Making Sense of Reporting Obligations to the IRB. fully accredited since 2006

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1 Making Sense of Reporting Obligations to the IRB fully accredited since 2006

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6 About Quorum Review IRB Accredited o o Fully Accredited by the Association for Accreditation of Human Research Protection Programs (AAHRPP) through 2014 Fully compliant with FDA and OHRP requirements International capabilities o Boards available for the review of US and Canadian Studies Strong Framework o Approx. 150 employees one of the largest IRBs in the US Certified IRB Professionals (CIP) o 60% of Affiliated IRB members, 40% of Regulatory staff and 20% of study management & study support positions 6

7 The Quorum Advantage 13 Board meetings each week 24-hour site turnaround, 36-hour amendment review, and same day site changes One time CV and audit documentation submission Support available 8am-8pm ET Dedicated Study Manager 7

8 The Quorum Advantage Secure portal with Smart Forms, status reports, and approval documents Customized Phase I and Post-Marketing processes Flexible, customized process for AMCs 100% Quality Control on all documents 8

9 About the Presenters Regulatory Attorney Claire Carbary, JD, CIP IRB Experience Joined Quorum Review IRB in September 2009 WIRB prior to Quorum CIP certification since 2010 Member of the Northwest Association for Biomedical Research (NWABR) and Public Responsibility in Medicine and Research (PRIM&R) Legal Background Juris Doctor from Seattle University Member of the Washington State Bar Association (WSBA) Member of the Health and Corporate Law Sections of the WSBA 9

10 About the Presenters Regulatory Attorney Mitchell Parrish, JD, CIP IRB Experience Joined Quorum Review IRB in January 2010 Regulatory Counsel with WIRB prior to Quorum Former Regulatory Advisor to the National Cancer Institute Central IRB CIP certified since 2009 Legal Background Juris Doctor from the University of Oregon School of Law Member of the Washington State and American Bar Associations Member of the Health and Corporate Law Sections of the WSBA 10

11 Making Sense of Reporting Obligations to the IRB 11

12 Webinar Overview Description of Topic Page Role of the IRB 13 Problems with Reporting 17 Regulatory Landscape 20 Obligations for Reporting Safety Information 28 Unanticipated problems that are Adverse Events SUSAR UADE Recommended practices for reporting Safety Information Obligations for Reporting Non-Safety Information 51 Unanticipated Problems that are not Adverse Events Recommended practices for reporting Non-Safety Information Key Take Aways 65 12

13 13 Role of the IRB

14 Role of the IRB The primary purpose of both initial and continuing review of [a] study is to assure the protection of the rights and welfare of the human subjects ( (f). To fulfill its obligations an IRB must have, among other things, information concerning unanticipated problems involving risk to human subjects in the study, including adverse events that are considered unanticipated problems. FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009) 14

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17 17 Problems With Reporting

18 Problems with Reporting Unnecessary Reporting Much of the information that is being reported does not meet reporting requirements and therefore results in the unnecessary expenditure of resources by all stakeholders Specifically, the way that unanticipated problem is interpreted does not yield information about adverse events that is useful to IRBs and thus hinders their ability to ensure protection of human subjects. FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009) 18

19 Problems with Reporting No Explanation Provided Not only is unnecessary information reported, but also reported information is not explained: In the years since the IRB and IND regulations issued, changes in the conduct of clinical trials (e.g., increased use of multi-center studies, international trials) have complicated the reporting pathways for adverse event information described in the regulations. IN particular the practice of local investigators reporting individual, unanalyzed events to IRBs, including reports of events from other study sites that the investigator receives from the sponsor of a multi-center study often with limited information no explanation of how the event represents an unanticipated problem has led to the submission of large numbers of reports to IRBs that are uninformative. FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009) 19

20 20 Regulatory Landscape

21 Regulatory Landscape Regulations (HHS/FDA) 45 CFR 46 (Protection of Human Subjects) 21 CFR 56 (Institutional Review Boards) 21 CFR 312 (Investigational New Drug Application) 21 CFR 320 (Bioavailability and Bioequivalence Requirements) 21 CFR 812 (Investigational Device Exemptions) Guidance (HHS/FDA) HHS, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, January 15, 2007 FDA, Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs Improving Human Subject Protection, January, 2009 FDA, Draft Guidance for Industry and Investigators, Safety Reporting Requirements for INDs and BA/BE Studies, September,

22 Regulatory Landscape From Where is the Obligation to Report Safety Information to the IRB derived? FDA and HHS regulations require the IRB to receive safety and other information throughout study and during continuing review to ensure the criteria for approval is still met and to ensure the safety, rights, and welfare of subjects are protected. 45 CFR and ; 21 CFR and

