Research Impropriety

1
Research Impropriety

• Alan K. Jacobson, MD
• ACOS/RD
• Loma Linda VAMC

2
What have we covered so far?

• Responsible Institutions
• Responsible IRB Committees
• Responsible Investigators
• Responsible Auditing and Monitoring
• So what more could one ask for?

3
Murphys Law

• If anything can go wrong,
• it will.

4
Major John P. Stapp, M.D.

• Not well known in the compliance literature
• Human Guinea Pig, 1949
• 632 mph, 46.2Gs force
• our good safety record was due to a firm belief
  in Murphys Law and in the necessity to try and
  circumvent it.
• Died age 89 of natural causes

5
So who was Murphy?

• Captain Edward A. Murphy
• Edwards AFB
• Engineer on project MX981 - deceleration
• When technician wired a transducer incorrectly -
  If there is any way to do it wrong, hell find
  it.
• Recorded by George E. Nichols, Northrop project
  manager, who kept a list of laws.

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Colonel John P. Stapp, M.D.

• a firm belief in Murphys Law and in the
  necessity to try and circumvent it.
• The Essence of Local Accountability

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Research Impropriety

• Why does it occur?
• What is it?
• How should it be managed?
• Can it be prevented?
• Is there any good news?

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Research Impropriety

• Does medicine have a culture that turns a blind
  eye to research misconduct?

Dr. Richard Smith Former Editor, British Medical
Journal
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Research ImproprietyWhy does it occur?

• Why wouldnt it happen? It happens in all other
  human activities.
• Pressure to publish.
• Inadequate training. Not taught good practice.
  Indeed, sometimes taught the opposite.
• Does sloppy behaviour spill over to fraud?
• You can get away with it. The system works on
  trust.

Dr. Richard Smith Former Editor, British Medical
Journal
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Research Impropriety What is it?Multitude of
Terms

• Research or Scientific
• Impropriety
• Misconduct
• Misbehavior
• Noncompliance
• Fraud
• Sloppy science / research
• Junk science / research
• Egregious abrogation of investigator
  responsibilities
• Scientists behaving badly

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Scientists Behaving Badly

• Research on Research Integrity (Office of
  Research Integrity/NIH)
• Brian C. Martinson and colleagues
• 3,600 surveys to NIH funded scientists
• 1,768 (52) usable responses
• of scientists who say that they engaged in the
  behaviour listed within the past three years
• researchers can no longer afford to ignore a
  wide range of questionable behaviour that
  threatens the integrity of science.

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Top Ten Scientific MisbehaviorsLikely or Very
Likely to be Sanctionable
1. Falsifying or cooking research data 0.3
2. Ignoring major aspects of human subject requirements 0.3
3. Not properly disclosing involvement in firms whose products are based on ones research 0.3
4. Relationships with students, research subjects or clients that may be interpreted as questionable 1.4
5. Using anothers ideas without permission or due credit 1.4
6. Unauthorized use of confidential information in connection with ones own research 1.7
7. Failing to present data contradicting ones own previous research 6.0
8. Circumventing minor aspects of human subject requirements 7.6
9. Overlooking others flawed data or questionable interpretation of data 12.5
10. Changing the design, methodology or results of a study in response to pressure from a funding source 15.5
Martinson et al, Scientists Behaving Badly,
Nature 2005420739-740
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Scientists Behaving BadlyOther Behaviours
11. Publishing same data or results in two or more publications 4.7
12. Inappropriately assigning authorship credit 10.0
13. Withholding details of methodology or results of a study in papers or proposals 10.8
14. Using inadequate or inappropriate research designs 13.5
15. Dropping observations or data points from analyses based on a gut feeling that they were inaccurate 15.3
16. Inadequate record keeping related to research projects 27.5
Martinson et al, Scientists Behaving Badly,
Nature, 2005
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The Spectrum of Research Impropriety
Fatal / Criminal
Administrivia
administrivia - the tiresome but essential
details that must be taken care of and tasks that
must be performed in running an organization "he
sets policy and leaves all the administrivia to
his assistant TheFreeDictionary
15
Nothing New Under the Sun

