RESEARCH Integrity

1. RESEARCH Integrity • Patricia Kerby, MPA • Office of Research Compliance • April 8, 2010

2. What is Integrity?Webster’s definition- firm adherence to a code especially moral or artistic values; incorruptibility Tiger Woods "lived a lie“

3. Public Accountability • Bernard Madoff lost $50 billion invested with him • President of business indicted in Deutsche Bank fire linked to companies with rich N.Y. contracts • John Edwards, the disgraced former Democratic presidential candidate. • Jesse James Seems 'Very Upset‘ • Badge Stops Bullet: Former Cop Charged With Lying

4. Clinical Research • FDA Warns Against Use Of Zocor • Merck unit held liable in Australian Vioxx case • Massachusetts doctor pleads guilty to research fraud • Top Pain Scientist fabricated data in studies

5. Office of Research Integrity (ORI) The Office of Research Integrity (ORI) oversees and directs Public Health Service (PHS) research integrity activities on behalf of the Secretary of Health and Human Services with the exception of the regulatory research integrity activities of the Food and Drug Administration.

6. The PHS is composed of the following offices and agencies • National Institutes of Health. • The Centers for Disease Control and Prevention • The Food and Drug Administration • The Substance Abuse and Mental Health Services Administration • The Health Resources and Services Administration • The Agency for Healthcare Research and Quality. • The Agency for Toxic Substances and Disease Registry • The Indian Health Service • Office of Regional Health Administrators

7. FDA is responsible for protecting the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products, medical devices, our nation’s food supply, cosmetics, dietary supplements, and products that give off radiation

8. Definition of Research Misconduct Research misconduct means fabrication, falsification or plagiarism in proposing, performing or reviewing research, or in reporting research results. 42 CFR 93.103

9. Definitions _______ is making up data or results and recoding or reporting them.

10. Definitions Fabrication is making up data or results and recoding or reporting them

11. Definitions ________ 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

12. definitions 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

13. Definitions ________ is the appropriation of another person’s ideas, processes, results, or words without giving appropriate credit.

14. definitions Plagiarism is the appropriation of another person’s ideas, processes, results, or words without giving appropriate credit.

15. The Misconduct scale Innocent Ignorance- misconduct of the uninformed kind Noncompliance is based on lack of understanding the regulatory consequences of an action. The act itself is usually intentional but the noncompliance is unintentional, not usually done to deliberately deceive

16. Innocent Ignorance • Backdating the subject’s signature on a consent form • Discarding source documents after accurate transcription and reporting transcribed data as original. • Using Case Report Forms as only source document

17. The Misconduct scale Surprising Sloppiness- misconduct of the lazy kind Noncompliance is due to inaction, inattention to detail, inadequate staff, lack of supervision. The act itself may be intentional or unintentional and is usually repeated.

18. Surprising sloppiness • Consent forms inadvertently not obtained from subjects • Blood pressures rounded to the nearest 5mm • Data estimated rather than actually measured • Data inaccurately transcribed as recorded • Protocol ignored or shortcuts taken

19. Examples In FDA’s review of the source documents for the records audited during the inspection, there were numerous instances where either (a) information entered into the case report forms (CRFs) did not match the information in the source documents or (b) information in the source documents was changed after the subject had completed the study, up to two years post-completion, and it could not be determined where the information related to the change was derived.

20. Surprising Sloppiness

21. examples Four subjects signed the 2002 ICD version in 2004. The 2002 ICD version did not include updated data regarding sample purity rates, subject pregnancy rates, malformation rates and changes in success rates that would have been available to subjects had the proper version been used.

22. Innocent Ignorance

23. examples In FDA’s review of 12 of 12 subject records, there were numerous study visits where your site’s records do no indicate that your site conducted the protocol specified physical exams and at either the screening visit, during study treatment visits and/or termination visits. In addition, in review of your site’s records, documentation could not be found to verity comments made in the CRF that a physical exam was done.

24. Surprising sloppiness

25. Our investigation indicates that you permitted individuals to conduct study tasks which they had not been delegated the authority to execute, and that your supervision of personnel to whom you delegated study tasks was not adequate to ensure that the clinical trials were conducted according to the signed investigator statement, the investigational plan, and applicable regulations and in a manner that protected the rights, safety and welfare of human subjects.

