Required Findings & Determinations

1. Required Findings & Determinations Jeffrey M. Cohen, Ph.D. CIP President HRP Associates, Inc. © HRP Associates, Inc.

2. Overview Three types of required findings and determinations • Required findings for all protocols • Required findings where appropriate to the protocol • Other determinations © HRP Associates, Inc.

3. Required Findings: All Protocols For each protocol, the IRB must determine and document: • The research meets all of the criteria for approval in 45 CFR 46.111 • Additional safeguards to protect vulnerable populations • The level of risk (minimal or more than minimal) • Approval period © HRP Associates, Inc.

4. Required Findings: Where Appropriate • When approving research that involves populations covered by Subparts B, C, or D of 45 CFR 46, the IRB must find and document that the research meets the criteria in the Subparts • When waiving consent, the IRB must find and document that the research meets the criteria in 45 CFR 46.116(d) • When waiving documentation of consent, the IRB must find and document that the research meets the criteria in 45 CFR 46.117(c) © HRP Associates, Inc.

5. Other Determinations • Investigator Conflict of Interest • Serious or Continuing Noncompliance • Unanticipated Problems • Multi-site/Collaborative Research © HRP Associates, Inc.

6. Criteria for Approval

7. Criteria for IRB Approval of Research 45 CFR 46/21 CFR 56 §111(a) “In order to approve research covered by these regulations the IRB shall determine that all of the following requirements are satisfied” © HRP Associates, Inc.

8. Criteria for IRB Approval 46.111 When appropriate: • data collection is monitored to ensure subject safety • privacy and confidentiality of subjects is protected • additional safeguards are included for vulnerable populations • Risks to subjects are minimized • Risks are reasonable in relation to anticipated benefits • Selection of subjects is equitable • Informed consent is sought from each subject • Informed consent is appropriately documented © HRP Associates, Inc.

9. BENEFICENCE JUSTICE RESPECT FOR PERSONS Privacy & ConfidentialityVulnerable Populations Informed consent Surrogate consent Assent Criteria for IRB Approval 46.111 Subject selection Inclusion/exclusion Recruitment Risk/Benefit AnalysisData Safety Experimental Design Qualifications of PI © HRP Associates, Inc.

10. Risk/Benefit © HRP Associates, Inc.

11. Identifying Risks • The term “risk” involves two dimensions • Magnitude of harm • Probability of harm • Assessing the level of risk involves taking both into account © HRP Associates, Inc.

12. Identifying Risks • Identifying risk requires scientific expertise on the part of the IRB • When the IRB does not have the necessary expertise it must use outside consultants • An IRB that reviews research without the necessary expertise is not in compliance with the regulations © HRP Associates, Inc.

13. Minimizing Risk Three ways to minimize risk • Alternatives • other procedures that are less risky • Precautions • procedures to decrease the likelihood that harms will occur • Contingencies • procedures to deal with harms if they occur © HRP Associates, Inc.

14. Subject Selection & Recruitment © HRP Associates, Inc.

15. Subject Selection • Justice requires equitable distribution of both the burdens and benefits of research • Individuals and groups that bear the burden should share in the benefits • Individuals and groups that benefit from research should share in the burden • Selection of subjects should be justified by the science • IRBs should not overprotect vulnerable populations so that they are excluded from participating in beneficial research • If the study is funded by NIH, exclusions of women, minorities or children MUST be justified. © HRP Associates, Inc.

16. Subject Recruitment • Subject recruitment is part of the consent process • Information in recruitment should be consistent with protocol • Recruitment should not be coercive or unduly enticing • Recruitment should clearly indicate that it is for research and not make unfounded claims (e.g., “cure” or “free treatment”) • IRBs must review recruitment procedures, including any advertising • Difference between FDA and OHRP guidance © HRP Associates, Inc.

17. Informed Consent Beyond the Consent Form © HRP Associates, Inc.

18. The Consent Process Informed consent is not a single event or just a form to be signed -- rather, it is an educational process that takes place between the investigator and the prospective subject. The basic elements of the consent process include: • full disclosure of the nature of the research and the subject's participation, • adequate comprehension on the part of the potential subjects, and • the subject's voluntary choice to participate. © HRP Associates, Inc.

19. Procedures for Obtaining Consent • Subject has the legal and mental capacity to give consent • legally authorized representative; • Sufficient opportunity is provided to consider • The possibility of coercion or undue influence is minimized • Language understandableto the subject • No “exculpatory” language 46.116 © HRP Associates, Inc.

20. Documentation of Consent Documentation of "legally effective informed consent" usually involves the use of a written consent form signed by the subjector the subject's legal representative. • The consent form is merely the documentation of informed consentand does not, in and of itself, constitute informed consent. • The fact that a subject signed a consent form does not mean that he/she understood what was being agreed toor truly gave their voluntary consent. 46.117 © HRP Associates, Inc.

21. Data Safety Monitoring © HRP Associates, Inc.

22. Safety Monitoring • Oversight and monitoring to ensure the safety of participants • Investigators need Data Safety Monitoring Plan • How subject reactions and data being monitored • Unanticipated Problems detected and reported • What to do in case of problems

23. Privacy and Confidentiality © HRP Associates, Inc.

24. Definitions • Privacy - having control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) with others. • Confidentiality - methods used to ensure that information obtained by researchers about their subjects is not improperly divulged. © HRP Associates, Inc.

25. Regulations 46.102(f) Human subject means a living individual about whom an investigator… conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. © HRP Associates, Inc.

26. Regulations • Private information - 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). • Identifiable information – information where the identity of the subject is or may readily be ascertained by the investigator or associated with the information. © HRP Associates, Inc.

