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

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

3. © HRP Associates, Inc. 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

4. © HRP Associates, Inc. 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)

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 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. 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

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

10. © HRP Associates, Inc. Risk/Benefit

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

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 © HRP Associates, Inc. Beyond the Consent Form

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 understandable to the subject No “exculpatory” language © HRP Associates, Inc. 46.116

20. Documentation of Consent Documentation of "legally effective informed consent" usually involves the use of a written consent form signed by the subject or the subject's legal representative. The consent form is merely the documentation of informed consent and 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 to or truly gave their voluntary consent. © HRP Associates, Inc. 46.117

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

33. 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 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.” 45 CFR 46.102(i)

35. © HRP Associates, Inc. Approval Period

36. © HRP Associates, Inc. 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)

37. © HRP Associates, Inc. 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

38. © HRP Associates, Inc. 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

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

40. © HRP Associates, Inc. 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.

41. © HRP Associates, Inc. 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

42. © HRP Associates, Inc. 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.

43. © HRP Associates, Inc. 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

44. © HRP Associates, Inc. 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

45. © HRP Associates, Inc. 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

46. © HRP Associates, Inc. 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;

47. © HRP Associates, Inc. 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)

48. © HRP Associates, Inc. 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.

49. © HRP Associates, Inc. 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)]

50. © HRP Associates, Inc. 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)]

51. © HRP Associates, Inc. Subpart D - Children Categories of Research Minimal Risk – Assent & Parental Permission required [46.404] Risk but with direct benefit to subjects – Risk justified by benefits – Risk/Benefit at least as favorable as alternatives – Assent & Parental Permission required [46.405]

52. © HRP Associates, Inc. Subpart D - Children Categories of Research Risk but with no direct benefit – Minor increase over minimal risk – Intervention or procedure reasonably commensurate with what they already experience – Likely to yield generalizable knowledge about the subject’s disorder or condition – Assent & Parental Permission required [46.406]

53. © HRP Associates, Inc. Subpart D - Children Categories of Research Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children – can be approved if the Secretary consults with panel of experts. [46.407]

54. Other Vulnerable Populations Decisionally or cognitively impaired Non-English speaking Desperately ill Economically disadvantaged Educationally disadvantaged Students Employees © HRP Associates, Inc.

55. IRB Review How should IRBs review vulnerability? – IRBs and investigators need to be sensitive to possible vulnerabilities of subjects – IRBs need to ask detailed questions on the characteristics of the potential populations – IRBs need to evaluate potential vulnerabilities – IRBs need to ask investigators what extra protections are in place for vulnerable subjects – IRBs need to asses adequacy of extra protections © HRP Associates, Inc.

56. IRB Review IRBs need sufficient expertise on vulnerable populations – 46.107(a) If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects – Outside Consultation – Community Consultation © HRP Associates, Inc.

57. Consent Waivers

58. © HRP Associates, Inc. An IRB may approve a waiver or alteration of some or all of the consent requirements provided the IRB finds and documents that: – The research involves no more than minimal risk to subjects; – The waiver will not adversely affect the rights and welfare of subjects; – The research could not practicably be carried out without the waiver; and – Whenever, appropriate, the subjects will be provided with additional pertinent information after they have participated in the study. Waiver of Consent 46.116(d)

59. © HRP Associates, Inc. An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds and documents that: – the research presents no more than minimal risk; and – the research involves procedures that do not require written consent when performed outside of a research setting. Waiver of Documentation 46.117(c)(2)

60. © HRP Associates, Inc. An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds and documents that: – the principle risks are those associated with a breach of confidentiality concerning the subject’s participation in the research; and – the consent document is the only record linking the subject with the research Waiver of Documentation 46.117(c)(1)

61. © HRP Associates, Inc. Other Determinations

62. Conflict of Interest Initial review made by Chair or designee Chair makes recommendation that the disclosed financial interest is: – not acceptable (in which case the financial interest must be divested or other action taken); or – acceptable with some form of management (such as disclosure, restrictions on the activities of the investigator, or such other form as determined appropriate); or – acceptable without any need for management. © HRP Associates, Inc.

63. Conflict of Interest IRB makes final determination regarding COI management. Possible management plans: – Disclosure to subjects through the consent process – Modification of the research protocol or safety monitoring plan – Monitoring of research by independent reviewers – Disqualification of the conflicted party from participation in all or a portion of the research – Appointment of a non-conflicted Principal Investigator – Divestiture of significant financial interests – Severance of relationships that create actual or potential conflicts. – Prohibition of the conduct of the research at the hospital © HRP Associates, Inc.

64. Noncompliance Definition – failure to comply with or adhere to rules, regulations, policies and standards of conduct that govern human subject research, – failure to follow the determinations of the IRB, – failure to follow institutional policies. Noncompliance may be minor or serious, or it may be sporadic or continuing.

65. Noncompliance Serious noncompliance. – Noncompliance which increases risks to participants, decreases potential benefits, or compromises the integrity of the human research protection program. – Research being conducted without prior IRB approval is always considered serious noncompliance.

66. Noncompliance Continuing noncompliance. – A pattern of noncompliance that suggests a likelihood that without intervention instances of noncompliance will continue. – Failure to respond to a request to resolve an episode of noncompliance.

67. Noncompliance The IRB makes a determination about whether the incident is serious or is part of a pattern of non-compliance. The IRB then makes a determination about what action is warranted, including taking any additional action it deems necessary to protect the rights and welfare of the research subjects involved in the study.

68. Noncompliance Possible actions – Corrective action plan – Education – Modification of protocol – Increased monitoring – Informing subjects – Suspension or termination of research © HRP Associates, Inc.

69. Unanticipated Problems Unanticipated Problems involving risk to subjects or others, include any incident, experience, or outcome that meets ALL of the following criteria: – Unexpected – Related to the research – Increased risk of harm

70. Unanticipated Problems Not all Adverse Events are Unanticipated Problems – Some are not unanticipated Depressed subject commits suicide – Some are not related Child falls out of bed and is injured

71. Unanticipated Problems Not all Unanticipated Problems are Adverse Events – Determined by risk of harm, not actual harm Lost laptop New risk in literature © HRP Associates, Inc.

72. Unanticipated Problems Not all Unanticipated Problems involve the subjects – “…risk to subjects or others.” – Researcher injured by subject – Family member “outed” by subject © HRP Associates, Inc.

73. Unanticipated Problems IRB makes final determination as to whether an event is an unanticipated problem Possible actions – Change protocol – Change consent form – Inform subjects – Suspension or termination of research © HRP Associates, Inc.

74. Multi-site/Collaborative Research For multi-site or collaborative research, the IRB must determine that the procedures for dissemination of protocol information (IRB initial and continuing approvals, relevant reports of unanticipated problems, protocol modifications, and interim reports) between all participating institutions are adequate. © HRP Associates, Inc.

75. Multi-site/Collaborative Research If McLean Hospital is the coordinating facility, the Principal Investigator must document (and the IRB approve) how important human subject protection information (such as safety information or information affecting an individual’s willingness to participate or continue in the study) will be communicated to the other participating facilities engaged in the research study. © HRP Associates, Inc.

76. Documentation of Required Findings

77. © HRP Associates, Inc. Documentation For each of the required findings the IRB must provide protocol-specific information justifying why the IRB considers the research to meet each criterion or the IRB’s agreement with the findings and justifications as presented by the investigator on IRB forms. For full-review protocols the findings must be documented in the IRB minutes For expedited-review protocols the findings must be documented in the record along with the reviewer’s signature