26. Innocent Ignorance

27. The case history for Subject #002 had two different copies of CRF page 12 from Visit 1. One copy was a pink duplicate copy of CRF page 12, signed and dated as having been completed by Barbara Harris on May 10, 2007. The second copy was a photocopy of CRF page 12 also signed and dated as having been completed by Barbara Harris on May 10, 2007 but apparently filled out by a different person (as evidenced by different handwriting) and contains different information.

28. Surprising sloppiness

29. Research Misconduct Does not include honest error or differences of opinion

30. The misconduct scale Malicious Malfeasance- misconduct of the sleazy kind Usually noncompliance is due to deliberate action to deceive or mislead: Falsification

31. Falsification/Malicious Malfeasance • Creating data that were never obtained • Altering data that were obtained by substituting different data • Recording or obtaining data from a specimen, sample or test whose origin is not accurately described or in a way that does not accurately reflect the data • Omitting data that were obtained and ordinarily would be recorded

32. The FDA is revamping its debarment and disqualification procedures against clinical investigators by increasing staff and centralizing coordination, and will list investigators against whom it has completed proceedings on its website. “The number of clinical investigators debarred will rise in the near term as the agency reviews cases,” said Matthew Warren of the agency's Office of Research Integrity and Responsibility Ref: Washington Drug Letter 41(32), 17 Aug 2009

33. Classification of Inspection The FDA Classification of the Inspections is according to the following: • NAI – No Action Indicated • VAI – Voluntary Action Indicated • OAI – Official Action Indicated Recommend that Study Data be Disqualified Recommend Restrictions placed on the PI Recommend Disqualification of the PI Recommend that the PI be prosecuted

34. Fraud in Bioresearch Monitoring • Defined as the deliberate reporting of false or misleading data or the withholding of reportable data. • Altered data - generating biased data or changing data that is legitimately obtained. E.g. changing laboratory data, altering weights, breaking the blind and/or randomization • Omitted data - not reporting data that has an impact on study outcome. E.g. removing subjects from a study for bogus reasons, disguising AEs, and replacing subjects • Manufactured data - Fabricating information or creating results without performing the work. E.g. filling in values (BP, lab values, x-ray reports) for which no data were obtained, photocopying data from one patient for another, and creating fictitious patients

35. Actions Taken by the FDA From Restrictions to Disqualifications to Prosecution • “If an explanation is offered but not accepted by CDER or CBER, the investigator will be given an opportunity for a regulatory hearing under part 16 on the question of whether the investigator is entitled to receive investigational new drugs”. Ref: 21 CFR 312.70(a) • An investigator who has been determined to be ineligible to receive investigational drug may be reinstated as eligible when the commissioner is assured that the investigator will comply with all applicable regulations. Ref: 21 CFR 312.70(f)

36. Investigator Misconduct • Fortunately not common but one can check theFDA web sites for a listing of: • FDA Debarment www,fda.gov/ora/compliance_ref/debar/ • FDA Disqualified / Restricted www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.htm • FDA Warning letters www.fda.gov/foi/warning.htm

37. The power of Law - Form 1572 Signing a 1572 is the PI’s legally binding commitment in writing that she / he will be responsible for the study in question; totally responsible and for everything This means she / he agrees to follow: 21 CFR 50 - Protection of Human Subjects - IC process 21 CFR 56 - Institutional Review Board 21 CFR 312 - Investigational New Drug Application 21 CFR 312.64 - Investigator Reports - AE reporting 21 CFR 312.62 - Record keeping and retention 21 CFR 312.68 - Being audit ready

38. Recent Headlines Truth of the MMR vaccine scandal After an epic misconduct hearing, the doctors who caused panic over the vaccine are about to learn their fate. A report on the greatest health scare of recent times

39. Headlines Doctor pleads guilty to health care fraud A Massachusetts doctor pleaded guilty to one count of health care fraud stemming from accusations that he faked research for a dozen in published studies that suggested after surgery benefits from painkillers including Vioxx and Celebrex. He agreed to repay $361,932 of research grants and forfeit assets worth atleast $50,000. Prosecutors have recommended up to 10 years in prison.

40. Headlines Cuomo: NY Research used actors to fake testimony A former University of Buffalo addictions researcher hired professional actors to testify on his behalf in a investigation into whether he fabricated data in federally funded studies. He paid 3 actors to speak by phone during a university misconduct hearing in 2007– and then sued the state for $4 million when their false testimony helped exonerate him. The Attorney General’s Office charged him with grand larceny, perjury, identity theft, and falsifying business records.

41. Headlines Accused Scientist Dies A researcher who was suspected of fabrication data and who hired actors to lie at his misconduct trial in New York in 2004 was found dead last week.