clinical & translational research seminar may 17, 2010 david a. crouse, phd associate vice...

Clinical & Translational Research Seminar

May 17, 2010David A. Crouse, PhD

Associate Vice Chancellor for Academic AffairsExecutive Associate Dean for Graduate Studies

Responsible Conductin Research

Why does integrity in all aspectsof research matter?”

Responsible Conduct in Research

2

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

So, What isResponsible 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 DefinedFabrication 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.

Research misconduct does not include: Honest error or differences of opinion Authorship disputes Misallocation of resources

8

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 committedintentionally, 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”

variability haste intentional or knowing or reckless

instrument carelessness FFP

technique inattention NO EXCUSE

10

What is NOT Research Misconduct?

Authorship disputesDetermine conditions of authorship ahead

of timeDispute 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 beINCLUDED IN:

Misrepresentationof personal credentials

(i.e., the C.V.)

12

Misrepresentation* of Authorship Among Applicants to Training Programs

# # with # pubs % pubsDiscipline Year Applicants pubs total invalid

•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, 19954. 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

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

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 yesRIO sequesters research recordsRIO notifies respondent of specific allegations

in writing

Inquiry conducted – initial fact-finding to determine whether allegation warrants an investigationRIO may appoint committee that includes

subject matter experts 15


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 isNotify any federal funding sources (Office of

Research Integrity [ORI] for Public Health Service grants)

16

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

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 itNo: case closedYes: Make settlement recommendations to HHS

Respondent can contest HHS charges & request a hearing through the Administrative law process

ORI Review

18

Disposition of AllegationsReceived 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 5

19

Types of Allegations in Closed Cases 2008

Allegation Inquiry Investigation ORI findings

Fabrication 0 0 0

Falsification 0 10 6

Falsif./Fabric. 0 7 7

Plagiarisim 0 0 0

TOTAL 0 17 13

20

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 559-676721

23


Are there requirementsfor RCR instruction?

NIH Requirement for Instruction inthe 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

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

Requirement Applies to:

25

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.

Format:

26

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

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:

Subject Matter (1):

27

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

Subject Matter (2):

28

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.

Duration of Instruction:

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 misconductResponsible authorshipMentoringPeer reviewData acquisition & monitoringConflict of interestCollaborative relationships &

collaborative science

31

32


Examples of misconduct in research

Journal of Cell Biology 116:11-15, 2004

Image Manipulation

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

ResolutionA new research field: Digital Forensics

33

Image Manipulation

Journal of Cell Biology 116:11-15, 2004, Figure 1

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

Image Manipulation

Journal of Cell Biology 116:11-15, 2004, Figure 6

Misrepresentation of image data.

Cells from various fields have beenjuxtaposed 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

Image DuplicationHwang 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: Appropriate duplication of own work with

publisher approved reuse of data? Self-plagiarism? Outright plagiarism of another author’s work?

37

Duplicate Publications - Déjà vu Project

http://discovery.swmed.edu/dejavu/38

Déjà vu Project

http://discovery.swmed.edu/dejavu/39

Nature 451:397-399

2008

Figure 2

Déjà vu Project

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 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

42

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

Other Recent Cases

43

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.

“10 Easy Ways to Commit Research Misconduct & Create Havoc in the Lab”

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

“Whatever the rationalization is,in the last analysis

one can no more be a little bit dishonestthan one can be a little bit pregnant.”

Honor in Science, p 14Sigma Xi, The Scientific Research Society

1997

The Bottom Line:

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 Deanwith concerns about fabrication of an imagein 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 Conductof Research Through a Case Study Approach. Washington DC, AAMC, 1994.

48

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.”


49


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.



50

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.



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 Conductof 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

“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.”

Source: NY Times October 3, 2008http://www.nytimes.com/2008/10/04/health/policy/04drug.html

Senator Grassley - Iowa

55

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 SCHNEIDERThe Atlanta Journal-ConstitutionTuesday, October 14, 2008Emory 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

mailto:[email protected]

mailto:[email protected]

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 non-invasion device should eliminate the adverse effects of medication overdoses.

58

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???

COI Committee Information

59

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.

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/

60

Further Reading:

http://ori.dhhs.gov/

clinical & translational research seminar may 17, 2010 david a. crouse, phd associate vice...

Documents

research slide

research misconduct

research materials

research subjects

research record

finding of research

reporting research results

persons research ideas