Why Comply? Protection of Human Subjects in Research and the Costs of Non-Compliance NCURA Region III Spring Meeting

1. Why Comply? Protection of Human Subjects in Research and the Costs of Non-ComplianceNCURA Region III Spring Meeting Lauren Solberg, Vanderbilt University Law School Mark Davis, BearingPoint, Inc.

2. 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)

3. What is “Research”? • Systematic investigation designed to develop or contribute to generalizable knowledge • General rule: Final analysis intended for publication, presentation, or public discussion = research • If project is research, it must have IRB review 45 CFR 46.102(d)

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

5. 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

6. 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)

7. 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

8. 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

9. 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

10. Beneficence • Maximize benefit • Minimize harm

11. 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

12. What Does This Mean For Us? • Research with humans and animals based in ethical principles, governed by law • Law = federal statutes and regulations

13. 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 in research

14. 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.

15. 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.

16. 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

17. 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

18. OHRP • Office for Human Research Protections • Part of the DHHS • Enforces the regulations guiding research with human subjects – 45 CFR 46 • OHRP does not MAKE regulations • Regulations have force of law • Regulations created with basic ethical principles in mind

19. Federalwide Assurance (FWA) • University’s contract with government to comply with applicable regulations • 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

20. Evaluation or Research? • Evaluation • For internal purposes • Not intended for contribution to a particular field • Not intended for publication • Research • Intended for publication, presentation, public discussion

21. Full Review • Research poses greater than minimal risk to subjects • Minimal Risk = Probability and magnitude of harm or discomfort anticipated are no greater than those encountered in daily life or during performance of routine physical or psychological tasks (45 CFR 46.102(i)) • Research involves use of experimental drugs or medical devices • Research with incarcerated persons

22. Expedited Review • Study must involve no greater than minimal risk • Not necessarily a “faster” review • Performed by just one committee member • 45 CFR 46.110(a) - 9 categories of expedited review • Generally includes low risk surveys and interviews, collection of hair samples, nail clippings, small amounts of blood taken by finger stick

23. Exempt Research • Involves human subjects • Does not mean project does not need IRB review – IRB or other qualified individual makes determination – NOT THE PI • Categories listed in 45 CFR 46.101(b) • Generally includes some surveys and interviews, chart reviews, study of normal educational practices

24. Criteria for Approval of Research • Risks are minimized • Risks are reasonable in relation to potential benefit • Equitable selection of subjects • Appropriate informed consent obtained and documented • Provision for monitoring data when appropriate • Protection of privacy and confidentiality of data 45 CFR 46.111

25. The IRB, In Practical Terms… • Ensure sufficient rationale for the study • Evaluate how subjects are recruited • Participation without coercion is key • Does methodology make sense? • Weigh the risks/benefits • Look at how privacy is protected • IS THE STUDY ETHICALLY SOUND?

26. Risk/Benefit Ratio • Research with human subjects always involves SOME 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 • Risks can be physical, psychological, social, legal

27. Vulnerable Populations:What You Should Know • 45 CFR 46 recognizes specific populations as vulnerable • Includes pregnant women, neonates, prisoners, children • Grant applications generally ask about the enrollment of vulnerable populations in research – review the regulations to understand why!

28. Some Points of Note • Pregnant women can participate in surveys • Parolees and probationers living in the community are NOT prisoners protected by Subpart C • Research involving survey or interview procedures is not exempt if children are involved

29. Consent • The process by which an individual is fully informed about a research study and decides whether to participate • Process governed by regulation • 8 required elements • 6 other elements, to be included when appropriate 45 CFR 46.116 (a)(b)

30. Cost-Related Issue - Compensation of Research Subjects • Justified based on the risk level • Justified based on the study procedures • Justified based on population • Must inform subjects up front about compensation

31. Common Acceptable Forms of Compensation • Cash • Lottery tickets • Gift cards • Small token items such as journals or books • Entry into a drawing for a larger “prize” • Reimbursement for expenses

