Responsible Conduct
in Research
Clinical & Translational
Research Seminar
May 17, 2010
David A. Crouse, PhD
Associate Vice Chancellor for Academic Affairs
Executive Associate Dean for Graduate Studies
Responsible Conduct in Research
Why does integrity in all aspects
of research matter?”
2
Responsible Conduct in Research
 Protects research subjects and assets.
 Maintains integrity of scientific process.
 Reinforces public support of science
and medicine.
 There is no room for misconduct in the
search for “TRUTH”.
3
Responsible Conduct in Research
So, What is
Responsible Conduct in Research?
4
“Rules of the Road”
5
From ORI website
Research Misconduct?
“Lying?”
“Cheating?”
“Stealing?”
“Copying?”
“Misrepresenting?”
“Fudging?”
“Cleaning Up Data?”
6
Research Misconduct Defined
“Research misconduct is defined as
fabrication, falsification, or plagiarism
in proposing, performing, or reviewing
research, or in reporting research
results.”
Office of Science and Technology Policy,
Federal Policy on Research Misconduct, 2000
DHHS Public Health Service Policies
on Research Misconduct, 2005
7
Terms Defined
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.
Plagiarism is the appropriation of another person’s research
ideas, processes, results, or words without giving
appropriate credit.
8
Research misconduct does not include:
 Honest error or differences of opinion
 Authorship disputes
 Misallocation of resources
Evidentiary Standards
“A finding of research misconduct requires that:
1. There be a significant departure from
accepted practices of the relevant research
community; and
2. The research misconduct be committed
intentionally, or knowingly, or recklessly; and
3. The allegation be proven by a preponderance
of the evidence.”
9
The Possible Range of Events
“Honest Error”  “Negligent Error”  Misconduct “Error”
10
 variability
 haste
 intentional or
knowing or
reckless
 instrument
 carelessness
 FFP
 technique
 inattention
 NO EXCUSE
What is NOT
Research Misconduct?
Authorship disputes
Determine conditions of authorship ahead
of time
Dispute resolution is the responsibility of
the home institution
Self-plagiarism --but watch out for
copyright restrictions!
Journal editors hold universities
accountable
11
But Research Misconduct Rules:
DO NOT apply to authorship
except for plagiarism.
Plagiarism and falsification can be
INCLUDED IN:
Misrepresentation
of personal credentials
(i.e., the C.V.)
12
Misrepresentation* of Authorship Among
Applicants to Training Programs
#
# with # pubs
Applicants pubs
total
% pubs
invalid
Discipline
Year
Pediatrics1
‘95
404
147
401
19.7
Radiology2
‘92-95
201
87
261
15.0
Gastroenterology3
‘95
236
53
92
30.2
Emergency Medicine4 ‘96
350
113
276
20.4
Orthopaedics5
‘98-99
213
64
138
18.0
Internal Medicine6
’02-03
497
234
634
25 - 1.8
Emergency Medicine7 ’02-03
173
47
13.3
•Non-existent or unverifiable journals or books; non-existent articles/chapters; abst, not paper;
“in press” but never appeared; inaccurate author position. Ref#6 used different methods
1. Acad Med 73:532, 1998 2. Am J Radiol 170:577, 1998 3. Ann Int Med 123:38, 1995
4. Ann Emerg Med 27:327, 1996 5. J Bone & Joint Surg 81A:1679, 1999
6. Ann Int Med 138:390, 2003 7. Acad Emerg Med 9:992, 2004
13
Institutional Responsibilities
 Appoint a Research Integrity Officer (RIO)
 Maintain a Research Misconduct Policy
 UNMC Policy 8003 “Research Integrity”
 Provide policy education to all researchers
 Respond to allegations
 Conduct an Inquiry and Investigation as
appropriate and report to federal funding
sources
 The Omaha VA also has a RIO (Dr. Fred
Hamel) and parallel policies
14
Reporting & Responding to Suspected
Research Misconduct at UNMC
 Contact Research Integrity Officer (RIO)
 May informally discuss concerns
 RIO determines if suspected misconduct
