1. How to Maintain Responsible Conduct in Research - Part 2 Human Subjects and Animal Welfare Lauren Solberg Clinical Research Center Research Skills Workshop January 25, 2008

2. Office of Research Integrity (ORI) http://ori.dhhs.gov Oversees PHS research integrity activities on behalf of Secretary for HHS 1 exception – FDA oversees their own regulatory research activities 2000 – PHS initiated requirement that all PHS-funded research staff undergo RCR education

3. ORI Emphasis on RCR Data Acquisition, Management, Sharing and Ownership Conflict of Interest and Commitment Human Subjects Animal Welfare Research Misconduct Publication Practices and Responsible Authorship Mentor / Trainee Responsibilities Peer Review Collaborative Science

4. Why Do We Care? Research with humans and animals is governed by law Law = federal statutes and regulations Vanderbilt and its researchers must comply with these laws – our policies were not written just for the fun of it!

5. Who Makes Laws? Congress – subject to approval of Senate and House of Representatives AND President Congress delegates authority to agencies to carry out their legislative mandate Congress delegated authority to Secretary of HHS to make regulations to guide protection of human subjects and animals in research

6. 5 U.S.C. 301 The head of an Executive department or military department may prescribe regulations for the government of his department, the conduct of its employees, the distribution and performance of its business, and the custody, use, and preservation of its records, papers, and property. This section does not authorize withholding information from the public or limiting the availability of records to the public.

7. 42 U.S.C. 289(a) The Secretary shall by regulation require that each entity which applies for a grant, contract, or cooperative agreement under this chapter for any project or program which involves the conduct of biomedical or behavioral research involving human subjects submit in or with its application for such grant, contract, or cooperative agreement assurances satisfactory to the Secretary that it has established (in accordance with regulations which the Secretary shall prescribe) a board (to be known as an “Institutional Review Board”) to review biomedical and behavioral research involving human subjects conducted at or supported by such entity in order to protect the rights of the human subjects of such research.

8. OHRP Office for Human Research Protections Part of the DHHS Enforces regulations for research with human subjects – 45 CFR 46 OHRP does not MAKE regulations - regulations have force of law

9. Federalwide Assurance (FWA) University’s contract with government Allows researchers to conduct federally funded research with human subjects Specifies University’s responsibilities Must be approved by OHRP – assures OHRP that University will comply with federal regulations

10. Food, Drug, and Cosmetic Act Passed by Congress in 1938 to oversee safety of food, drugs, and cosmetics Replaced Food and Drugs Act of 1906 Influenced by Elixir Sulfanilamide tragedy Chapter VII, Subpart A, Section 701 – vests authority in the Secretary of HHS to make regulations for efficient enforcement of Act

11. Food and Drug Administration Agency of DHHS Enforces regulations pertaining to research with human subjects involving investigational drugs and medical devices, foods - including dietary supplements - that bear a nutrient content claim or a health claim, infant formulas, food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products 21 CFR 50, 21 CFR 56

12. Animal Welfare Act Regulation of animals and activities involving animals necessary to ensure that animals intended for use in research facilities or for exhibition purposes or for use as pets are provided humane care and treatment Assigns authority to Department of Agriculture to oversee research with animals Authorizes Secretary of Agriculture to make regulations as needed to promote this goal

13. Health Research Extension Act of 1985, Section 495 Delegated authority to Secretary of HHS to establish guidelines for protection of animals in research –Secretary acts through OLAW Provided specific statutory requirements with respect to the proper care and treatment of animals used in research which must be met by institutions that conduct research supported by NIH

14. OLAW Office of Laboratory Animal Welfare Office of DHHS (similar to OHRP) Enforces PHS Policy on Humane Care and Use of Laboratory Animals Issues assurances (much like OHRP)

15. USDA Regulations 9 CFR Parts 1, 2, 3 –Federal regulations for research with animals Created by Department of Agriculture Similar to human subjects regulations

16. What Can You Do To Influence the Regulatory Process? Make your voice heard!!! Notice and Comment Rulemaking required for major regulatory actions Anyone can submit comments Requests for comments published in Federal Register

17. Recent Requests for Public Comment Request for comments on research that involves adult individuals with impaired decision-making capacity Request for comments on categories of research that may be reviewed by the IRB through expedited review procedure

18. What is a Human Subject? Living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information –Intervention – physical procedure, manipulation of subject or subject’s environment –Interaction – communication between PI and subject 45 CFR 46.102(f)

19. Why is it important to protect human subjects in research? A brief history: The Nuremberg Code The Declaration of Helsinki Tuskegee Syphilis Study

20. Nuremberg Code 10 basic principles for conducting experiments with humans Developed following Doctors’ Trials at Nuremberg Key concepts – informed consent, animal experimentation first, scientifically qualified persons only, no unnecessary risk, ability to terminate experiment

