1. IRB Member Refresher Course 2010 Melissa Epstein, PhD Senior Education Specialist melissa.epstein@nyumc.org 1

2. Thank you for joining us. We hope to enhance your thinking as an IRB Member by refreshing your knowledge of Federal Regulations and NYU SoM IRB Policies. Please return your contact information updates. 2

3. Course Outline Specimen banking Vulnerable populations –Pregnant women –Persons with impaired decision-making capacity Data Safety Monitoring Plans 3

4. Specimen Banking 4

5. What is a specimen bank? A facility for storing and maintaining a collection of specimens (biospecimens) for future use that distributes specimens to multiple investigators and for multiple projects 5

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7. Specimen Banking in the News Havasupai Indians – Blood samples collected for diabetes research were used to study mental illness and migration patterns of American Indians from Asia. –The consent document stated that the research was to “study the causes of behavioral/medical disorders.” –In 2010 ASU agreed to pay $700,000 to 41 of the tribe’s members, return the blood samples and provide other forms of assistance. –Settlement is significant because it implies that the rights of research subjects may be violated when they are not fully informed of the future use of their tissue samples. 7

8. Specimen Banking in the News Henrietta Lacks –Cells taken from tumor in 1951 formed basis for HeLa cell line. –No consent obtained from Ms. Lacks or her family. –Original PI did not make money from HeLa, but the line has now been commercialized. –Family members of Ms. Lacks later participated in other studies – but thought they were being tested for cancer. –Highlights gulf between scientists and research subjects and the necessity for good communication 8

9. Specimen Banking in the News Texas newborn blood specimens 2010 –Five million blood samples taken from babies without parental consent and stored indefinitely for scientific research will be destroyed. The blood samples were originally collected to screen for birth defects. –The lawsuit alleged that the state’s failure to ask parents for permission to store and possibly use the blood violated constitutional protections against unlawful search and seizure. –The plaintiffs cited fears that their children’s private health data could be misused. 9

10. Banks have three parts Collection system Maintenance of specimens Sharing of specimens 10

11. Collection system issues Clinical or research specimens Identifiable or coded or anonymized Status of informed consent Number of institutions involved Vulnerable populations 11

12. Maintenance of specimen issues Single or multiple institutions Disease specific or broad number of conditions Who owns it? Who is responsible for it? Non-profit or for-profit? What are the long-term plans for the bank? 12

13. Sharing of specimens issues Open or restricted access? Who determines access? Identifiable or coded or anonymized Do you have to return research results? To the bank? To the subject? 13

14. Regulatory criteria for a specimen banking protocol Risks to subjects are minimized Risks to subjects are reasonable in relation to anticipated benefit Selection of subjects is equitable Informed consent will be obtained Informed consent will be documented Adequate monitoring to ensure safety Privacy is protected Vulnerable populations have been additionally safeguarded 14

15. Risks vs. benefits Risks are minimized by anonymizing samples Benefits are often maximized by maintaining a link between the specimen and the subject 15

16. What needs to be in a specimen banking protocol? Purpose of the repository Type of specimen to be stored Recruitment and consent of subjects –Subjects have an opportunity to refuse. How long will specimens be stored and where Procedures for collection of specimens Labeling of specimens –Terms such as “deidentified” or “anonymized” used consistently Other information stored along with specimens Who has access to the repository Sample distribution procedures Method for subject withdrawal of specimens 16

17. What needs to be in the specimen banking consent? Description of purpose How long specimens will be stored Procedures used to collect specimens Information stored along with specimens Labeling of specimens Who maintains specimens and what is the release process Return of research results Withdrawal of specimens Participation is optional 17

18. Sample specimen banking protocol 18

19. 19 Purpose of the bank possible future testing specific to the development of elvitegravir and for possible scientific research relating to HIV-1 disease, diagnostics or drug safety Type of specimen to be stored blood Recruitment and consent of subjects Covered elsewhere in the protocol How long will specimens be stored and where 10 years at Gilead Procedures for collection of specimens Discussed

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21. Sample specimen banking consent 21

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26. Summary – specimen banking Increasingly seen in sponsored clinical trials. Reviewed by the same criteria as any other protocol Protocols and consent information are often deficient and inconsistent 26

27. Vulnerable Populations 27

28. Populations that will be covered Pregnant women, fetuses and neonates (subpart B) Persons with mental disabilities or persons with impaired decision-making capacity 28

