Human Research Protections at UCI

1. Human Research Protections at UCI Beverley W. Alberola, CIP Interim Director – IRB Operations Office of Research University of California, Irvine

2. Learning Objectives • Discuss the principles, regulations, and statutes • Define human subject research • Describe the IRB submission process 4. Describe the IRB review process

3. Learning Objective 1:Principles, Regulations, & StatutesResponse to Research Abuses • Prior to 1906, when the Pure Food and Drug Act was passed, there were no regulations regarding the ethical use of human subjects in research. There were no consumer regulations, no Food and Drug Administration (FDA), no Common Rule, and no Institutional Review Board (IRB). • Nazi atrocities in World War II drew attention to the lack of international standards on research with human participants and led to the formulation of the Nuremburg Code (1947), stating that "The voluntary consent of the human subject is absolutely essential," making it clear that subjects should give consent and that the benefits of research must outweigh the risks. Although it did not carry the force of law, the Nuremberg Code was the first international document which advocated voluntary participation and informed consent.

4. Principles, Regulations, & Statutes Response to Research Abuses • The thalidomide disaster led to the adoption of the "Kefauver Amendment" (1962) to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the safety and effectiveness of their products and physicians to obtain informed consent from potential subjects before administering investigational medications. • The Declaration of Helsinki drafted by the world Medical Association in 1964 (most recently updated in 2000) builds on the Nuremberg Code and is the basis for Good Clinical Practices used today. • The National Research Act (1974) passed primarily in response to the syphilis study, codified the requirement that human participants in research must be protected. • Carrying out its charge, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research prepared the Belmont Report in 1979. The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations.

5. Belmont Principles (1979) • Respect for Persons (Be Respectful) • Individuals should be treated as autonomous agents • Individuals with limited autonomy are entitled to protection • Beneficence (Be Nice) • Do no harm • Minimize risk/maximize benefits • Justice (Be Fair) • Fair distribution of risks and benefits of research

6. Regulations & Statues Protecting Human Subjects in Research • In 1981, the Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) issued regulations based on the Belmont Report. DHHS issued Code of Federal Regulations (CFR) Title 45 (public welfare), Part 46 (protection of human subjects). The FDA issued CFR Title 21 (food and drugs), Parts 50 (protection of human subjects) and 56 (Institutional Review Boards). • In 1991, the core DHHS regulations (45 CFR Part 46, Subpart A) were formally adopted by more than a dozen other Departments and Agencies that conduct or fund research involving human subjects as the Federal Policy for the Protection of Human Subjects, or "Common Rule." In 1991, the Department of Veterans Affairs promulgated this same rule at 38 CFR Part 16. Today, the 1991 Federal Policy is shared by 17 Departments and Agencies, representing most, but not all, of the federal Departments and Agencies sponsoring human-subjects research.

7. Regulations & Statues Protecting Human Subjects in ResearchThe Common Rule – Newly revised! The main elements of the Common Rule include : • Requirements for assuring compliance by research institutions; • requirements for researchers obtaining and documenting informed consent; • requirements for Institutional Review Board (IRB) membership, function, operations, review of research, and record keeping.

8. Regulations & Statues Protecting Human Subjects in ResearchThe Common Rule – Newly revised! • Revised in 2019 (‘2018’ Common Rule) • New (expanded) definition of human subject research • New exempt categories • Removal of requirement for continuing review for some research • More Information on HRP Webpage

9. Regulations & Statues Protecting Human Subjects in Research Federal • 45 CFR Part 46 – OHRP (includes pre and post 2018 Common Rule) • 21 CFR Parts 50 (protection of human subjects) and 56 (IRBs) – FDA • Health Insurance Portability and Accountability Act – HIPAA • Family Educational Rights and Privacy Act – FERPA • Protection of Pupil Rights Amendment – PPRA • Right to Try Act - RTT State • Health and Safety Code: Protection of Human Subjects in Medical Experimentation Act • Health and Safety Code: Consent for Minors • Health and Safety Code: Use of Death Data Records • Right to Try Act (more stringent requirements like IRB review) International • The European Union General Data Protection Regulation