falls within definition; if yes
 RIO sequesters research records
 RIO notifies respondent of specific allegations
in writing
 Inquiry conducted – initial fact-finding to
determine whether allegation warrants an
investigation
15
 RIO may appoint committee that includes
subject matter experts
Reporting & Responding to Suspected
Research Misconduct at UNMC
 Inquiry report created containing
recommendations to Deciding Official (Vice
Chancellor for Academic Affairs)
 End proceeding or,
 Proceed to Investigation
 Investigation: determine if misconduct has
occurred, and if so, who is the responsible
person and how serious the misconduct is
 Notify any federal funding sources (Office of
Research Integrity [ORI] for Public Health
Service grants)
16
Reporting & Responding to Suspected
Research Misconduct at UNMC
 Investigation report created with recommended
findings to Deciding Official who:
(1) determines if the institution accepts the report; and
(2) determines appropriate institutional actions in
response to the findings
 Final investigation report submitted to federal
funding agencies (ORI for PHS grants)
17
ORI Review
 Determines if proceedings were conducted in
accordance with regulation
 May conduct additional analyses & develop
the evidence
 Decide whether research misconduct
occurred, and if so, who committed it
 No: case closed
 Yes: Make settlement recommendations to HHS
 Respondent can contest HHS charges &
request a hearing through the Administrative
law process
18
Disposition of Allegations
Received by ORI 2008
Allegations made to ORI
201
No action possible now or no action
113
Pre-inquiry assessment of allegations by ORI
54
Referred to other federal agencies
13
Handled by agency (NIH)
16
Received by agency (NIH) & referred to ORI
19
5
Types of Allegations in Closed Cases 2008
Allegation
Inquiry
Fabrication
0
0
0
Falsification
0
10
6
Falsif./Fabric.
0
7
7
Plagiarisim
0
0
0
TOTAL
0
17
13
20
Investigation
ORI
findings
Research Misconduct References
Federal Guidelines:
NIH (Federal Register 70(94):28370-28400, May 17, 2005
42 CFR Parts 50 and 93 – Research Misconduct
UNMC Research Integrity Policy #8003
(2/11/2005):
See UNMC Intranet: Policies and Procedures
Applies to ALL faculty, Staff and Students
UNMC Research Integrity Officer at 559-6767
21
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Responsible Conduct in Research
Are there requirements
for RCR instruction?
23
NIH Requirement for Instruction in
the Responsible Conduct of Research
 NOT-OD-10-019
 Published November 24, 2009
 “This policy will take effect with all
new and renewal applications submitted
on or after January 25, 2010, and for all
continuation (Type 5) applications with
deadlines on or after January 1, 2011. ”
24
Requirement Applies to:
All trainees, fellows, participants, and scholars
receiving support through any NIH training, career
development award, research education grant, and
dissertation research grant.
Includes: D43, D71, F05, F30, F31, F32, F33, F34,
F37, F38, K01, K02, K05, K07, K08, K12, K18, K22, K23,
K24, K25, K26, K30, K99/R00, KL1, KL2, R25, R36, T15,
T32, T34, T35, T36, T37, T90/R90, TL1, TU2, and U2R.
This policy also applies to any other NIH-funded
programs that require instruction in responsible conduct
of research as stated in the relevant funding opportunity
announcements
25
Format:
 Substantial face-to-face discussions among the
trainees/fellows/scholars/participants;
 A combination of didactic and small-group
discussions (e.g. case studies); and
 Participation of research training faculty members in
instruction in responsible conduct of research are
highly encouraged.
 While on-line courses can be a valuable supplement
to instruction in responsible conduct of research,
online instruction is not considered adequate as the
sole means of instruction.
