Comprehending Research Misconduct and Malfeasance

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• Comprehending Research Misconduct and Malfeasance
• Peter H. Abbrecht, M.D., Ph.D.
• Medical Expert
• Office of Research Integrity

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Why be concerned about prevention of research
misconduct?
Advances in research depend on the reliability of
the research record. In clinical trials, the
research results may be the basis for life or
death decisions Sustained public trust in the
research enterprise requires confidence in the
research record and the processes Involved in its
ongoing development Occurrence of research
misconduct has serious consequences for all
involved respondents, co-workers,
complainants, institutions, sponsors, journals
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What is research misconduct?

• Fabrication, falsification, or plagiarism in
  proposing,
• performing, or reviewing research, or in
  reporting
• research results
• Fabrication is making up data or results and
• recording or reporting them.
• Falsification is manipulating research
  materials,
• equipment, or processes, or changing or
  omitting
• data or results such that the research is
  not
• accurately represented in the research
  record.

42 CFR Part 93.103
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• (c) Plagiarism is the appropriation of
  another persons ideas, processes,
• results, or words without giving
• appropriate credit.
• (d) Research misconduct does not
  include honest error or differences of
  opinion.

42 CFR Part 93.103
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Requirements for findings of research misconduct

• There must be a significant departure from
  accepted practices of the relevant research
  community.
• and
• The misconduct must be committed intentionally,
  knowingly, or recklessly.
• and
• The allegation must be proven by a preponderance
  of the evidence.

42 CFR Part 93.104 (Proposed)
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Not all allegations of misconduct in clinical
research meet the definition for Research
Misconduct

• The distinction between research misconduct and
  other problems (such as protocol violations or
  fiscal malfeasance) is important because
• (a) institutions have different mechanisms for
  handling the different situations
  (e.g.inquiry/investigation research misconduct
  process vs IRB oversight and corrective actions
  for protocol violations)
• (b) reporting requirements (to oversight
  agencies such as ORI, OHRP, FDA, sponsors, etc)
  are different

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Examples of Falsification

• Substituting one subjects record for that of
  another subject
• Altering dates and results from subjects
  eligibility visits
• Altering results of laboratory tests
• Backdating test or interview dates to fit
  protocol time window

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Examples of Fabrication

• Creating records of interviews that were never
  performed
• Making up progress notes for patient visits that
  never took place and inserting them into the
  medical record
• Preparing records for calls and follow-up
  contacts for participants who had already died

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IRB, OHRP, FDA issues that are not research
misconduct(in the absence of falsification/fabric
ation)

• Failure to report adverse event to IRB/sponsor
• Protocol deviations (entering ineligible
  participant or using off-protocol drug)
• Forging physicians signature on orders
• Failing to obtain or properly document informed
  consent
• Breaching human subject confidentiality

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Some illustrations of instances of falsification
or fabrication in clinical records from cases
with PHS findings of research misconduct
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Circumstances That Led to Misconduct Detection in
ORI Cases
Detection by co-workers or colleagues 14
Detection by an external quality control
group (data coordinating center, external
audit) 12 Discovery by direct supervisor or
graduate advisor 9 Detection by an
institutional quality control group (separate
from supervisor) 7 Detection by others
(patients or caregivers contacting the
appointment desk, IRB member noting
discrepancies) 3
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Lessons From ORI Clinical Cases

• Any person involved in clinical research may be
  responsible for scientific misconduct, regardless
  of rank or duties on the project
• The majority of respondents in ORI clinical cases
  are in technical positions (not doctoral degree
  holders)
• Many of these respondents worked with inadequate
  supervision or training
• Respondents may have had excessive work loads or
  time pressure or pressure to enroll subjects

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• There are many different motivations for F / F
• financial (enrollment or accrual bonuses)
• professional advancement (papers,
• grants, tenure, job promotion/change)
• personal
• misguided altruism
• Falsification / fabrication may be accompanied
• by sloppiness or carelessness in recordkeeping
• Misconduct commonly discovered by
• routine data audit
• whistle blower
• substitute staff member

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• Common areas of F/F include
• protocol entrance criteria(date, lab, history)
• biased randomization assignments
• filling in missed data f/u visits, etc.
• Interview protocols are at high risk for
  misconduct, especially if single interviewer
  and/or lack of adequate quality assurance
• Both scientific misconduct and violations of
  human subjects protection may occur in the same
  clinical activity
• In such cases all oversight agencies involved
  (ORI, OHRP, FDA, IRBs, etc.) work together

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Suggestions for Preventing and Identifying
Scientific Misconduct

• The P.I., Lab director, etc. must establish a
  climate in the lab in which scientific integrity
  (and the reasons for it) are emphasized
• All staff must be thoroughly trained in integrity
  principles and in conducting their portion of the
  protocol
• The P.I. and other supervisors must maintain
  strong communication with staff and a presence
  in the study setting, verifying personally at
  least a sampling of the research records

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• Staff should be questioned about data alterations
  in the research record (overwrites, erasures,
  whiteouts, changes in electronic records)
• If possible, in interview studies request
  informed consent to recontact the patient for
  quality control reasons, and follow up with a
  sampling of these patients
• Keep staff work loads reasonable
• Protocols should be designed with realistic
  requirements that can be met by both staff and
  patients

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• Protocol research forms should be as simple as
  possible, yet with clear designation of the
  required information
• In continuing studies, if possible, train more
  than one staff member to do follow-up

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• Any alterations on data forms must be done by
  striking through the original entry (no whiteout
  or writing over) and initialing and dating the
  new entry
• Copies of all laboratory reports should be
  retained by originating facility (to be spot
  checked on routine and special audits)
• Protocol sponsors should attempt to avoid paying
  bonuses based on number of patients enrolled

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PARTIAL LISTING OF INVESTIGATOR COMMITMENTS FDA
Form 1572(for studies requiring FDA approval)

• to conduct the study in accordance with the
  relevant, current protocol
• personally conduct or supervise the described
  investigation
• ensure that all associates, colleagues, and
  employees assisting in the conduct of the studies
  are informed about their obligations in meeting
  the above commitments
• maintain adequate and accurate records in
  accordance with 21 CFR 312.62

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Detecting and Handling Possible Scientific
Misconduct in Clinical Research

• On routine audits, be alert for possible clues of
  F / F on clinical records (white outs,
  overwritten data, numbers out of physical
  alignment, errors in form completion)
• Prompt sequestration of records if
  suspicion/allegation of scientific misconduct

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• ORI Guidelines for Handling Allegations of
  Scientific Misconduct in Clinical Research
  (currently in draft form)
• ORI can provide assistance to institutions
  assessing possible scientific misconduct through
  its Rapid Response Technical Assistance (RRTA)
  program