29. Pregnant women and fetuses – general considerations Where scientifically appropriate, preclinical studies, including studies on animals, and clinical studies, including studies on non-pregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses. 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. Individuals engaged in the research will have no part in determining the viability of a neonate. 29

30. Pregnant women, fetuses and neonates – general considerations The consent of the father generally does not need to be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest. 30

31. Pregnant women and fetuses Risks to fetus: –Risks to the fetus caused solely by interventions or procedures that have the prospect of direct benefit for the women or the fetus OR –The risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means 31

32. Pregnant women and fetuses - consent Only the consent of the pregnant woman: –Prospect of direct benefit to the pregnant woman and the fetus –Prospect of direct benefit to just the pregnant woman –No prospect of direct benefit to the woman or the fetus, when the risk to the fetus is not greater than minimal, and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means Consent of both the pregnant woman and the father (if available): –If the research holds out the prospect of direct benefit solely to the fetus 32

33. Consent signature requirements 33 Direct benefit to mother only Direct benefit to mother and fetus Direct benefit to fetus only No direct benefit or societal benefits only Risk is more than minimal Mother's consent Mother and father's consent NOT APPROVABLE BY IRB Risk is no more than minimal Mother's consent Mother and father's consent Mother's consent

34. Scenario #1 Description –An interventional study on the effects of strict control of maternal diabetes (e.g. insulin requirements, diet, exercise etc.) on pregnancy outcome. Who benefits? –Pregnant woman and fetus Who provides consent? –Only the pregnant woman 34

35. Scenario #2 Description –An study on the effects of pregnancy on women with cardiac disease. Data is collected through surveys and blood tests. Who benefits? –Only the pregnant woman Who provides consent? –Only the pregnant woman 35

36. Scenario #3 Description –A prospective chart review and monthly survey to determine the optimal gestational age for delivery of post-term pregnancies (beyond 42 weeks of gestation). Maternal and neonatal variables are assessed and compared with those of “normal” pregnancies (37-40 weeks of gestation) to determine at what gestational age does the benefit of induction outweigh that of expectant management. Who benefits? –Neither the pregnant woman nor the fetus What is the risk level for the fetus? –Not greater than minimal Who provides consent? –Only the pregnant woman 36

37. Scenario #4 Description –A study about a new technique for fetal transfusion for Rh incompatibility. Who benefits? –Only the fetus Who provides consent? –Both the pregnant woman and the father 37

38. Neonates (including uncertain viability, nonviable and viable) – general considerations Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data for assessing potential risks to neonates. Each individual providing consent is fully informed regarding the foreseeable impact of the research on the neonate. Individuals engaged in the research will have no part in determining the viability of a neonate. 38

39. Neonates of uncertain viability Research can only be conducted if: –The research holds out the prospect of enhancing the probability of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective of the research OR –The purpose of the research is the development of important knowledge which cannot be obtained by other means and there will be no risk to the neonate resulting from the research. 39

40. Neonates of uncertain viability Consent –The legally effective informed consent of either parent of the neonate or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent's legally authorized representative is obtained 40

41. Nonviable neonates Research can only be conducted if: –Vital functions of the neonate will not be artificially maintained –The research will not terminate the heartbeat or respiration of the neonate –There will be no added risk to the neonate resulting from the research –The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means 41

42. Nonviable neonates Consent –The legally effective informed consent of both parents of the neonate If either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable fetus will suffice to meet the requirements, except that the consent of the father need not be obtained if the pregnancy resulted from rape or incest. The consent of a legally authorized representative of either or both of the parents of a nonviable neonate will not suffice to meet the requirements. 42

43. Viable neonates Treated the same as children in subpart D. 43

44. Persons with impaired decision- making capacity Psychiatric, cognitive or developmental disorders or conditions; mental disabilities; substance abusers Disorder may compromise ability to make an informed and reasoned decision May be vulnerable to undue influence 44

45. Persons with impaired decision- making capacity Approval criteria: –Only this population is suitable as research subjects –Evaluation of risks: No significant risks OR If there is a probability of harm, there is a greater probability of direct benefit to the subject –Procedures developed for obtaining permission from subjects’ representatives and assent (or consent) from subject 45