26
Subject Matter (1):
There are no specific curricular requirements for
instruction in responsible conduct of research but
the following topics have been incorporated into
most acceptable plans for such instruction:
1. conflict of interest – personal, professional, and
financial
2. policies regarding human subjects (IRB), live
vertebrate animal subjects in research (IACUC), and
safe laboratory practices (IBC and more)
3. mentor/mentee responsibilities and relationships
4. collaborative research including with industry
27
Subject Matter (2):
5. peer review
6. data acquisition and laboratory tools;
management, sharing and ownership
7. research misconduct and policies for handling
misconduct
8. responsible authorship and publication
9. the scientist as a responsible member of society,
contemporary ethical issues in biomedical
research, and the environmental and societal
impacts of scientific research
28
Duration of Instruction:
Instruction should involve substantive contact hours
between the trainees/fellows/scholars/participants and
the participating faculty.
Acceptable programs generally involve at least eight
contact hours.
A semester-long series of seminars/programs may
be more effective than a single seminar or one-day
workshop because … learning will be better
consolidated, and the subject matter will be
synthesized within a broader conceptual framework.
29
Frequency of Instruction:
 Instruction should recur throughout a
scientist’s career:
 Undergraduate
 Post-Baccalaureate
 Pre-doctoral
 Post-doctoral
 Faculty
 At least ONCE in each career stage
 Not less than ONCE every FOUR years
 Faculty, Senior Fellows and K awardees
may fulfill the requirements by participating
as instructors
30
CITI RCR Modules
Research misconduct
Responsible authorship
Mentoring
Peer review
Data acquisition & monitoring
Conflict of interest
Collaborative relationships &
collaborative science
31
Responsible Conduct in Research
Examples of misconduct in research
32
Image Manipulation
Journal of Cell Biology 116:11-15, 2004
 Blots & Gels:


Gross misrepresentation
Subtle manipulation
(brightness, contrast, bkgd, splicing lanes)
 Micrographs:



Enhancing a specific feature
Linear vs nonlinear adjustments
Misrepresentation of a microscope field
 Resolution
A new research field: Digital Forensics
33
Image Manipulation
Gross manipulation of blots.
(A) Example of a band deleted
from the original data (lane 3).
(B) Example of a band added
to the original data (lane 3).
34
Journal of Cell Biology 116:11-15, 2004, Figure 1
Image Manipulation
Misrepresentation of image data.
Cells from various fields have been
juxtaposed in a single image,
giving the impression that they
were present in the same
microscope field.
A manipulated panel is shown
at the top. The same panel,
with the contrast adjusted by
us to reveal the manipulation,
is shown at the bottom
35
Journal of Cell Biology 116:11-15, 2004, Figure 6
Image Duplication
Hwang et al:
Science 308:1777-1783,
2005 (duplicate in paper)
Article Retracted
Verfaillie et al:
Nature 418:41-49,
2002 (Fig 1b)
Exp Hematol 30:896-904,
2002 (Fig 2)
Corrigendum in Nature
447:880-881, 2007
36
Déjà vu database
 Database created by Southwest Medical
Center researchers
 Searches Medline for potential duplicate
articles --- 1,000s listed beginning in early
’90’s
 Interpretation:



37
Appropriate duplication of own work with
publisher approved reuse of data?
Self-plagiarism?
Outright plagiarism of another author’s work?