27. Confidentiality • Confidentiality and anonymity are not the same • Anonymous means no one, anywhere, ever can identify individual subjects • Names are not the only identifiers • Subjects’ participation in the research may need to be kept confidential as well as their data © HRP Associates, Inc.

28. Confidentiality • More elaborate procedures may be necessary for studies in which data are collected on sensitive matters such as sexual behavior or criminal activities. • Any written record linking subjects to the study can create a threat to confidentiality, including consent forms © HRP Associates, Inc.

29. Vulnerable Populations © HRP Associates, Inc.

30. Vulnerable Populations • Federal regulations involving human subjects in research include specific protections for children, pregnant women and fetuses (Subpart B), prisoners (Subpart C), and children (Subpart D). • In addition, the IRB expects the investigator to provide additional information regarding cognitively impaired individuals in research or others who are likely to be vulnerable to coercion or undue influence. © HRP Associates, Inc.

31. Conclusion • The IRB must be satisfied that all of the review criteria have been met before it approves a protocol • The IRB must have sufficient information upon which to base its decision • OHRP frequently cites IRBs for not having enough information to make a decision © HRP Associates, Inc.

32. Risk Level © HRP Associates, Inc.

33. Risk Level • For each protocol the IRB must determine and document the level of risk • Minimal risk • More than minimal risk © HRP Associates, Inc.

34. Minimal Risk “…the probability and magnitude of harmor discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily lifeor during the performance of routine physical or psychological examinations or tests.” 45 CFR 46.102(i) © HRP Associates, Inc.

35. Approval Period © HRP Associates, Inc.

36. Continuing Review “An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year” 45 CFR 46.109(e) © HRP Associates, Inc.

37. Approval Period • Appropriate to the degree of risk and not less than once per year • Should be set for each protocol, not a routine annual review © HRP Associates, Inc.

38. Continuing Review • Must be substantive and meaningful • Criteria for approval still being met • Whether any new information has emerged, either from the research itself or from other sources, that could alter the IRB’s previous determinations, particularly with respect to risk to subjects • At least one member should review entire protocol • Full IRB reviews summary and progress report © HRP Associates, Inc.

39. 45 CFR 46 Subparts © HRP Associates, Inc.

40. Subpart B -Pregnant Women, Human Fetuses and Neonates • Applies to all research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates • For research where the risk to the fetus is no more than minimal and is not funded by DHHS, no additional safeguards are required and there are no restrictions on the involvement of pregnant women. • For research involving more than minimal risk to fetuses not funded by DHHS or research funded by DHHS, pregnant women or fetuses may be involved if the IRB must find and document that the following criteria are met. © HRP Associates, Inc.

41. Subpart B -Pregnant Women, Human Fetuses and Neonates • Where appropriate, preclinical studies have been done • Direct benefit to woman or fetus • If no direct benefit, no more than minimal risk to fetus and knowledge can’t be obtained by other means (For DHHS-funded research: biomedical knowledge) • Any risk is the least possible for achieving the objectives of the research • If benefit is solely to fetus, then consent from father, if available, is required. Otherwise only mother’s consent required © HRP Associates, Inc.

42. Subpart B -Pregnant Women, Human Fetuses and Neonates • Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate; • For children who are pregnant, assent and permission are obtained in accord with the provisions of subpart D of this part; • No inducements, monetary or otherwise, will be offered to terminate a pregnancy; • Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and • Individuals engaged in the research will have no part in determining the viability of a neonate. © HRP Associates, Inc.

43. Subpart B -Pregnant Women, Human Fetuses and Neonates Research involving neonates • Neonates of uncertain viability • Either research holds out prospect for enhancing viability or no added risk • Consent from either parent allowed • Nonviable neonates • Vital functions not artificially maintained • Research will not terminate heartbeat or respiration • No added risk • Consent from both parents required • Viable neonates are children and come under Subpart D © HRP Associates, Inc.

44. Subpart C - Prisoners • Definition of Prisoner • Involuntarily confined or detained in a penal institution as a result of sentencing • Detained in alternative institutions as a result of sentencing • Detained pending arraignment, trial, or sentencing • Includes individuals who are prisoners at the time of enrollment in the research or who become prisoners after they become enrolled in the research © HRP Associates, Inc.

45. Subpart C - Prisoners IRB Findings: • Research is in one of the permissible categories • Advantages from research can’t be coercive • Risks commensurate with risks acceptable to non-prisoners • Selection fair to all prisoners • Information understandable to population • Can’t have an effect on parole • If applicable, provisions made for follow-up after release © HRP Associates, Inc.

46. Subpart C - Prisoners Permissible Categories: • Study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects; • Study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects; © HRP Associates, Inc.

47. Subpart C - Prisoners • Research on conditions particularly affecting prisoners as a class (only after special panel) • Research which has the intent and reasonable probability of improving the health or well-being of the subject (control groups require special panel) © HRP Associates, Inc.

48. Subpart C - Prisoners Waiver for Epidemiology Research: The categories of permissible research do not apply for epidemiology research where the IRB has approved the research and determined and documented that • The research presents no more than minimal risk and no more than inconvenience to the prisoner-subjects, and • Prisoners are not a particular focus of the research. © HRP Associates, Inc.

49. Subpart D - Children Definition: • "Children" are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. [46.402(a)] © HRP Associates, Inc.

50. Subpart D - Children Parental Permission: • Adequate provisions are to be made to secure permission from the parents or guardians of each child. • For minimal risk research or risk research with direct benefit, the IRB may allow permission from one parent. • For risk research without direct benefit, permission from both parents is required.[46.408(b)] © HRP Associates, Inc.