Use of Human Subjects in Research

1. Use of Human Subjects in Research Ruth A. Mulnard, RN, DNSc, FAAN Associate Professor, Nursing Science Vice Chair, Institutional Review Boards

2. Definition of Research • Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge (45CFR 46.102).

3. Definition of Human Subject • Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains: • (1) Data through intervention or interaction with the individual, or(2) Identifiable private information.

4. Definition of INTERVENTION / INTERACTION • Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes. • Interaction includes communication or interpersonal contact between investigator and subject. • What about web-based research?

5. Definition of PRIVATE INFORMATION • Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.

6. How Are We Regulated? • International • ICH Guidelines • Federal • OHRP (Office for Human Research Protections) has jurisdiction over Department of Health and Human Services (DHHS) via 45CFR46 • FDA (Food and Drug Administration) has jurisdiction over all research involving food, biologics, drugs and devices via 21 CFR • State of California • Department of Health Services (DHS) • Local guidance and policy • UC Office of the President (UCOP) • Institutional Review Board (IRB)

7. Department of Health and Human Services (DHHS) • 45CFR Part 46 “Common Rule” (enforced by OHRP): “The Common Rule”: Federal Policy for the Protection of Human Subjects • Subpart A: Basic HHS Policy (basic human subjects, IRB regulations) • Subpart B: Pregnant women, Fetuses and Neonates • Subpart C: Prisoners • Subpart D: Minors

8. Food and Drug Administration (FDA) • 21CFR Parts 50 and 56 (enforced by FDA) • IDE (Part 312) - Investigational New Device Exemption • IND (Part 812) - Investigational New Drugs/ Biologics

9. State of California - CA Health and Safety Code: Section 24170-24179.5 • Protection of Human Subjects in Medical Experimentation Act • Requires "experimental subject's bill of rights" • Last page of the ICF • Defines Legally Authorized Representative (use of surrogate) • Specifies that children 7 years of age or older must also consent to research, not just their parent (LAR)

10. Key Events that Influenced Policy Development • Nazi doctors trial 1946 • The Tuskegee syphilis study 1932-1972 • Radiation exposure studies 1944-1974 • Thalidomide tragedy (Kefauver Amendment 1962) • The Milgram obedience experiments 1972 • U. Pennsylvania gene therapy 1999

11. The Tuskegee Study • U.S. Public Health Service project • 600 low-income African-American males, 400 of whom had syphilis infections, monitored for 40 years. • Free medical examinations were given but participants were not told about their disease. • When penicillin became available in the 1950s, the study continued and participants were denied treatment. In some cases, researchers intervened to prevent treatment by other physicians. • Many participants died of syphilis. The study was stopped in 1973 by the U.S. DHEW only after its existence was publicized.

12. The Development of Human Subjects Protection Policy • The Hippocratic Oath • The Nuremburg Code of 1947 • Declaration of Helsinki 1964 • National Research Act of 1974 • The Belmont Report of 1979

13. The Nuremburg Code • Informed consent without coercion • Human experiments should be based on animal experimentation • Anticipated results should justify the experiment • Only qualified scientists should conduct medical research • Physical and mental suffering should be avoided • No expectation of death or disabling injury

14. Basic Ethical Principles • Respect for Persons • Individuals should be treated as autonomous agents • Individuals with diminished autonomy are entitled to protections • Beneficence • Do not harm • Maximum possible benefits, and minimize potential harms • Justice • Fair distribution of burdens and benefits of research

15. Respect for Persons • Treat individuals as autonomous persons; allow individuals to choose for themselves • Persons with limited autonomy need additional protection, even to the point of excluding them from activities that may harm them. The extent of protection should depend upon the risk of harm, and the likelihood of benefit. • The judgment that any individual lacks autonomy should be periodically re-evaluated, and will vary across situations.

16. Respect for Persons: Autonomy • Subject must be capable of acting on personal goals • Investigator must respect the considered opinions of the subjects • Participation MUST be freely given. Cannot deny medical care for decision not to participate in research.

