Stem Cells and Cloning by jizhen1947


									 Clinical Trials Research: Should
You Audit or Should You Monitor?

Kristin Bialobok, RN, MSN, CCRC, CCRA
 Director, Clinical Research Compliance
            University of Texas
      M. D. Anderson Cancer Center
      Definition of Research

Research is designated as an activity that
permits conclusions to be drawn, and
develops or contributes to generalizable
           Research Activities

• Research may involve direct interactions or
  interventions with subjects.

• Research may also involve indirect activities such
  as the analysis of specimens or data from people.

• Both are considered human subjects research and
  subject to FDA and OHRP regulation
“Science is a community venture
dependent upon shared values and
 trust. In the end, that’s where we
       have to put our faith.”

            Donald Kennedy

•   Trust “bank account”
•   Hard to save
•   Easy to spend
•   Once “lost” difficult to “find”
 Dr. Werner
 Failed to produce medical charts for about two-thirds of the
      patients allegedly enrolled in the study

 He Failed to obtain informed consent from any of the patients

 Failed to obtain IRB approval from the University to actually
      conduct the study
 Failure to administer the regimen to the control group that
      was listed in his protocol
 Scandal discovered in 1999, but had been publishing since
      1995 thus invalidating results from his previous studies
                    University of
                    Oklahoma at Tulsa
                    Dr. Michael McGee
    Ineligible patients
    Failure to follow protocol
    Failure to notify IRB of protocol revisions
    Failure to control investigational drug
    Failure to protect safety and welfare of subjects
    Disqualification from conducting further clinical trials
   OHRP ordered University to to immediately stop all
    government-supported trials
   University ban was lifted after the IRB was disbanded
University of
Pennsylvania- IHGT
   Patient death
   Lacked regulatory reporting/monitoring program
   Lacked standard operating procedures
   Enrolled ineligible patients
   Inadequate informed consent document
   Shut down all gene therapy trials
                   Scientific Misconduct

Current: (42 CFR Part 50, Subpart A)
“Fabrication, falsification, plagiarism or other practices that
seriously deviate from those that are commonly accepted
within the scientific community for proposing, conducting or
reporting research. It does not include honest error or
honest differences in interpretations or judgments of data.”

Falsification of data:
- could occur in proposing, designing, performing,
  recording, reporting, supervising, or reviewing research
- Includes acts of omission and commission
       Omission-consciously not revealing all data (eg reportable adverse
        events, concomitant meds, etc)

       Commission-consciously altering data or fabricating data (eg lab
         values, BP readings, specimens)
      Consequences of Scientific Misconduct

      Investigator                         FDA applications   Sponsors
              A                                  91              47
              B                                  49              25
              C                                  43              21
              D                                  21              17
               E                                 12              6
               F                                  6              6
              G                                  92              48
Stan W. Woollen and Antoine El Hage, PhD
Office of Good Clinical Practice
“Scientific Misconduct - The „F‟ word”
October 2001
       Types of Data Falsified

•   EKGs
•   Vital Signs
•   Physical exams
•   Lab specimens
•   Subject identities
•   Drug accountability and compliance records
•   Informed consent
          Dr. Robert Fiddes
 Fabricated patients
 Failed to follow protocol
 Substituted information
 Worked for 42 drug companies/91 protocols
 Found Guilty - 1) conspiracy to commit an offense
                    against the US and
                 2) making false statements in matter within
                     jurisdiction of the FDA (18 USC 1001)
 Sentenced to 15 months prison and repay $800,000
 Study coordinators sentenced to probation
North Forest Medical Associates
Getzville, NY

                          Allyn M. Norman, D.O.

 Enrolled 7 fictitious subjects into an osteoarthritis study
 Forged informed consent and case report forms
 Fabricated telephone contact information with subjects
 Substituted subject blood and urine for samples from surplus
 Failed to conduct the study according to the approved protocol
 Never administered study drug to any subject but destroyed it on site
 License suspension for 3 yrs, fined $5000, and required education
 FDA Disqualified October 2003
                                    Dr. Roger

   Enrolled ineligible patients
 Kept double set of files
 Submitted progress reports after patient’s death
 Failed to follow protocol
 Found guilty of scientific misconduct and 115 instances of fraud
 Repayed $1,000,000
                                                 Vickie L. Hanneken, R.N.,
                                                 former Clinical Research

Engaged in Scientific Misconduct by fabricating data in the clinical/study
records of 35 participants in the Selenium and Vitamin E Cancer Prevention
Trial (SELECT), with a total of 60 separate acts, which included:

 Fabrication of laboratory reports on PSA concentration for 2 participants;
 Falsification of the physician's and nurse's records for 10 participants;
 Fabrication of the nurse's records for 2 participants;
 Falsification of patients' history and physical forms for 21 participants;
 Falsified data into the SWOG computerized data base for 13 participants

Entered into a Voluntary Exclusion Agreement (Agreement ) in which she
has agreed for a period of three (3) years to not participate in contracting
or subcontracting with any agency receiving government money.
Nancy J. Strout, Ph.D.

Engaged in scientific misconduct by

• Fabricating interview data for at least 50 interviews of
  human subjects enrolled in the Maine Evaluation of
  Consumer-Operated Services Project for mental health

• The project had to nullify all 346 interviews due to her
  involvement at one or more stages with the subjects.

