1. Ethical issues in clinical research Bernard Lo, M.D. August 24, 2011 1

2. Conflicts of interest  None 2

3. Outline of session  Historical background  IRB review  Informed consent  Research misconduct 3

4. STD transmission research 1946-8  Intentionally infected subjects with syphilis, GC, chancroid  Female sex workers Males directly innoculated  Prisoners, patients in mental hospitals  In Guatemala 4

5. STD studies 1946-8  Intentionally infected subjects with syphilis, GC, chandroid  Female sex workers inoculated on cervix  Males directly inoculated into skin or urethra 5

6. STD studies 1946-8  Study carried out in Guatemala  Subjects were prisoners, residents of mental asylums 6

7. STD studies 1946-8  Most but not all treated with penicillin  One subject died of status epilepticus  US government involved: NIH, PHS, Surgeon General 7

8. Senior PHS official  “I am a bit, in fact more than a bit, leery of the experiment with the insane people. They can not give consent, do not know what is going on, and if some goody organization got wind of the work, they would raise a lot of smoke” 8

9. 9 Fundamental ethical tension in research  Primary goal is generalizable knowledge, benefit to society  Participants experience risks but benefit to others

10. 10 Ethical violations 1. Serious harm to participants  Deliberately cause harm 2. No informed consent 3. Unfair selection of participants  Take advantage of vulnerable population

11. 11 Regulations respond to scandal 1. Beneficence  Risks must be acceptable in light of benefits  Risks must be minimized  Independent IRB must approve study

12. 12 Regulations respond to scandal 2. Respect for persons  Informed and voluntary consent  Not capable of consent (children, adults who lack decision-making capacity)

13. 13 Regulations respond to Tuskegee 3. Justice  Equitable selection of subjects  Protections for vulnerable subjects

14. Federal regulations 1. Risks acceptable in light of benefits 2. Informed and voluntary consent 3. IRB review and approval 14

15. 15 Questions?

16. Do you need IRB review?  Just give out questionnaires?  Just review medical records? 16

17. Only need IRB review if  Participants identifiable OR  Interact with participants OR  Questionnaire covers sensitive topics  Ask IRB staff 17

18. Do you need IRB review?  Student project that will not be published?  “It’s not research” 18

19. Do you need IRB review?  Can’t get IRB approval before study begins 19

20. What is research misconduct? 20

21. Bone growth factors  Recombinant human bone morphogenetic protein-2  13 early trials claimed no complications compared to controls 21

22. Bone growth factors  Serious adverse events actually 10%- 50%  Male sterility, infection, bone loss and unwanted bone growth 22

23. Bone growth factors  Original studies were sponsored by manufacturer  Authors received up to $12-$16 million in payments from company 23

24. 24 Federal definition of research misconduct  Fabrication  Falsification  Plagiarism  Must be intentional

25. 25 Research misconduct excludes  Unintentional “honest” error  Sloppiness, incompetence, laziness  Differences of opinion or interpretation

26. 26 Research misconduct excludes  Lack of IRB approval  Lack of informed consent  Financial mismanagement  Discrimination  Poor mentoring

27. 27 Federal definition of misconduct  Legal requirements set a minimum standard  Ethical and professional standards may be higher

28. How do people respond to plagiarism?  Using computer programs, identify 212 pairs of similar articles  Survey to authors, journal editors of these articles Science 2009; 323; 1293. 28

29. Individual response to misconduct  “It is my understanding that copying someone else’s description virtually word-for-word is considered a compliment to the person whose words were copied.” 29

30. Individual response to misconduct  “I have no idea why the pieces are similar, except that I am sure I do not have a good enough memory to have allowed me to ‘copy’ his piece.” 30

31. 31 Consequences of research misconduct  Suspension of federal grant  Debarment from future grants  Institutional penalties  Termination of employment  Civil and criminal liability

32. Questions? 32

33. Take home points  IRB review and informed consent essential  Don’t plagiarize, fabricate, falsify data  Ask if you’re uncertain or concerned 33