Duplicate Publications - Déjà vu Project
38
http://discovery.swmed.edu/dejavu/
Déjà vu Project
39
http://discovery.swmed.edu/dejavu/
Déjà vu Project
Nature
451:397-399
2008
Figure 2
40
Cartoon from Nature
“A Tale of Two Citations”
“It is the best of times, it is the worst of times”
41
Recent ORI Enforcement
 Robert Fogel, MD, Harvard Medical
School (March, 2009)
 Falsified & fabricated baseline data from
a sleep apnea study in severely obese
patients
42

Falsified half of the physiologic data

Fabricated 20% of data from CT images

Falsified 50-80% of other anatomic data

Falsified 50% of sleep data
Other Recent Cases
 Aug 24, 2006: Dr. Kui Zhu, Cleveland Clinic
 Fabricated/falsified data
 Debarred from contracting with U.S. Govt
 University of Iowa Anesthesia Researchers
 Regional Anesthesia and Pain Medicine journal
allegations
 University of Iowa found no misconduct
 Dr. Eric Poehlman, University of Vermont
 Fabricated/falsified data from 1992-2002
 21 Journal articles retracted
 1 year prison sentence; debarment
43
“10 Easy Ways to Commit Research Misconduct
& Create Havoc in the Lab”
By: Chris Pascal, Director of Office of Research Integrity
1) Don’t review the raw data prior to publication; accept
summary data or prepared tables and graphs instead.
2) On a project where expected results have not been
achieved over several months, demand significant
results to meet a publication deadline.
3) Hire a new post-doc, but leave him/her without
guidance or supervision.
4) Tell your staff to do the right thing, but do the
convenient thing when it is expedient.
44
5) Publish results of a team research project, but leave
out two members who made substantive contributions.
6) Provide no guidance or standards for keeping
laboratory data.
7) Tell your lab members to ask questions, but don’t make
yourself available because you are too busy.
8) Have a large lab of junior scientists and provide little
guidance or supervision.
9) Drop data points in order to “clean up” your graph or
table without a clear rationale.
10) Tell your lab tech what results you expect from
the experiment and that you need them now.
45
The Bottom Line:
“Whatever the rationalization is,
in the last analysis
one can no more be a little bit dishonest
than one can be a little bit pregnant.”
Honor in Science, p 14
Sigma Xi, The Scientific Research Society
1997
46
Time to Volunteer
You receive a telephone call from the UNMC
Research Integrity Officer (RIO) asking you to
participate on a research misconduct inquiry
committee
A prominent journal editor called the Dean
with concerns about fabrication of an image
in a recent submission by a post doc,
Dr. Jim Newby
47
Dr. Newby’s Interview (1)
Dr. Newby tells the committee he completed a set of
experiments characterizing the receptor for a new class
of hormones. During the course of his work, he studied
binding characteristics and normal responses in tissue
culture and in vitro, utilizing gels to characterize the
molecular weights of receptor variants.
His mentor asks him to prepare an abstract for an
upcoming meeting and a paper for journal submission
on his work.
Adapted from SG Korenman & AC Shipp. Teaching the Responsible Conduct
of Research Through a Case Study Approach. Washington DC, AAMC, 1994.
48
Dr. Newby’s Interview (2)
As Dr. Newby examined the data, he noted that some of
the cell culture plates failed to respond to the hormonal
stimulus and that there was considerable variability in
the dose response relationship. Furthermore, on
reexamination, he noted that several gels were not very
“clean”, yet he was sure they demonstrated the
molecular weight, agonist binding and subunit
characteristics of the receptor.
He mentioned his distress to Dr. Pam Pro, a more senior
Post-doc, who suggested that it was OK to “clean up the
data.”
Adapted from SG Korenman & AC Shipp. Teaching the Responsible Conduct
of Research Through a Case Study Approach. Washington DC, AAMC, 1994.
49
Dr. Newby’s Interview (3)
Dr. Pro suggested that several outlier points could be
dropped because the cultured cells were probably dead.
She also showed him how easy it was to use Photoshop
to clean up messiness in some of the gel files by cutting
and pasting the nicer experimental lanes with the best
control lanes.
She did not think it really altered the results and it
certainly made the distinction between the groups more
clear.
Adapted from SG Korenman & AC Shipp. Teaching the Responsible Conduct
of Research Through a Case Study Approach. Washington DC, AAMC, 1994.
50
Dr. Newby’s Interview (4)
 Dr. Newby took Dr. Pro’s advice & cleaned
the images up and dropped a couple of
outlier data points.