• Charles Babbage 1791 - 1891
• Primary Legacy - Inventor of Difference Engine
  - first advance in computers since abacus
• Less renown - author on dishonesty in science
• Trimming - clipping off little bits here and
  there
• Cooking - selective reporting of a group of
  results
• Forgery - made up results

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History of Research ImproprietyFailure of an
entire society
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History of Research ImproprietyFailure of
Oversight Committees
1931 Rosenwald Fund cuts support to development
projects. Clark and Vondelehr decide to follow
men left untreated due to lack of funds in order
to show need for treatment program. 1968 Concern
raised about ethics of study by Peter Buxtun and
others. 1969 CDC reaffirms need for study and
gains local medical societies' support (AMA and
NMA chapters officially support continuation of
study). 1972 First news articles condemn
studies. 1972 Study ends and participants
compensated with cash and continued medical
treatment. 1973 Congress holds hearings and law
suit initiated. 1997 On May 16th President
Clinton apologizes on behalf of the Nation.
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History of Research ImproprietyFailure of
Investigator Responsibilities

• Dr. William Summerlin, Oncology (1974)
• Never returned to research
• Dr. John Darsee, Cardiology (1981)
• Left research, barred from federal funds
• Brigham Womens had to return NIH funds
• Eric Poehlman, Aging, (2000-2005)
• Fined 180,000 barred from federal funds
• Currently in federal prison
• Hwang Woo Suk, Stem Cell Research (2005-2006)
• Fired from Seoul University, possible criminal
  charges

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Research ImproprietyWhy Should WE Care?

• The Hall Affair
• Sadly, as it unfolded, the Hall affair
  illustrated the reality that allegations of
  research impropriety affect the careers of both
  the accused and the accusers and, in the process,
  can divide an institution and damage its
  reputation M.B. Van Der Weyden
  http//www.mja.com.au/public/issues/180_04_160204/
  van10035_fm.html
• Imanishi-Kari / Baltimore / OToole
• Post-doc accuser 1986, cleared by MIT, Tufts
  NIH investigations, but congressional panel and
  secret service investigations resulted in 1994
  ORI ruling of 10 years barred from federal funds
• 1997 DHHS arbitration panel overturned ORI ruling

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The Cost of Research Impropriety I

• Research Integrity Cost
• Scientific Record
• Public Confidence
• Impropriety of any type in the conduct of
  research is abhorrent to the inherent purpose of
  all scientific inquiry the discovery and
  dissemination of truth.

Research Related Policies and Procedures State
University of New York (SUNY)
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The Cost of Research Impropriety II

• Cost to subjects and patients
• President Lincolns commitment
• to care for him who shall have borne the
  battle, and for his widow and his orphan.

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The Cost of Research Impropriety III

• Direct Investigative and Management Cost
• Distraction Cost
• What isnt getting done while resources are
  utilized to investigate and manage the
  impropriety and its fallout.

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Impact of Research Impropriety

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Research Impropriety
So, What IS it?
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Definition of Research ImproprietyUnder VHA
Handbook 1058.2

• Research impropriety is any ethical lapse or
  other impropriety involving or occurring in
  connection with research other than research
  misconduct as defined in the Federal Policy on
  Research Misconduct
• VHA Handbook 1058.2 Research Misconduct

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Types of Research Impropriety
Research Impropriety
All Other Research Impropriety
Research Misconduct
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Types of Research Impropriety
Research Impropriety
All Other Research Impropriety
Research Misconduct
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Research MisconductVHA Policy Conforms to
Federal Policy

• Research misconduct is defined as fabrication,
  falsification, or plagiarism in proposing,
  performing, or reviewing research, or in
  reporting research results.
• Research misconduct does not include honest error
  or differences of opinion.
• Federal Register Notice Vol. 65, No. 235, Dec.
  6, 2000

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Research MisconductDefinitions

• Fabrication (1058.2 - 5c)
• Making up data or results and recording or
  reporting them
• Falsification (1058.2 - 5d)
• 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
• Plagiarism (1058.2 - 5i)
• Appropriation of another persons ideas,
  processes, results, or words without giving
  appropriate credit

