body Hunters.‖
   • 1999-2001 National Bioethics Advisory
     Commission Report on research
     compliance
   • 2001 GAO report on progress in
     strengthening protections
   • 2005 Office of Research Integrity/HHS
     Annual Report
Studies examining weaknesses

   •   Clinical Trial Web Sites: A Promising Tool to Foster Informed Consent (OEI-01-
       97-00198 May 2002)
   •   FDA Oversight of Clinical Investigators (OEI-05-99-00350 June 2000)
   •   Institutional Review Boards: The Emergence of Independent Boards (OEI-01-97-
       00192 June 1998)
   •   Institutional Review Boards: Their Role in Reviewing Approved Research (OEI-01-
       97-00190 June 1998)
   •   Institutional Review Boards: A Time for Reform (OEI-01-97-00193 June 1998)
   •   Institutional Review Boards: Promising Approaches (OEI-01-98-00191; 6/98)
   •   Protecting Human Research Subjects: Status of Recommendations (OEI-01-97-
       00197; 4/00)
   •   Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research
       (OEI-01-97-00195 June 2000)
   •   Recruiting Human Subjects: Sample Guidelines for Practice (OEI-01-97-00196;
       6/00)
   •   The Globalization of Clinical Trials: A Growing Challenge in Protecting Human
       Subjects (OEi-01-00-00190; 09/01)
   •   Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research
       (OEI-01-97-00195; 6/00)
Summary of hot spots

   • Investigator financial conflicts and
     interests, including consulting
     relationships
   • Reporting requirements, including
     adverse event reporting
   • Conducting studies outside the U.S. and
     harmonizing GCP obligations
   • Enforcement focusing on device studies
     – Device regulatory environment becoming
       more like drugs
               Topics
1. Importance of quality assurance
2. Overview of risk management approach
3. Good Clinical Practices
4. GCP experience
5. Quality and risk management techniques
    A.   Quality Management system
    B.   Procedures and agreements
    C.   Training
    D.   Monitoring
    E.   Auditing
    F.   Metrics
Quality Management System,
definition based on ISO 9000


    • A set of interacting elements established
      to direct and control an organization with
      regards to quality
    • QMS is a tool to establish and
      continuously & consistently achieve
      quality objectives based on customers‘
      requirements.
    • In clinical research these objectives are:
       – Compliance with ethical, regulatory and
         GXP standards
       – Credibility and reliability of clinical data
Standard components of QMS in clinical
research



                              Quality Assurance

                                Quality Control


      Trial                                                      Trial
                          Collection & analysis of data
    protocol                                                    report


               Training                            Procedures
Procedures: Investigator

 • Trial-related instructions, protocol,
   CRFs, etc. – usually provided by the
   Sponsor
 • Investigator / Research Site may have
   own internal procedures: e.g.,
   procedures for financial agreements, trial
   management, investigational medicinal
   product handling
 • Ethics committee procedures
 • Laboratory procedures
Procedures: Sponsor

   • High level documents, e.g. Policies
     & Guidelines describe standards /
     customer requirements that the
     sponsor is going to comply with
   • SOPs & Working Instructions detail
     how these standards and
     requirements will be implemented
     in core activities within the clinical
     research process
     – The ‗every day work‘
Procedures: Sponsor SOPs

   • SOPs may include the following
     sections:
     – Approval Process SOPs
     – Subject Recruitment SOPs
     – Advertising SOPs
     – Trial Monitoring SOPs
     – Record Keeping SOPs
     – Data and Safety Monitoring Board
       SOPs
     – Adverse Event Reporting SOPs
Procedures: Benefits

   • Clear instructions on what should be
     done, when and by whom, plus
     specification of required inputs & outputs
   • Training tool
   • Maintain consistency of work and
     consistency in achieving quality
     objectives
   • Facilitate change management (may be
     easily updated & reviewed when
     requirements change)
Other written controls: Contracts

  • In addition to being required in certain instances,
    clinical trial agreements set expectations and
    establish obligations for all parties– e.g.,
     – Sponsor
     – Institution
     – Investigator
     – CRO
     – SMO
     – Others
  • Make the budget and payment schedule part of the
    agreements and review just as you would other
    provisions
  • Be cognizant of institution and investigator SOPs
    that may affect their ability to agree to certain
    provisions
Training

   • Sponsor‘s staff must be trained before
     being delegated any tasks
   • Sponsor is responsible for providing trial-
     related training to investigators:
     Investigator‘s Meetings, initiation visits,
     GCP courses
   • Investigator is responsible for training his
     personnel
   • Training records, CVs – are required as
     evidence of training & qualifications
Training

   • Many folks at the sponsors, at the
     sites and at contractors need to be
     trained
   • Common shortcoming: many
     training materials are developed in
     a vacuum
     – Not validated with input from real
       world setting
     – Therefore not effective or robust
       enough
   • Be sure to measure effectiveness
     of training
Quality Control

   • ISO: activities & techniques
     applied to ensure that products
     consistently fulfill requirements
   • Clinical Research: systematic
     checks on the compliance of the
     trial process & reliability and
     credibility of data
     – Performed at every step of the clinical
       trial process
     – Applied to each stage of data
       handling.
Quality Control