 Dr. Newby drafted a journal article, with
himself, Dr. Pro, and his mentor as authors
 All 3 researchers reviewed the article &
images prior to submission.
Adapted from SG Korenman & AC Shipp. Teaching the Responsible Conduct
of Research Through a Case Study Approach. Washington DC, AAMC, 1994.
51
The Dr. Newby Case
 Was there research misconduct in
this scenario?
 If so, who committed it?
 Who could be harmed if this is
misconduct?
 Who maintains stewardship of the
research data?
Adapted from SG Korenman & AC Shipp. Teaching the Responsible Conduct
of Research Through a Case Study Approach. Washington DC, AAMC, 1994.
52
Review - Conflict of Interest
 When an individual’s private financial
interests either conflict with or create the
appearance of conflicting with UNMC’s
public interests
 “Individual” includes family members
 UNMC Policy 8010
 Business COI Procedures
 Research COI Procedures
 COM Relationships with Healthcare
Vendors Policy
 Effective July 1, 2008
53
Research COI
 Researchers complete a conflict disclosure
form upon grant submission
 Reviewed by COI officer
 Significant COIs reviewed by UNMC COI
committee
 Management plans developed for all COIs
 Management plans forwarded to the IRB if
Human Subject Research
 Must identify all conflicts when submitting
articles to journals
54
Senator Grassley - Iowa
“After questioning about 20
doctors and research
institutions, it looks like
problems with transparency
are everywhere, the current
system for tracking financial
relationships isn’t working.”
55
Source: NY Times October 3, 2008
http://www.nytimes.com/2008/10/04/health/policy/04drug.html
Depression expert at Emory pulls out
of research projects
NIH freezes grant money; Emory to begin
monitoring potential conflicts of interest
By GAYLE WHITE, CRAIG SCHNEIDER
The Atlanta Journal-Constitution
Tuesday, October 14, 2008
Emory psychiatry professor Dr. Charles B. Nemeroff is
stepping down from university research projects
funded by the National Institutes of Health, as the
federal agency cracks down on the school’s handling of
potential conflicts of interest, university officials said.
The NIH has frozen funds for a $9.3 million project on
depression led by Nemeroff, acknowledged Ron
Sauder, a university vice president. The project had
been under way for two of its proposed five years.
56
Being “Conflicted” is Not a
DSM - IV Diagnosis
You are a member of the UNMC COI
committee and have been presented with
the following:
Dr. Jones, a UNMC pioneer in Neurology
research has invented a control system to
automatically regulate Parkinson’s disease
patients’ medication --- the HELP device
(Home-based Empowered Living for
Parkinson’s Disease)
57
COI Committee Information
The HELP device administers the exact
dose of medication required by the patient
according to his/her level of activity. The
portable infusion pump is based on a
combination of accelerometers and
gyroscopes and can be integrated into a
patient’s everyday clothing. This noninvasion device should eliminate the
adverse effects of medication overdoses.
58
COI Committee Information
Dr. Jones has submitted a Phase I clinical
protocol to test the HELP device on
Nebraska Medical Center patients, listing
himself as the PI
Any potential conflict of interest issues to
consider???
59
Further Reading:
1. “Complainant Issues in Research Misconduct: The Office of
Research Integrity Experience”, Chris B. Pascal, Department of
Research Integrity, U.S. Department of Health & Human Services
2.
“Truth and Consequences”, Jennifer Couzin, Science, Vol. 313,
September 1, 2006
3. “Integrity in Scientific Research: Creating an environment that
promotes responsible conduct”, Institute of medicine – National
Research Council, The National Academies Press, Washington
DC, 2002.
60
4.
“ORI Introduction to the Responsible Conduct of Research”, NH
Steneck, DHHS – PHS, ORI, 2003.
5.
“On Being a Scientist”. National Academy of Sciences, National
Academies Press, Third Edition, 2009.
6.
The Office of Research Integrity: http://ori.dhhs.gov/