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Research MisconductDefinitions

• Research Integrity Officer (1058.2 - 5l)
• The RIO is the appointed official at each VA
  facility who is responsible for receiving and
  coordinating reviews of formal allegations of
  research misconduct.
• Role further defined in 1058.2 - 7
• Liaison with ORO 1058.2 - 7b(1)

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Responsibilities of Federal Agencies and Research
Institutions

• The Federal Policy on Research Misconduct applies
  to all federally-funded research and proposals
  submitted to Federal agencies for research
  funding.
• Federal agencies have ultimate oversight
  authority for Federally funded research, but
  research institutions bear primary responsibility
  for prevention and detection of research
  misconduct and for the inquiry, investigation,
  and adjudication of research misconduct alleged
  to have occurred in association with their own
  institution.
• Federal Register Notice Vol. 65, No. 235,
  Dec. 6, 2000

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Research MisconductDefinitions II

• Federal and VHA definitions are extremely precise
• Research Misconduct is specifically restricted to
  FFP
• Non-federal institutions, i.e. affiliated
  universities, may have variable policy
  definitions, even though they are required to
  follow federal policy on federally funded projects

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Research MisconductHow Should Allegations be
Handled?

• VA Handbook 1058.2 identifies individuals
  responsible for investigating allegations of
  misconduct and provides guidance for procedures
  and roles.
• Responsible authorities must determine whether
  the conduct was deliberate, or honest error.
• Investigations must be conducted confidentially
  and with discretion to protect both informant and
  accused parties.

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Research MisconductManagement

• VERY detailed process
• In summary, if a question of Research Impropriety
  arises and there is any hint that it may be
  related to FFP - DO NOT START LOCAL INVESTIGATION
  !
• If any question of FFP - notify RIO and have RIO
  coordinate with Peter Poon in ORO
• The evaluation will likely be done locally, but
  due to the complexity of the process it should be
  coordinated with ORO.

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Research MisconductManagement

• Defined Phases
• Allegation
• Inquiry
• Investigation
• Adjudication
• Departmental Review
• Appeals

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Research MisconductCorrective Actions -
Considerations

• The extent of the misconduct (amount, duration,
  scope)
• Degree to which the misconduct was knowing,
  intentional or reckless
• Presence or absence of a pattern of misconduct
• The consequences or possible consequences of the
  misconduct
• The respondents position and responsibility for
  the project
• Cooperation of the respondent during Inquiry and
  Investigation
• Likelihood of rehabilitation
• Presence of similar cases - commensurate action
• Any other extenuating or aggravating
  circumstances

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Research MisconductExamples of Corrective
Actions

• Government-wide debarment (in development)
• Removal from a particular project,
  suspend/terminate award
• Restitution of funds or civil penalties
• Prohibition from receiving VA research funds for
  a period
• Correction or retraction of published article
• Monitoring or supervision of future work
• Required certification of data
• Required certification of sources (references and
  contributors)
• Remedial education or mentoring

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Types of Research Impropriety
Research Impropriety
All Other Research Impropriety
Research Misconduct
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All Other Research Impropriety

• All Other Research Impropriety is
  asill-defined as Research Misconduct is
  rigorously defined

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The Spectrum of Research Impropriety
Fatal / Criminal
Administrivia
administrivia - the tiresome but essential
details that must be taken care of and tasks that
must be performed in running an organization "he
sets policy and leaves all the administrivia to
his assistant TheFreeDictionary
41
All Other Research ImproprietyDefinitions /
Examples

• Examples of research impropriety include, but
  are not limited to, conflicts of interest,
  misallocation of funds, sexual harassment,
  discrimination, and breaches of human subjects
  protections and animal welfare requirements.
• VHA Handbook 1058.2 Research Misconduct

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All Other Research Impropriety Examples