21. Declaration of Helsinki Adopted by World Medical Association in 1964 32 points – specific guidance for physicians conducting medical experiments Specific to biomedical research (Nuremberg more general)

22. Tuskegee 1932 – 1972 – PHS-conducted experiment on 400 African-American men with syphilis Data collected from their autopsies – so they were deprived of any treatment 1972 – story published in Washington Star

23. National Research Act Created National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1974 Commission identified the basic ethical principles that govern research involving human subjects –Respect for Persons, Beneficence, and Justice

24. Respect for Persons Subjects must be treated as autonomous individuals Subjects must be given enough information about the study to make an informed decision about participating – and their decision must be voluntary

25. Beneficence Maximize benefit Minimize harm

26. Justice All genders, classes, races, ethnicities should be selected as equitably as possible within the confines of the research question Populations should equally receive benefits of research and bear burdens

27. Protection of human subjects in research today 5 Important Issues to Consider: Consent Understanding the subject population Understanding the risk/benefit ratio Compensation of research subjects Understanding regulations versus institutional policy

28. What is consent? The process by which an individual is fully informed about a research study and decides whether to participate A subject’s right to withdraw is part of the consent process

29. Understanding the subject population Is the population “vulnerable”? –Children, prisoners, mentally disabled persons, non-native English speakers, homeless, students and employees Avoid perception of coercion (even if no intention of coercion) Is it possible to use another population? If not – how to ensure that position of authority does not influence participation?

30. Students Particularly vulnerable to coercion because they are a convenient sample for faculty Use broad recruitment methods (recruiting via flyers on campus, not through class) Students should not feel as though grades may be impacted by participation College students under 18 must obtain parental consent to participate in research

31. Risk/Benefit Ratio Research with human subjects can involve risk Risk must be outweighed by, or in proportion to, the benefits Benefits can be to subjects themselves or future populations If risk is significant, protocol must contain adequate justification

32. What are the risks? Physical Psychological Social Legal *Most common risk in SBS research – loss of confidentiality

33. Compensation of Research Subjects Must be justified based on the risk level Must be justified based on the study procedures Must be justified based on population Must inform subjects up front about compensation Must include this information in IRB application *Compensation is NOT a benefit!

34. Regulations & Institutional Policy Many regulations are open to interpretation and leave the institution to make decisions about how research should be conducted Cannot always compare the way various IRBs conduct reviews

35. Human Subjects Research at Vanderbilt IRB: http://www.mc.vanderbilt.edu/irb/http://www.mc.vanderbilt.edu/irb/ Research Misconduct Policy: http://www.vanderbilt.edu/oor/gcm/policies /research-misconduct-policy.pdf http://www.vanderbilt.edu/oor/gcm/policies /research-misconduct-policy.pdf Vanderbilt General Counsel: http://www.vanderbilt.edu/generalcounsel/r esearch.html Take advantage of education and training opportunities

36. What is an Animal? According to PHS - any live, vertebrate animals used or intended for use in research, research training, experimentation, or biological testing or for related purposes According to AWA - dog, cat, monkey (nonhuman primate mammal), guinea pig, hamster, rabbit, or such other warm-blooded animal BUT EXCLUDES birds, rats of the genus Rattus, mice of the genus Mus, bred for use in research

37. Differences Between Research with Humans and Animals Besides the obvious… Research with animals primarily for the benefit of humans, not for the animals Animals have no ability to consent to research

38. The Three R’s Replacement alternative –Use non-animal models where possible Reduction alternative –Use the minimum number of animals possible Refinement alternative –Alleviate or reduce potential pain and distress

39. Contemporary Issues Limiting pain and suffering Extra protection for some species Eliminate unnecessary experimentation

40. Limiting Pain and Suffering Some pain and suffering is inevitable in animal research But how much is too much?

41. Extra Protection for Some Species General agreement that primates need greater protection than worms But what about other species?

42. Eliminate Unnecessary Experimentation Are animals essential to the research? Can valid scientific data be produced without animal research?

43. Animal Research at Vanderbilt IACUC: http://www.vanderbilt.edu/oor/animalcu/http://www.vanderbilt.edu/oor/animalcu/ Research Misconduct Policy: http://www.vanderbilt.edu/oor/gcm/policies/resea rch-misconduct-policy.pdf http://www.vanderbilt.edu/oor/gcm/policies/resea rch-misconduct-policy.pdf Vanderbilt General Counsel: http://www.vanderbilt.edu/generalcounsel/resear ch.html Take advantage of education and training opportunities

44. Responsible Conduct in Research With Human Subjects and Animals Involves: Knowing what research is subject to regulation Understanding and following the rules for project approval Training appropriately Accepting responsibility for compliance through all stages of a project

45. Summary Understand the regulations for research with humans and animals Get involved in the regulatory process Respect your human subjects Minimize harm to animals

46. Contact Information Email: lauren.b.solberg@vanderbilt.edulauren.b.solberg@vanderbilt.edu Campus Phone: 6-0399