Research Impropriety

1. Research Impropriety Alan K. Jacobson, MD ACOS/R&D 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. Murphy’s 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 Murphy’s 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, he’ll find it.” • Recorded by George E. Nichols, Northrop project manager, who kept a list of laws.

6. Colonel John P. Stapp, M.D. “… a firm belief in Murphy’s Law and in the necessity to try and circumvent it.” The Essence of Local Accountability

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

8. Research Impropriety “Does medicine have a culture that turns a blind eye to research misconduct?” Dr. Richard Smith Former Editor, British Medical Journal

9. Research Impropriety:Why does it occur? • Why wouldn’t 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

10. 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”

11. “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.”

12. Top Ten Scientific Misbehaviors:Likely or Very Likely to be Sanctionable Martinson et al, “Scientists Behaving Badly”, Nature 2005;420:739-740

13. Scientists Behaving Badly:Other Behaviours Martinson et al, “Scientists Behaving Badly”, Nature, 2005

14. 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

16. History of Research Impropriety:Failure of an entire society

17. History of Research Impropriety:Failure 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.

18. History of Research Impropriety:Failure of Investigator Responsibilities • Dr. William Summerlin, Oncology (1974) • Never returned to research • Dr. John Darsee, Cardiology (1981) • Left research, barred from federal funds • Brigham & Women’s 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

19. Research Impropriety:Why 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 / O’Toole • 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

20. 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)

21. The Cost of Research Impropriety II • Cost to subjects and patients • President Lincoln’s commitment: • “…to care for him who shall have borne the battle, and for his widow and his orphan.”

22. The Cost of Research Impropriety III • Direct Investigative and Management Cost • Distraction Cost • What isn’t getting done while resources are utilized to investigate and manage the impropriety and it’s fallout.

23. Impact of Research Impropriety

24. Research Impropriety So, What IS it?

25. 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”

26. Types of Research Impropriety Research Impropriety “All Other” Research Impropriety Research Misconduct

27. Types of Research Impropriety Research Impropriety “All Other” Research Impropriety Research Misconduct

28. Research Misconduct:VHA 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

29. Research Misconduct:Definitions • 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 person’s ideas, processes, results, or words without giving appropriate credit

30. Research Misconduct:Definitions • 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)

31. 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

32. Research Misconduct:Definitions 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

33. Research Misconduct:How 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.

34. Research Misconduct:Management • 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.

35. Research Misconduct:Management • Defined Phases • Allegation • Inquiry • Investigation • Adjudication • Departmental Review • Appeals

36. Research Misconduct:Corrective 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 respondent’s 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

37. Research Misconduct:Examples 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

38. Types of Research Impropriety Research Impropriety “All Other” Research Impropriety Research Misconduct

39. “All Other” Research Impropriety • “All Other” Research Impropriety is asill-defined as Research Misconduct is rigorously defined

40. 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 Impropriety:Definitions / 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”

42. “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

43. “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

44. “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 subject’s 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

45. “All Other” Research Impropriety:Compromise 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

46. “All-Other” Research Impropriety • Authorship (other than plagiarism which is research misconduct) • Conflict-of-interest • Noncompliance • Oversight / Supervision • Sloppy Science

47. 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”

48. Conflict of Interest

49. “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

50. ORO Reporting:September 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