32. 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

33. 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

34. 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 • http://www.hhs.gov/ohrp/requests/

35. The Costs of Non-Compliance

36. Research Involving Human Subjects • The risk environment • Understanding the regulatory scheme • Becoming aware of a problem • Common triggers • Investigations and settlements • Self-disclosure • Reporting and timing issues • Corrective action plans

37. The Risk Environment • Whistleblowers • Office of the Inspector General • Fraud and Abuse • Compliance Officers • Technology and Reporting

38. The Risk Environment • The landscape is getting more complex: • Research and Training projects • Clinical Trials • Subcontracts • Human Subjects • Payment Process • Effort Reporting • IP / Technology Transfer • Cost Accounting Standards

39. The Risk Environment • The Constituency: • Faculty, Scientists, Staff, Students • Administration • Boards • Federal Government • Other Sponsors • Human Subjects • Advocacy groups

40. The Risk Environment • Direct Charging Practices • 4 Principles • Allowable • Allocable • Reasonable • Consistent • A-21 Section F.6.b.(2) • Administrative and clerical salaries should normally be treated as F&A costs. • Unallowable costs

41. Regulatory Environment • Office of Mgmt. Assessment (OMA) • Reviews actions involving: • Misuse of NIH grant and contract funds • NIH grantee and contractor conflict of interest • Issues referred by the OIG when prosecutive or civil action has been declined and/or OIG plans no further investigation • Unrestricted access to books and records • OMA has “the right of timely and unrestricted access to any books, documents, papers, or other records or recipients that are pertinent to the awards, in order to make audits, examinations excerpts, transcripts and copies of such documents.” • Timely and reasonable access to personnel • This right includes “timely and reasonable access to a recipient’s personnel for the purposes of interview and discussion related to such documents.”

42. Regulatory Environment • The OIG • Investigates criminal, civil & admin. matters • Can refer criminal matters to: • United States Attorney for the district in which the alleged violation occurred • U.S. Department of Justice • Federal Bureau of Investigation • Maintains confidential, toll-free reporting hotline • For reporting matters involving fraud, waste and mismanagement

43. Regulatory Environment • The NIH • May initiate administrative action during an OIG investigation Program decisions to suspend, limit, or terminate funds must be made in accordance with Federal regulations and HHS policy based upon the best judgment as to what the facts show regarding impact on the program, potential loss to the Government, and credibility of the allegation.”

44. Regulatory Environment • Office of Research Integrity • Addresses research integrity and misconduct issues related to PHS supported activities • PHS/HHS may take administrative actions against respondents who have a finding of research misconduct made against them • ORI is prepared to provide technical assistance to any institution that is responding to an allegation of research misconduct through its Rapid Response Technical Assistance Program

45. Regulatory Environment • Enforcement Tools • Recovery of funds • Administrative offset; withholding advance payments • “Debts” are considered delinquent after 30 days • Interest, penalties and administrative collection costs • Modification of the terms of award • Suspension, termination, withholding of support

46. Regulatory Environment • Conversion from advance payment method to a reimbursement method • Suspension or debarment • Civil and/or criminal action

47. Awareness • Internal Controls: • Poor accounting / internal controls • Red flag indicators • Failure to discover errors within a reasonable timeframe • The grantee should have systems in place to detect mistakes within a reasonable time frame • Frequent errors in recording costs • “If such errors occur, grantees are encouraged to evaluate the need for improvements and to make whatever improvements are deemed necessary to prevent reoccurrence.” • NIH also may call for a grantee to take corrective action by imposing additional terms and conditions on an award(s)

48. Awareness • Common Triggers: • Routine compliance reviews • Department referrals • Noted errors • Non-compliant activity • Reports / allegations by employees • Anonymous tips, Internal hotline calls • False claims (whistleblower) actions • Self-audits; internal investigations • Government audits • OMA/NIH, OIG, GAO • Government investigations • OIG, DOJ, FBI

49. Investigations and Settlements • Cost Disallowances • Loss of expanded authorities • Loss of funding • Suspension of programs • Negative publicity