Stem Cells and Cloning

1
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
2
Definition of Research

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

3
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

4

• Science is a community venture dependent upon
  shared values and trust. In the end, thats where
  we have to put our faith.
• Donald Kennedy
• Editor-in-chief
• Science

5
Trust

• Trust bank account
• Hard to save
• Easy to spend
• Once lost difficult to find

6
Dr. Werner Bezwoda
? 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
7
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

8
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
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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.

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Falsification

• Falsification of data
• could occur in proposing, designing, performing,
  recording, reporting, supervising, or reviewing
  research results
• 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)

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Consequences of Scientific Misconduct
Stan W. Woollen and Antoine El Hage, PhD Office
of Good Clinical Practice Scientific Misconduct
- The F word October 2001
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Types of Data Falsified

• EKGs
• Vital Signs
• Physical exams
• Lab specimens
• Subject identities
• Drug accountability and compliance records
• Informed consent

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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
14
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

15
Dr. Roger Poisson

• ? Enrolled ineligible patients
• ? Kept double set of files
• ? Submitted progress reports after patients
  death
• ? Failed to follow protocol
• ? Found guilty of scientific misconduct and 115
  instances of fraud
• ? Repayed 1,000,000

16
Vickie L. Hanneken, R.N., former Clinical
Research Associate

• 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.

17
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
• services,
• 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.

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Who Complains?Everybody!FY 2000
Stan W. Woollen and Antoine El Hage, PhD Office
of Good Clinical Practice Scientific Misconduct
- The F word October 2001
2
2
5
14
8
3
3
11
9
8
8
9
19
n 118
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What Are They Complaining About?
Stan W. Woollen and Antoine El Hage, PhD Office
of Good Clinical Practice Scientific Misconduct
- The F word October 2001

• Failure to follow the protocol (70)
• Falsification (67)
• Informed Consent Issues (55)
• Failure to report adverse events (40)
• Qualifications of persons performing physicals
  (27)
• Inadequate Records (25)
• Failure to get IRB approval, report changes in
  research (20)

• Failure to follow FDA regulations (13)
• Charging for the test article (9)
• Drug accountability (7)
• No active IND (7)
• Violations of GLP regs (7)
• Misleading advertisements (5)
• Blinding (3)
• No 1572 (2)
• Monitoring practices (2)
• IRB shopping (1)

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Whats 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).

21
Whats 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

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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 subpart.

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What the Institution Must Do

• Applicability
• Definition
• Mechanism of reporting allegations
• Inquiries
• Investigations
• Data sequestration

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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 staff
• Lotus Notes Tiles
• Intranet Website

25
Additional Suggestions for Institutional
Prevention

• Audit Program
• Establish an internal research auditing program
• Institutional Level
• Departmental Level
• Encouraged by the FDA but not mandatory

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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

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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?

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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

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Additional Suggestions for Institutional
Prevention

• Audit Program (Institutional Level)
• Develop SOPs for conducting audits (cont)
• How are results to the research team
  communicated?
• How does investigator respond to findings?
• To whom is the final report addressed?

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Additional Suggestions for Institutional
Prevention

• Audit Program (Institutional Level)
• Process should be
• As friendly as possible,
• Not punitive,
• Educational focused
• Evaluated regularly
• ?

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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
• ?

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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
• ?

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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
• ?

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Puzzle Pieces to Successful Research
Education
Institutional SOPs
Auditing / Monitoring
Team Work