46. Persons with impaired decision- making capacity Decision-making capacity may fluctuate – re-consenting may be required –Situation vs. disorder-related impairments (e.g. emergency room vs. stroke) –Static vs. progressive vs. episodic vs. time-limited impairments (e.g. severe mental retardation vs. Alzheimer’s disease vs. manic depressive disorder vs. TBI) 46

47. Persons with impaired decision- making capacity Greater than minimal risk research requirements –Capacity to consent must be assessed Who will assess? What procedures? –Is surrogate consent allowed? Direct benefit – yes No direct benefit - no 47

48. Persons with impaired decision- making capacity Watch out for: –Research design that includes washout periods, placebo or symptom provocation –Research that does not offer direct benefit to the subjects 48

49. Summary for vulnerable populations Is the risk/benefit profile approvable for this study? Who will be giving consent? What is the consent process? 49

50. Data Safety Monitoring Plans 50

51. Definition of data and safety monitoring The process for reviewing accumulated outcome data from an ongoing research study to ensure the continuing safety of current participants and those yet to be enrolled. An effort to ensure the continuing validity and scientific merit of the research study. A data and safety monitoring plan is the strategy used to conduct data and safety monitoring. 51

52. Why does the IRB need to see a DSMP? To help the IRB understand how the overall safety of the trial will be monitored during the course of the trial. 45CFR46.111 (6) –When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. 52

53. When is a DSMP required? All studies considered greater than minimal risk. Multi-site research where NYU SoM or its affiliates is the coordinating site. Studies where there is an NIH or FDA requirement for a plan. Studies when requested by the IRB. 53

54. What does a DSMP include? The type of data or events that are to be captured under the monitoring plan. Who will be responsible for monitoring the data collected and their roles. –The plan is not required to have a DSMB or DSMC 54

55. What does a DSMP include? The time frames for reporting adverse events and unanticipated problems to the monitoring entity. The frequency of assessments of data or events captured by the monitoring plan. This can be points in time (3 months, 6 months etc.) or after a specific number of participants are enrolled. 55

56. What does a DSMP include? Definition of stopping rules that will dictate when some action is required. Stopping rules are predetermined guidelines that are used to determine that the study should be altered or stopped, based on review of study related events that occur during the conduct of the study. –Should be specific about the endpoints that will be used and the decisions that will be made. Greater than expected rate of morbidity or mortality. When the experimental arm of a head to head comparison study is shown to be better or worse statistically than the standard care arm. 56

57. What does a DSMP include? As appropriate, procedures for communicating to the IRB, the study sponsor, and other appropriate entities the outcome of the reviews by the monitoring entity. 57

58. What type of DSMP is appropriate? The plan should be tailored for: –the nature, size, and complexity of the research protocol –the expected risks of the research –the type of subject population being studied 58

59. What is a monitoring entity? An identified individual or group assigned to conduct interim monitoring of accumulated data from research activities to assure –the continuing safety of research participants, –relevance of the study question, –appropriateness of the study, –integrity of the accumulating data. Membership should include expertise in the relevant field of study, statistics and research design. 59

60. Who or what can be the monitoring entity? Investigator Monitor/Monitoring Group Data Safety Monitoring Board (DSMB) / Data Monitoring Committee (DMC) 60

61. Who or what can be the monitoring entity? Investigator –Study involves a small number of subjects –Study is conducted only at one site –The range of possible study events that could have an important impact on the risks and benefits of research participants is narrow. 61

62. Who or what can be the monitoring entity? Monitor/Monitoring Group –A qualified and objective individual or group not directly involved with the design and conduct of the study safety officer designated medical monitor or monitoring group –These individuals may or may not be employees of NYU SoM or Medical Center or its affiliates or the study sponsor. Watch conflict of interest! 62

63. Who or what can be the monitoring entity? Monitor/Monitoring Group is appropriate for research studies that involve: –endpoints that are not serious irreversible events; –an intervention (for example, to relieve symptoms) that is not high risk and the effects of which would not generally be so compelling as to ethically warrant early termination for effectiveness; –short term treatments where effects are evaluated over periods of a few days to a few months –a smaller number of subjects where the study is completed quickly and the risk can be adequately assessed through simple comparisons. 63