17. Respect for Persons: Protections • Those not fully capable of self determination must be protected, including: • The very young, the cognitively impaired, some physically incapacitated • Those who are subject to coercion • staff and students of investigator • prisoners

18. Respect for Persons: Available Protections • Exclusion from study • Surrogate consent • Assent of minors age 7 or older • Prohibition on excessive inducements for participation

19. Application of Respect for Persons • Informed Consent Process • Information - Does the consent form provide all the information necessary for the individual to make a reasoned decision? • Comprehension - Is the consent form crafted in language understandable to the potential participant? • Voluntariness - Does the consent form clearly indicate that participation in the research is voluntary? • What additional protections can be in place to protect those with limited autonomy? • How to determine whether one lacks the autonomy to make a reasoned decision? (per study assessment, not a blanket decision)

20. Beneficence • “First, do no harm.” • Maximize possible benefits and minimize possible harms. Risk-benefit analysis • Unavoidable risks • Benefits may not accrue to research subject

21. Beneficence • The IRB should determine whether the risks to subjects are reasonable in relation to anticipated benefits • Obligations of beneficence affect both the researcher and society – • investigators are required to give forethought on maximization of benefits and reduction of risk that may be involved in the research • society should recognize the longer term benefits and risk that may result from the improvement of knowledge, and from the development of novel medical, psychological, and social processes and procedures

22. Applications of Beneficence • Assessment of Risks and Benefits • Risk refers to the probability of harm; when considering risk, one should consider both the probability and the severity of the envisioned harm; while the term, benefitrefers to something that promotes health, well-being, or welfare. • What are the risks of harm to the participants (consider physical, psychological, social, and economic harms)? Are the risks justified? Can they be minimized? • Can the research design be improved to minimize risk and maximize benefit? • What are the benefits (to the participant; to society)?

23. Justice • Treat people fairly • Do not exploit those who are readily available or malleable • Fair distribution of the risks and the benefits of research based upon the problem/issue under investigation

24. Applications of Justice • Selection of Subjects • Is the potential subject pool appropriate for the research? • Is it appropriate to involve vulnerable populations (e.g., economically disadvantaged; limited cognitive capacity) in the research or are they being enrolled because it is convenient or because they are easily manipulated as a result of their situation? • Are the recruitment procedures fair and impartial? • Are the inclusion and exclusion criteria fair and appropriate?

25. Implementation: Informed Consent • Informed consent is a process, not a piece of paper. • Consent for all full committee protocols must be written and for clinical studies must be witnessed. • Verbal consent (a waiver of documentation) may be possible for other kinds of research [using a study information sheet] • Consent form must be understandable to the subject and not excessively technical.

26. Informed Consent (con’t) • Consent must identify risks, benefits, and possible outcomes. • Consent must be obtained by an appropriate member of the investigative team. • The subject must have an opportunity to ask questions and raise concerns. • Financial interests must be disclosed.

27. Applications of the General Principles • Consideration of the three general principles in the conduct of research lead to the consideration of: • Informed Consent process • Risk/Benefits assessment • Selection of research participants

28. Implementation: The IRB (Institutional Review Board) • Delegated to institution • Federal-Wide Assurance (FWA) in place with OHRP • Reports to VC for Research • UCI – 2 medical, 1 social-behavioral, 1 compliance, plus a separate biomedical team for all expedited studies • Medical committee composed of physicians, scientists, other medical personnel, pharmacists, community representatives. • Community member (non-scientific) must be present for IRB to proceed.

29. IRB Responsibilities • Safeguard rights, safety and well-being of all trial subjects (with special attention to vulnerable subjects) • Obtain the following documents: • Trial protocol and all amendments • Informed consent and any updates • Subject recruitment procedures, anything written to subjects • Investigator’s Brochure and applicable safety data • Investigator’s qualifications

30. IRB Responsibilities • Review of the proposed research • Approval / favorable opinion • Minor changes required to make it approvable • Disapproval / negative opinion • Termination / suspension of prior approval • Consider the qualifications of the investigator to conduct the research

31. IRB Responsibilities • May request additional information not supplied by investigator and/or sponsor • Must conduct continuing review of protocol at least once a year (time interval should be appropriate to risk) • Review the amount and method of payment • No coercion, pro-rated for partial completion

32. IRB Responsibilities • Require that information given to subjects as part of informed consent is in accordance with the regulations; • Require documentation of informed consent or may waive documentation in accordance with the regulations; • Notify investigators and the institution in writing of its decision to approve or disapprove proposed research or of modifications required to secure IRB approval of the research activity;