• Failing to retain significant research data for a
  reasonable period
• Maintaining inadequate research records,
  especially for results that are published or are
  relied on by others
• Conferring or requesting authorship on the basis
  of a specialized service or contribution that is
  not significantly related to the research
  reported in the paper
• Refusing to give peers reasonable access to
  unique research materials or data that support
  published papers
• Responsible Science
  Ensuring the Integrity of the Research Process,
  National Academy of
  Sciences/Institute of Medicine Report, 1992

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All Other Research Impropriety Examples

• Using inappropriate statistical or other methods
  of measurement to enhance the significance of
  research findings
• Inadequately supervising research subordinates or
  exploiting them and
• Misrepresenting speculations as fact or releasing
  preliminary data to allow peers to judge the
  validity of the results or to reproduce the
  experiments.
• Responsible Science Ensuring the Integrity
  of the Research Process, National Academy of
  Sciences/Institute of Medicine Report, 1992

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All Other Research Impropriety Examples

• Engaging in inappropriate authorship practices on
  a publication and failing to acknowledge that
  data used in a grant application were developed
  by another scientist
• Inappropriate data analysis and use of faulty
  statistical methodology
• Failure to document and incorporate subjects
  feedback in findings
• Misuse or misallocation of funds for unauthorized
  purposes
• Financial conflict of interest of self or close
  relatives (e.g., spouse)
• Time and effort reporting errors or omissions or
  over-commitment
• Inappropriate staff assignments
• Neglect of research-related administrative tasks

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All Other Research ImproprietyCompromise of
Research Subject Protections

• Inadequate adverse event reporting
• Privacy violations
• Breach of patient confidentiality
• Failure to inform subjects of new information
• Failure to warn subjects of possible side effects
• Failure to ensure that subjects understand
  informed consent
• Failure to conduct adequate literature review
  prior to starting clinical trials

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All-Other Research Impropriety

• Authorship (other than plagiarism which is
  research misconduct)
• Conflict-of-interest
• Noncompliance
• Oversight / Supervision
• Sloppy Science

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Adherence to Editorial Guidelines

• International Committee of Medical Journal
  Editors (ICMJE) guidelines for
• - Authorship and Contributorship
• - Peer Review
• - Conflicts of interest
• - Privacy and Confidentiality
• - Protection of Human Subjects
• - Corrections, Retractions, Expressions of
  Concern

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Conflict of Interest
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All Other Research ImproprietyManagement

• Research Issue or Personnel Issue
• No proscribed initial investigatory process
• What to report to ORO
• September 2005 Guidance Document
• VHA Handbook 1058.1
• VHA Handbook 1058.2

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ORO ReportingSeptember 2005 Guidance Document

• What to Report to ORO
• Protection of Human Subjects in VA Research
• Laboratory Animal Welfare in VA Research
• Safety and Security in VA Research
• Misconduct in VA Research

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ORO Reporting - Human Subjects I

• Any adverse event in a human subject, or an
  imminent threat of an adverse event, that results
  in a substantive action by the IRB under 1058.1
• Any unexpected death of a human subject under
  1058.1
• Any unanticipated problem involving risks to
  subjects or others that results in a substantive
  action by the IRB
• Any for-cause suspension or termination of VA
  human subject research by the IRB, the VA
  facility, or a VA affiliate institution
• Any serious or continuing noncompliance with
  federal regulations or VHA policies for the
  protection of human subjects, including
• 38 CFR Part 16
• 45 CFR Part 46
• 21 CFR Parts 50, 56, 312 or 812
• VHA Handbook 1200.5

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ORO Reporting Human Subjects II

• Any serious or continuing noncompliance with
  federal regulations or VHA policies for the
  protection of human subjects, including
• 45 CFR Part 46 (Protection of Human Subjects in
  Federal Research)
• Based on Belmont Report, became law in 1981
• Subpart A - Basic HHS Policy for Protection of
  Human Research Subjects
• Subpart B - Additional protections - pregnant
  women, fetuses, neonates
• Subpart C - Protections for Prisoners
• Subpart D - Protections for Children
• 38 CFR Part 16 (Protection of Human Subjects in
  VA Research) 1991
• VA promulgation of The Common Rule, identical to
  subpart A, 45 CFR 46
• FDA 21 CFR
• Part 50 (common rule)
• Part 56 (IRBs),
• Part 312312 (IND)
• 812 (IDE)
• VHA Handbook 1200.5
• Requirements for the Protection of Human Subjects
  in Research