      Sponsor        Monitoring Proof-reading,
                                                Identification
     approval &     of investiga-  validation,
                                                 of non-PPT
      sign off       tional sites generation of
                                                    cases
                                    queries



                                     pooling
           trial      collection     of data                         trial
                                                    analysis
         protocol      of data        in the                        report
                                    database



                                analysis of    variability &     approval &
     IEC approval
                                outlier data     trends           sign-off
Monitoring

   • Two functions that sound alike
     – Data Monitoring Committee
     – Site Monitors
   • They must work together
   • Requirement for written monitoring
     procedures (21 CFR 812.25(e))
Site monitor responsibilities
   a) Verifying that the staff and facilities, including laboratories and
      equipment, are adequate to safely and properly conduct the trial
      and these remain adequate throughout the trial period.
   b) Verifying, for the investigational product, its proper handling etc.
   c) Verify that all modifications to the study plan have been
      submitted to FDA and IRB prior to implementation.
   d) Verify that all modifications to the study plan have been
      approved by IRB prior to implementation.
   e) Verifying that the investigator follows the approved protocol and
      all approved amendments, if any.
   f) Verifying that written informed consent was obtained before
      each subject's participation in the trial.
   g) Ensuring that the investigator's trial staff is adequately informed
      about the trial.
   h) Verifying that the investigator and the trial staff are performing
      the specified trial functions in accordance with the protocol and
      the investigator has not delegated these functions to
      unauthorized individuals.
   i) Verifying that the investigator is enrolling only eligible subjects.
Site monitor responsibilities
   j) Reporting the subject recruitment rate.
   k) Verifying that source data/documents and other trial records are
      accurate, complete, kept up-to-date, and maintained.
   l) Verifying that the investigator provides all the required reports,
      etc., and that these documents are accurate, complete, timely,
      legible, dated, signed, and identify the trial.
   m) Checking the accuracy and completeness of the CRF entries,
      source data/documents, and other trial-related records against
      each other.
   n) Determining whether all adverse events are appropriately
      reported within the time periods required by GCP, the protocol,
      the IRB, and the applicable regulatory requirements.
   o) Determining whether the investigator is maintaining the essential
      documents.
   p) Communicating deviations from the protocol and the applicable
      regulatory requirements to the sponsor and investigator and
      taking appropriate action designed to prevent recurrence of the
      detected deviations including reporting deviations to IRB and
      FDA.
   q) Verify that the final study report is accurate
Data Safety and Monitoring Board
(DSMB)

    • A.K.A., Data Monitoring Committee,
      Data and Safety Monitoring Committee
    • Committee set up to oversee safety
      monitoring of the clinical trial
    • Reviews the accumulating data to detect
      evidence of early dramatic benefit or
      harm for patients while the clinical trial is
      in progress
    • Functions of DSMB should be clearly
      defined prior to initiating the study
Potential functions of DSMB

   • Review safety data
   • Review efficacy data
   • Review trial conduct
   • Review external data
     (e.g., related studies)
   • Issue recommendations
   • Keep meeting records
     (e.g., minutes and reports)
Reasons for DSMB oversight

   •   Protect patients‘ rights
   •   Ensure that risks are minimized
   •   Ensure data integrity
   •   Terminate a trial based on interim
       data if safety concerns arise or
       objectives have been met
Quality Assurance

   • ISO: a set of activities to provide
     confidence that quality
     requirements will be fulfilled
   • Clinical research: independent
     audits of all trial-related processes
     & functions
     – Performed by QA function not
       involved in the research process (no
       conflict of interests)
     – Assess efficiency of sponsors‘ QC
       processes.
Quality Assurance audits

   • Trial / project specific audits
   • Systems audits
     – System: A selected process plus all
       related activities, resources,
       organization, documents (including
       SOPs & records), facilities and
       equipment, e.g., Pharmacovigilance,
       Data Management
QA, trial specific audits

     audit of the
                     audits at     audit of trial                   audit of
       study
                     trial sites    database                      trial report
      protocol



                                     pooling
           trial      collection     of data                            trial
                                                       analysis
         protocol      of data        in the                           report
                                    database


                                                     audit of
     audit of CRF,                                  graphs,
           IB                                       tables &
                                                      stats
QA, systems audits

        audit of                              audit of IP        audit of
                            audit of
  computerized data                          management        document
                           monitoring
  collection systems                         & distribution   management
                            system
  (validation audits)                           system         & archiving




                             Collection & analysis of data




                audits of central       audit of sponsor‘s
                   lab & other          pharmacovigilance
                service providers             system
Benefit of QMS

   It supports continuous quality
      improvement
                                      development of
      implement                       trial protocol &
   recommendations                      instructions
                                           training
                      ACT    PLAN


     QA audits
                     CHECK    DO
    QC activities                   clinical trial process

                                      in line with SOPs
Using metrics in clinical trial quality
management

     • What gets measured, gets done
        – What does not get measured, may not get
          done
     • Two important types of metrics
        – For yesterday and today
           • For example, historical financial
             performance
        – For tomorrow
           • For example, how much are we
             improving (i.e., a rate of change)?
           • Where are we in important skills and
             abilities?
Questions and
 Discussion

								
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