Maintaining Integrity in Clinical Trials

1. Maintaining Integrity in Clinical Trials Harvey J. Murff MD, MPH Director of Research Safety GCRC, Vanderbilt

2. Bush Misuses Science Data, Report Says New York Times, August 8, 2003

3. “Rather fail with honor than succeed by fraud”Sophocles

4. Federal Definition of Research Misconduct • Fabrication, falsification, plagiarism, or other practices that seriously deviate from those commonly accepted within the scientific community

5. Traditional Definitions of Research Misconduct • Falsification • Fabrication • Plagiarism

6. Traditional Definitions of Research Misconduct • Falsification • Substituting one subject’s record for that of another; • falsely reporting to a data coordinating center that certain clinical trial staff, who were certified to perform the procedures on the subjects, had done so, when they had not; • altering the dates and results from subjects’ eligibility visits; • altering the dates on patient screening logs and or/submitting the same log with altered dates on multiple occasions;

7. Traditional Definitions of Research Misconduct • Falsification • failing to update the patients’ status and representing data from prior contracts as being current; • altering the results of particular tests on blood samples to show that the test accurately predicted a disease or relapse; • backdating follow-up interventions to fit the time window determined by the study protocol; • falsifying the times that blood samples were drawn fro subjects

8. Traditional Definitions of Research Misconduct • Fabrication • Creating records of interviews of subjects that were never performed • Making up progress notes for patient visits that never took place and inserting them into the medical record to support published and unpublished research records • Preparing records for calls and follow-up contracts to subjects who had already died

9. Traditional Definitions of Research Misconduct • Plagiarism Included both the theft or misappropriation of intellectual property and the substantial unattributed textual copying of another’s work -This includes use of privileged communications (such as a grant review)

10. Not Considered Research Misconduct by ORI Failing to report an AE to the sponsor or IRB Deviating from the protocol Forging a physician’s signature on medical orders Failing to obtain or properly document, informed consent Breaching human subjects confidentiality Failure to obtain IRB and/or FDA approval for protocol changes

11. IOM Definition of Research Misconduct • Significant misbehavior that improperly appropriates the intellectual property or contributions of others, that intentionally impedes the progress of research, or that risks corrupting the scientific record or compromising the integrity of scientific practices

12. Definition of Research Misconduct • Misappropriation • Plagiarize • Breach confidentiality • Interference • Sequester or damage material • Misrepresentation • Reckless disregard for the truth • Omit facts

13. Other forms of Research Misconduct • Obstruction of investigations of research misconduct • Noncompliance with research regulations

14. Integrity and Public Trust • Public funding • Advancement of public good • Support is qualified • Must trust scientists • Must trust institutions • Institutions are held accountable

15. Research Misconduct

16. Research Misconduct

17. Reports not Submitted to ORI • > 50% significantly deficient • 57% did not contain information establishing PHS jurisdiction • 57% did not include sufficient information to determine whether a formal inquiry was necessary

18. Who is Being Investigated By ORI • 150 investigations from 1993-1997 • 76 found misconduct and 74 no misconduct • Primary site • Medical Schools 68% • Hospitals 11% • Research institutions 10% • Primary funding mechanism • RO1 • ORI results 71% disbarred (range 18 months to 8 years)

19. Who is Being Investigated By ORI Allegations against • Associate professors 27% • Professors 19% • Postdoctoral fellows 19% • Technicians 13% Misconduct findings • Associate professors 22% • Postdoctoral fellows 28% Allegations most frequently supported • Students 73% • Postdoctoral fellows 66% • Technicians 62% • Professors 19% • Assistant professors 29%

20. Who is Being Investigated By ORI Whistleblowers • Senior personnel (Deans, professors, asso prof) 47% • Junior personnel 21% Support rate for whistleblowers Academic faculty 50% Students 100% Technicians 20%

21. Handling Misconduct • Few institutions have much experience • Investigations have profound implications • Are emotionally charged • For ORI from Allegation to final decision approximately 480 days