10. Criteria for IRB Approval BENEFICENCE JUSTICE RESPECT FOR PERSONS 45 CFR 46.111, 21 CFR 56.111 Experimental Design Risk/Benefit AnalysisData Safety Qualifications of Researchers Subject Selection Inclusion/exclusion Recruitment Fair Distribution Privacy & Confidentiality Vulnerable Populations Informed Consent Surrogate Consent Parent Permission / Assent

11. Learning Objective 2: Define Human Subject Research

12. Definition of Human Subject Research 45 CFR 46.102(l) Research: (l) Research means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. Activities that meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program that is considered research for other purposes. (See hyperlink for examples deemed by the regs to NOT be research.) 45 CFR 46.102(e) Human Subject: (e)(1) Human subject means a living individual about whom an investigator (whether professional or student) conducting research: (i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

13. What is Not Human Subjects Research? • Class projects (in general) • Simulations of human experiments or data gathering for educational purposes • Analysis of existing anonymous and/or de-identified data • Analysis of existing anonymous biological specimens • Department Quality Improvement evaluations • UROP= human subject research!

14. Human Subjects Research • Any UCI faculty, staff or student who intends to conduct human subject research must obtain IRB approval or confirmation of exemption PRIOR to initiating that research.

15. Level of Risk Generally Determines Level of Review Convened IRB Meeting-Full Committee > Minimal Risk Expedited* Subcommittee Minimal Risk Exempt* Lead Researcher Self Determination or Chair/ IRB Staff Confirmation Virtually No Risk RISK *defined by lists in regulations

16. Learning Objective 3:IRB submission Process • First, confirm: is the study human subject research? • If not sure, review the Determination of Non-Human Subject Research Form • If written confirmation is required, submit to the IRB for review at IRB@uci.edu

17. IRB submission Process • It is human subject research • Confirm: Is the research part of an undergraduate UROP project? • If yes, be sure none of the exceptions apply. • If none apply, all UCI faculty-mentored undergraduate research involving human subjects that meets the criteria for exempt review must submit for exempt confirmation through the Undergraduate Research Opportunities Program (UROP).

18. IRB submission Process • It is human subject research • Confirm: does the research activity meet one of the exemption categories? • Review the exemption categories. • Could the activity be confirmed via the Exempt Self-Determination Process? • If yes, researchers make their own confirmation. • If UCI IRB review is required: • Submit an IRB Application, Exempt Protocol Narrative and Consent or Recruitment Materials as applicable – for exemption confirmation. • Be sure all researchers have taken requisite trainings!

19. What is Exempt Research? • “Exempt” from federal regulations; Ensure research upholds Belmont Principles • Federally-defined categories • Verbal consent or no consent appropriate in most circumstances • IRB Chair or Human Research Protections (HRP) Staff reviews and confirms Exempt status; Research is registered for three years • Examples: • anonymous or identifiable surveys or interviews • passive observation of public behavior with or without the collection of identifiers • retrospective and prospective medical chart reviews (allowable under specific criteria for UCI Healthcare Workforce) • analyses of specimens that are publically available or if not publically available, where the identities of the subjects cannot be readily ascertained

20. IRB submission Process • It is human subject research – but not exempt • Confirm: is the research eligible for expedited review? • Review the definition of minimal risk. • Review the expedited categories. • If yes, UCI IRB review is required: • Submit an IRB Application, Biomedical or Social/ Behavioral / Educational Expedited & Full Committee Protocol Narrative and Consent or Recruitment Materials as applicable. • Review the HRP index page for specific information on how to submit, required language and FAQs. • Be sure all researchers have taken requisite trainings!