64. Who or what can be the monitoring entity? Data Safety Monitoring Board (DSMB)/Data Monitoring Committee (DMC) –A formal committee that is established specifically to monitor data throughout the life of a study to determine if it is appropriate, from both the scientific and ethical standpoint, to continue the study as planned. –Typically made up of individuals who have expertise in the field, experience in the conduct of clinical trials, and/or statistical knowledge, and do not have any serious conflicts of interest. –Meet at least annually. –Monitor the timeliness of accrual, the quality of data collection and management, and the accumulating outcomes. 64

65. Who or what can be the monitoring entity? DSMB/DMC is appropriate for research studies involving: –Large numbers of subjects –Blinded study treatment groups –Multiple clinical sites –High risk interventions –Controlled trials with mortality or major morbidity as a primary or secondary endpoint 65

66. Data and Safety Monitoring is not just Adverse Event review The monitor/committee also reviews study data to decide whether or not to continue the study 66

67. Physicians’ Health Study Placebo controlled trial of aspirin and beta carotene The trial's Data and Safety Monitoring Board stopped the aspirin arm of the PHS several years ahead of schedule because it was clear that aspirin had a significant effect on the risk of a first myocardial infarction. (http://phs.bwh.harvard.edu/index.html) 67

68. Trials of Antibiotic Treatment in Patients with Lyme Disease Tested the safety and efficacy of intensive antibiotic treatment in people with Lyme disease who had developed chronic symptoms, despite earlier treatments with antibiotics. DSMB recommended the termination of the treatment component since it had accomplished its objectives. –Their preliminary analysis showed that after 90 days of continuous antibiotic therapy there were no significant differences in the percentage of patients who felt that their symptoms had improved, gotten worse, or stayed the same between the antibiotic treatment and placebo groups in either trial. –The DSMB’s review suggested there was only a slight chance that a difference between the placebo- and antibiotic-treated groups would be found even with continued accrual of another 131 patients, the number needed to reach full enrollment. –(http://www.niaid.nih.gov/topics/lymeDisease/research/Pages/antibiotic.aspx) 68

69. Coloplast Virtue® Male Sling The Coloplast Virtue® Male Sling is a Class II, implantable, sub-urethral, permanent, non-absorbable support sling indicated for the surgical treatment of male SUI resulting from intrinsic sphincter deficiency (ISD). The sling is manufactured from polypropylene and is sold for single use only. The device consists of a knitted monofilament polypropylene mesh. The body of the device provides surface area for supporting the bulbous urethra. The four arms are covered with polyethylene sleeves. Extending from the ends of each arm are braided polyester sutures, which are attached to the mesh arms via heat sealed polyethylene cones. The sutures provide proper attachment to the introducer and allow for proper positioning of the sling in the body. The introducer allows for implanting both the transobturator arms and pre-pubic arms of the mesh sling. The introducer is sold as single use with the mesh sling in a kit. This investigation of the Coloplast Virtue® Male Sling device is a prospective, single-arm, nonrandomized study to assess efficacy and safety of suture fixation in 50 implanted subjects. Implants will not exceed 15 subjects at any particular center. 69

70. 70 Sample Monitoring Plan

71. 71 No section for a Data Safety Monitoring Plan The process for reviewing accumulated outcome data from an ongoing research study to ensure the continuing safety of current participants and those yet to be enrolled. An effort to ensure the continuing validity and scientific merit of the research study. *Adverse event reporting and review *Data quality assurance

72. Types of data or events SAEs, Severe Anticipated and Unanticipated AEs.... 72 Adverse events are reviewed – but it’s not clear what kind of assessment is done beyond classification.

73. Responsibilities and roles for gathering, evaluating and monitoring the data: 73 Role of PI, Staff, Sponsor specified for AE review, but not continuing analysis for safety. Verification of data accuracy will be done by Sponsor (frequency unspecified). Verification of compliance with protocol will be done by Site monitor (at least once).

74. Information about monitoring entity: 74 Independent Medical Advisor will review AEs – but this is not a data safety monitor.

75. Reporting adverse events and unanticipated problems to the monitoring entity: 75 Time frames – indicated Mechanisms – not indicated Who will prepare – PIs

76. Assessments 76 No information about a data safety monitor – just adverse event review.

77. Criteria for action: 77 No description of triggers for actions or stopping rules.

78. Procedures for communicating 78 Only described for adverse event reporting.

79. DSMP Review Summary A data safety monitoring plan is more than adverse event review. Plans are often incomplete or missing. 79

80. Questions? 80

81. Thank you. Melissa Epstein melissa.epstein@nyumc.org 212-263-4027 81

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