22. Impact of Research Misconduct • Scope of Misconduct • Length of time of the Misconduct • Prestige of Institution or Individual • Impact of Clinical Treatment • Mishandling or retaliation associated with allegations • Media Coverage

23. Guilt by Association

24. Preventive Strategies • Make it clear that fabrication will get caught • Personally verify data • Question strong marks or erasures • Consider re-contacting participants for quality purposes • Did data collector contact you • Eligibility criteria • Aquatinted with recruiter • Promote respect for the protocol • Johns Hopkins • Do not promote attitude of “data no matter what”

25. Preventive Strategies • Allow staff to discuss potential protocol changes but do not alter the experiment • Educate about biases • Institutional policies • Look for outliers • Data collection too fast • One RA recruits faster than others • Promote research integrity • Explicitly educate staff • Discuss rules of authorship, data ownership prior to study

26. Limitations to Regulations • Rigid regulations that dictate process often limiting flexibility without enhancing results • Rules imposed by multiple agencies have inconsistent requirements • Regulation of science by nonscience agencies often leads to additional and nonproductive regulatory burden • Poor communication between regulators and research institutions

27. Individual Level Intellectual honesty Accuracy in contributions Collegiality Transparency Protection of subjects Humane care Adherence to mutual responsibilities Institutional Level Provide leadership Encourage respect Promote productive interactions Advocate adherence to rules Manage COI Investigate allegations Educate Monitor Integrity in Research

28. External Environment Research Organization Inputs/Resources Funding -Level and source Human Resources -Training -Experience -Sociocultural and psychological Outputs/ Outcomes Research related activities -Quality/quantity of activity Research Integrity -Knowledge and Attitudes toward ethical standards Organizational StructurePolicies, procedures, code Roles and responsibilities Decision making practices Missions and goals, objectives TechnologyOrganizational ProcessesLeadership Competition Supervision Communication Socialization Organizational learning Ethical Culture and Climate Feedback

29. General Sociocultural, Political, and Economic Environment Government regulation Funding for Scientific Work Research Organization Journal policies and procedures Human resources Job market Policies and practices of scientific societies

30. Recommendations of Commission on Research Integrity • Uniform Federal definition • Institutional Assurances • Promote Education • Organization and Journal Code of Ethics • Responsible Whistle blowing • Administrative processes and Investigations • Effective Oversight of Misconduct Allegations • Impose Federal Sanctions

31. Recommendations of IOM • Establish research grants • Institution develop comprehensive program to promote integrity • Institute develop educational programs • Self-evaluation • Accreditation • Public database

32. Institutional Measures to Foster Integrity • Establish organizational components to comply with regulations • Offer educational programs • Implement policies and procedures • Delineate the normative practices of responsible conduct • Establish criteria for rewards

33. Measuring Integrity • Quality Improvement Techniques • Self-Assessment • Accredited not regulated • Lack of measures

34. ORI Core Content • Data acquisition,management, sharing, and ownership • Mentor-trainees relationships • Publication practices and responsible authority • Peer review • Collaborative science • Human subjects • Research involving animals • Research misconduct • Conflicts of interests

35. Performance-based Model • Public display of institutional goals • Create a bonus plan • Mentorship opportunities • Public accountability of actions inconsistent with institutional mission

36. FAQ for ORI • Who is covered? • Any institution or individual supported with PHS funds • Confessions • Must be fully documented • Must contact ORI • No specific deals can be made • May not need full investigation • Standard of proof • “preponderance of evidence” • Panel members • No COI

37. FAQ for ORI • Good faith whistleblowers • Cannot retaliate against • Ownership of data • Generally the institution • Credentials and Publications • May not fabricate this

38. FAQ for ORI • Foreign students • US standards apply • “No one told me” not acceptable • Confidentiality • Confidential treatment to the maximum extent possible • Disbarment • 3 years generally

39. “Most people say that it is the intellect which makes a great scientist. They are wrong: it is character”Albert Einstien