21. What is Expedited Research? • No more than minimal risk to subjects • Nine federally-defined categories • Documentation of informed consent (signed consent) can be waived with appropriate justification • Continuing review must occur annually for (generally) non-federally supported research • “Expedited” protocols are reviewed by a subcommittee of IRB members or HRP staff • IRB review occurs weekly- submissions are reviewed on a rolling basis • Examples • studies of existing pathological specimens with patient identifiers • noninvasive medical procedures (MRI, EEG, ECG) • collection of blood, saliva, hair • focus groups with videotaping

22. IRB submission Process • It is human subject research – but not expedited (likely full committee) • Re-review the definition of minimal risk. • UCI IRB review is required: • Submit an IRB Application, Biomedical or Social/ Behavioral / Educational Expedited & Full Committee Protocol Narrative and Consent or Recruitment Materials as applicable. • Be sure all researchers have taken requisite trainings!

23. What is Full-Committee? • More than minimal risk to subjects • Any human subjects research study that does not qualify for Exempt or Expedited review • Written (signed) consent required in almost all circumstances • Continuing review must occur annually if federally supported (including FDA regulated) • IRB meetings held monthly • Examples • Interviews about illegal behavior or sensitive information (SBE) • Research involving interaction/intervention with prisoners (SBE) • Clinical investigation involving an experimental drug or device

24. IRB submission Process • Anticipate 8 weeks for subcommittee and at least 4 weeks for full committee. • Full Committee Calendar • Other UCI Committees • IRB Fees • Single IRB Review • Required in 2019 for NIH multisite studies • Allowed for Phase 2b and above multisite – see web page for more information and exceptions.

25. IRB Approval • Read the UCI IRB Approval Letter • (yes please! all pages!). • Only use the IRB approved documents posted to the Document Depot. • Visit the EQUIP pages for guidance on best research practices. • Subscribe to the UCI IRB Listservto stay in the know.

26. Learning Objective 4:IRB Process

27. Composition of the IRB Per federal regulations each IRB is required to have: • Five members, with varying backgrounds to promote complete and adequate review of research activities. • One member whose primary concerns are in nonscientific areas. • Take a look at this OHRP video for membership requirements! • One member not otherwise affiliated with the institution and not part of the immediate family of a person who is affiliated with the institution. • No IRB member may participate in initial or continuing review of any research if the member has a conflicting interest.

28. UCI’s IRBs • UCI has four IRB Committees: • IRBs “A” and “B” review biomedical research • IRB “C” reviews social/behavioral research • IRB “E” reviews matters of non-compliance • UCI allows for the ability to rely on another IRB, including a commercial IRB

29. IRB “C” – Social, behavioral, Educational research • In general, the lead researcher’s primary school, department or program will determine if the research should be reviewed by the social/ behavioral/ educational IRB.

30. IRB “A” & IRB “B” – Biomedical Research that does not qualify for review by the social/behavioral IRB requires review by one of the biomedical IRB committees. Research that involves testing the safety and effectiveness of an investigational drug, biologic or medical device always requires review by a biomedical IRB.

31. IRB Authority • Protocol Review of all human subjects research covered by the regulations. • IRB must notify the institution and the investigator in writing of its decision • Approved as is (A). • Require minor changes to secure approval (M). Revisions can be reviewed and approved by the Chair outside of the Full Committee. • Require substantial revisions and tabled for re-review by Committee (T). Resubmit revised documents to Full Committee/Subcommittee. • Disapproved (D). Rarely occurs only after multiple attempts by IRB to resolve issues.

32. IRB Authority • Conduct Continuing Review Research (annually for federally supported, including FDA regulated) • Review progress report of study and subject accruals to reassess actual risks/discomforts to subjects • Research Oversight • May observe or have a third party observe the consent process and/or the research • May embargo of publications/presentations or disqualification of thesis/dissertation • May suspend or terminate approval of research • not conducted in accordance with the regulations • associated with unexpected serious harm to subjects

33. Questions? • Refer to the HRP webpage • Review HRPP policies • Contact HRP Staff!