33. Authority of the IRB • Approve or disapprove research • Suspend or terminate approval that is not being done in accordance with IRB requirements, or that has resulted in unexpected harm to subjects • May observe or have a third party observe the consent process and the research • May apply sanctions to investigators • No one can overturn IRB decision – not even university administration

34. Boundaries between Practice and Research • The distinction between practice and research is blurred; often because they occur together. • The IRB must ensure that the researcher (and the participant) distinguishes practice from research in both social science and biomedical research • Minimize the potential for therapeutic misconception – when one believes the purpose of clinical research is to treat rather then to gain knowledge

35. Investigator Responsibilities • Obtain all required approvals prior to commencing the research (CRFA, DSMB, IRB, CTPRMC, ICTS) • Obtain informed consent of all human subjects or their legally authorized representatives (unless waived) and use only the currently approved, stamped consent form • Make no changes without prior review and approval by the IRB • Obtain re-review at least every 365 days

36. Full Committee Review • Full Committee Research • Most common level of review • Requires full committee vote (majority decides) • 2 reviewers plus staff are assigned to review • Scientific review - IRB reviews the science as it relates to risk/benefit ratio

37. Other Levels of Review • Expedited • No greater than minimal risk (e.g. blood samples from healthy donors, hair or saliva specimens) • Reviewed by one committee member or Chair unless problems identified • No greater than minimal risk – • Means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests

38. Other Levels of Review • Exempt registration • Exempt from federal regulations • Virtually no risk (e.g. retrospective data analysis, discarded pathology materials – de-identified) • Investigator cannot decide if their research is exempt – IRB must decide • 3 year registration required at UCI • De Novo Review • Expedited and full committee research that extends beyond 7 years must be submitted as a new protocol

39. Case study #1 Investigator X wants to do a study where cadavers will be run through an x-ray machine to scan for healed fractures. No information about the cadavers or their living relatives is required. Is this research? Is this human subjects research?

40. Research or Not?? • Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge (45CFR 46.102). • Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains: • (1) Data through intervention or interaction with the individual, or(2) Identifiable private information.

41. Case study #2 An Instructor wants to have all students in a class interview each other to practice interviewing skills. The results will not be written up or distributed outside the classroom in any way. Is this research? Is this human subjects research?

42. Case study #3 A physician wants to compare Tylenol with Advil for controlling headache. He plans to prescribe Tylenol on odd days and Advil on even days. Then compare the results. Both drugs already are approved by the FDA to treat headache and are available over the counter. Is this research? Is this human subjects research? Does the physician automatically have access to his patients’ medical records for research purposes because of being the treating physician?

43. Case study #4 A Professor in a social science course includes 10% of the course grade for participation in various research projects within the school. Is this educational practice allowable? Does this violate anyone’s rights? How could this requirement be structured so it doesn’t violate any rights?

44. Advancement of IRB Processes • All IRB processes are now electronic: • Reporting of adverse events, unanticipated problems, protocol violations, protocol deviations • Modification requests (e-Mod) • Continuing protocol applications (e-CPA) • Initial IRB Application (e-APP) • Non Human Subjects Determination form

45. Case Study #5 A patient with a rare form of incurable cancer is offered a clinical trial opportunity at the Comprehensive Cancer Center by his treating physician. The clinical trial is testing whether two medications that are FDA-approved for other forms of cancer, are effective in this rare form of cancer. Is this research? What would be the level of review at the IRB? Is it coercive to offer this trial to somewhat so desperate?

46. Take Home LessonsHuman Subject Protection Rules • The rules are there to protect the subjects from excessive risk or exploitation. • The welfare and reputation of the institution and the investigators are also at stake. • The investigator is responsible for knowing the relevant regulations. • When in doubt, ask the IRB staff.

47. UCI IRB Accomplishments • UCI achieved re-accreditation from AAHRPP in Fall of 2011 - five-year accreditation • UCI is part of systemwide MOU for all UC campuses – intent to rely on one IRB • UCI has MOU with CHOC for research • UCI has MOU with Miller’s Childrens, Memorial Med Ctr, and CHOC • UCI has reliance agreements with commercial IRBs • http://www.rgs.uci.edu/ora/rp/hrpp/index.htm