Entered into a Voluntary Exclusion Agreement (Agreement ) in which she
has agreed for a period of three (3) years to not participate in contracting
or subcontracting with any agency receiving government money.
                                             Stan W. Woollen and Antoine El Hage, PhD
Who Complains?                               Office of Good Clinical Practice
                                             “Scientific Misconduct - The „F‟ word”
                                             October 2001

FY 2000
                     2%2%                    Sponsors
                5%          14%
           8%                                Anonymous
                                             Private Citizens
  3%                                         Govt Agencies
 3%                                    11%   IRBs
                                             Former Employees
                                             Health Profs
 9%                                          CROs
                                             Study Coordinators
      8%                                     Other
                     19%                     Informants
                            n = 118
                                                          Stan W. Woollen and Antoine El Hage, PhD
                                                          Office of Good Clinical Practice
What Are They Complaining About?                          “Scientific Misconduct - The „F‟ word”
                                                          October 2001

  • Failure to follow the protocol       • Failure to follow FDA
      (70)                                   regulations (13)
  •   Falsification (67)                 •   Charging for the test article (9)
  •   Informed Consent Issues (55)       •   Drug accountability (7)
  •   Failure to report adverse events   •   No active IND (7)
      (40)                               •   Violations of GLP regs (7)
  •   Qualifications of persons          •   Misleading advertisements (5)
      performing physicals (27)          •   Blinding (3)
  •   Inadequate Records (25)            •   No 1572 (2)
  •   Failure to get IRB approval,       •   Monitoring practices (2)
      report changes in research (20)
                                         •   IRB shopping (1)
               What’s being done?

• In May 1992 Office of Research Integrity (ORI) was
  founded as an independent entity within the
  Department of Health and Human Services (HHS).
                   What’s being done?

ORI Responsibilities
• Implement Public Health Service (PHS) regulations requiring
  institutions to respond to allegations of scientific misconduct

• Assure institutions requesting PHS funds have mechanisms in
  place to deal with allegations of scientific misconduct

• Provide assistance and guidance to institutions

• Can perform own investigation.

• Leaves primary responsibility with individual institutions
           PHS regulation 42 CFR Part 50(a)

“Each institution that applies for or receives assistance under the Act for
any project or program which involves he conduct of biomedical or
behavioral research must have an assurance satisfactory to the
Secretary that the applicant:

1) Has established an administrative process that meets the
requirements of this subpart, for reviewing, investigating and reporting
allegations of misconduct in science in connection with PHS sponsored
biomedical and behavioral research conducted at the applicant institution
or sponsored by the applicant; and

2) will comply with its own administrative process and requirement of this
              What the Institution Must Do

•   Applicability
•   Definition
•   Mechanism of reporting allegations
•   Inquiries
•   Investigations
•   Data sequestration
Additional Suggestions for Institutional Prevention

Standard Operation Procedures (SOPs)

• Create institutional SOPs and guidance documents defining how day-
  to-day research should be conducted
          – Research informed consent process
          – Serious Adverse Event reporting
          – Drug accountability

• Make SOPs and guidance documents easily accessible to research
          – Lotus Notes Tiles
          – Intranet Website
Additional Suggestions for Institutional Prevention

 Audit Program

 • Establish an internal research auditing program

          – Institutional Level

          – Departmental Level

 • Encouraged by the FDA but not mandatory
Additional Suggestions for Institutional Prevention

 Audit Program (Institutional Level)

 • Create a central Research Compliance or Quality
   Assurance group

 • Staff the group with experienced individuals
          – History of hands on protocol management (regulatory and
            conducting trials)
          – Will versed regarding GCPs and federal regulations
Additional Suggestions for Institutional Prevention

 Audit Program (Institutional Level)

 • Develop SOPs for conducting audits

           – Who comprises the audit team?

           – Which protocol are eligible to be audited?

           – How are trials chosen for audit?

           – How are research teams notified?

           – What items are reviewed during the audit?
Additional Suggestions for Institutional Prevention

 Audit Program (Institutional Level)
 • Activation/Continuing Review Information
 • Informed Consent
 • Eligibility
 • Protocol Compliance
 • Treatment
 • Toxicity/Adverse Event Reporting
 • Response/Disease Outcome
 • General Data Quality
Additional Suggestions for Institutional Prevention

 Audit Program (Institutional Level)
 • Develop SOPs for conducting audits (con‟t)

            – How are results to the research team communicated?

            – How does investigator respond to findings?

            – To whom is the final report addressed?
Additional Suggestions for Institutional Prevention

 Audit Program (Institutional Level)
 Process should be:

       • As friendly as possible,

       • Not punitive,

       • Educational focused

       • Evaluated regularly
Additional Suggestions for Institutional Prevention

 Audit Program (Departmental Level)

 • Could be specialized to meet each departments needs,

 • Research teams should be involved in developing program in
   order to promote „by in‟,

 • Department staff should be taught be institutional auditors
   how to audit,

 • Good idea to have departmental audit rotate team members
Additional Suggestions for Institutional Prevention

 Monitoring Program
 • Good for high risk trials (ie Investigator held INDs, high-risk trials, new
    investigator trials)

 • Prospective rather than retrospective

 • More pro-active

 • Allows for additional central control over the conduct of trial

 • Requires additional staff

 • Very time consuming
Additional Suggestions for Institutional Prevention

 Require Education for Investigators and Research Staff

 • Essential step

 • Research nurse and coordinator training

 • Existing and new faculty training

 • Ensure system in place to identify faculty/staff who do not
   comply with required training

 • Continuing education
Puzzle Pieces to Successful Research


     Institutional SOPs

                          Auditing /
       Team Work

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