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ORO Reporting - Human Subjects III

• Any serious or continuing noncompliance with IRB
  requirements or determinations
• Any findings of noncompliance in human research
  protections from ORD or other VA office
• Any findings of noncompliance in human subject
  protections from external oversight agencies such
  as OHRP, FDA,
• Any change in the facilitys accreditation status
  from a VA-recognized accreditation organization
  for human research protections
• Any change in the facilitys FWA or designated
  IRBs as filed with OHRP
• Any significant change in the facilitys MOU with
  an affiliate institution or other VA facility
  regarding the designation of IRB(s) or other
  human research protection function

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All Other Research ImproprietyManagement

• Research Issue or Personnel Issue
• If it is a Personnel Issue
• Is it a conduct issue?
• Is it a performance issue?

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All Other Research ImproprietyCorrective
Action / Consequences

• Examples from Research Misconduct
• The extent of the misconduct (amount, duration,
  scope)
• Degree to which the misconduct was knowing,
  intentional or reckless
• Presence or absence of a pattern of misconduct
• The consequences or possible consequences of the
  misconduct
• The respondents position and responsibility for
  the project
• Cooperation of the respondent during Inquiry and
  Investigation
• Likelihood of rehabilitation
• Presence of similar cases - commensurate action
• Any other extenuating or aggravating circumstances

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Research Impropriety ManagementWhen Scientists
Do Bad Things

• Does it involve FFP?
• Is it reportable to ORO?
• Is it a Personnel Issue?
• Otherwise

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Research ImproprietyCan it be Prevented?

• Educate - Training
• GCP, HRP, HIPAA, Privacy
• Verify - Monitoring and Audits
• Routine
• For-cause
• Provide a compliant environment
• Accreditation
• AAHRPP
• Exemplary Leadership
• Culture of Responsible Research
• Culture of Compliance

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Research ImproprietyCan it be Prevented?

• Organizational Options - VHA
• Institutional Options - individual facilities
• Division / Research Group Options
• Individual Investigator Options

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Finding the Balance

• Effective assurance of responsible conduct of
  research

• Suffocating oversight and bureaucracy

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Research ImproprietyCan it be Prevented?
61
Research ImproprietyCan it be Prevented?

• Steinberg Tips
• Make your position clear - Impropriety will not
  be tolerated and will be caught
• Avoid hyperbole and jokes about getting the data
  no matter what
• Dont improve the current study - let staff
  know that the current protocol is the only one
  approved
• Promote Research Integrity
• Verify, Verify, Verify

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Research ImproprietyCan it be Prevented?

• ORI Introduction to Responsible Conduct of
  Research
• Nicholas Steneck, PhD
• This booklet introduces the reader to the nine
  RCR core instructional areas in four sections
  that follows research from inception to planning,
  conducting, reporting, and reviewing research.
  The publication features case studies, text-box
  inserts, discussion questions, and electronic and
  printed resources.

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Colonel John P. Stapp, M.D.

• a firm belief in Murphys Law and in the
  necessity to try and circumvent it.
• The Essence of Local Accountability

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Research ImproprietyThe Good News

• Documented Research Impropriety is relatively
  rare
• ORI statistics

65
Useful Resources

• VA Office of Research Development (ORD)
• Program for Research Development Education
  (PRIDE)
• http//www1.va.gov/resdev/programs/pride/
• K. Lynn Cates, MD, [phone],
  lynn.cates_at_va.gov
• Marisue Cody, PhD, [phone],
  marisue.cody_at_va.gov
• VA Office of Research Oversight (ORO)
• http//www1.va.gov/oro/
• Research Misconduct Peter Poon, JD, MA
• [phone], peter.poon_at_va.gov
• HHS Office of Research Integrity (ORI)
• http//ori.hhs.gov/
• HHS Office for Human Research Protection (OHRP)
• www.hhs.gov/ohrp