23 Regulatory Landscape From Where is the Obligation to Report Safety Information to the IRB derived? (continued) There is a lot of safety data and other information in clinical trials, so where in the regulations does it say exactly what to report to the IRB? While the regulations do not contain specifics, they do provide the term Unanticipated Problem (UP) 23

24 Regulatory Landscape Unanticipated Problem 21 CFR The investigator shall...promptly report to the IRB... All unanticipated problems involving risk to human subjects or others. 21 CFR (b)(1) [E]ach IRB shall: Follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of: (1) Any unanticipated problem CFR (b) (4) An IRB must have [W]ritten procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others

25 Regulatory Landscape Unanticipated Problem Unanticipated Problem = Any incident, experience, or outcome that meets all of the following criteria: 1. Unexpected (in terms of nature severity or frequency) given(a) the research procedures that are described in the protocol-related documents, and (b) the characteristics of the subject population being studied; 2. related or possibly related to participation in the research; and 3. suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized. HHS Guidance, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (January 15, 2007) *Note: this general criteria is essentially the same for unanticipated problems under FDA regulations as well 25

26 Regulatory Landscape Unanticipated Problems and Adverse Events In addition to defining Unanticipated Problem, the HHS Guidance also explains that there are UPs that stem from adverse events, essentially safety related UPs, and those that do not stem from adverse events, essentially non-safety related UPs. Adverse Event: Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject's participation in the research, whether or not considered related to the subject s participation in the research. This encompasses both physical and psychological harms and can be categorized as internal (happening at the site) or external (happening at other locations) Note: The terms adverse effect and adverse experience are interchangeable with adverse event. FDA Guidance, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009) 26

27 Regulatory Landscape Unanticipated Problems and Adverse Events Safety Related: Do not report adverse events that are not UPs Safety Related: Must report adverse events that are UPs Non-Safety Related: Must report UPs that are not adverse events Adapted from HHS Guidance, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (January 15, 2007); See also FDA Guidance, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009) 27

28 Obligations for Reporting Safety Information to the IRB 28

29 Regulatory Landscape Unanticipated Problems and Adverse Events Safety Related: Do not report adverse events that are not UPs Safety Related: Must report adverse events that are UPs Non-Safety Related: Must report UPs that are not adverse events Adapted from HHS Guidance, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (January 15, 2007); See also FDA Guidance, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009) 29

30 Reporting Safety Information to the IRB SUSAR: Serious and unexpected suspected adverse reactions UP Unanticipated Problem By its very nature, if an event is an SUSAR or a UADE then it is a UP and must be reported to the IRB IRB UADE: Unanticipated Adverse Device Effect 30

31 Reporting Safety Information - SUSAR Serious and unexpected suspected adverse reaction (SUSAR) originates from 21 CFR 312 and is designed to guide sponsors on when to submit IND safety reports to the FDA and investigators Must report to the IRB all SUSARs that satisfy these three criteria: Serious (Death, life-threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity, substantial disruption of the ability to conduct normal life functions, and congenital anomaly/birth defect) Unexpected (an event not listed in the investigator brochure or not listed at the specificity or severity observed; or an event not consistent with the risk information described in the investigational plan) Suspected Adverse Reaction ( a reasonable possibility that the drug caused the adverse event ) Evidence to suggest a causal relationship between the drug and event 31

32 Reporting Safety Information - SUSAR Individual Occurrences A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 32

33 Reporting Safety Information - SUSAR Example: In a phase II study testing an investigational drug for Hepatitis C, a subject experiences hepatic injury. In addition to the investigational drug, the subject was continuing her standard Hepatitis C therapy at the time of hepatic injury. Is this reportable to the IRB as an individual occurrence? 33

34 Reporting Safety Information - SUSAR Example: In a phase II study testing an investigational drug for Hepatitis C, a subject experiences hepatic injury. In addition to the investigational drug, the subject was continuing her standard Hepatitis C therapy at the time of hepatic injury. Is this reportable to the IRB as an individual occurrence? NO 34

35 Reporting Safety Information - SUSAR One or more Occurrences One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture, progressive multifocal leukoencephalopathy) 35

36 Reporting Safety Information - SUSAR Example: A subject with extrapulmonary small-cell carcinoma receiving an investigational chemotherapy agent experiences a bowel perforation during his second cycle of chemotherapy. Is this reportable to the IRB as one occurrence? 36

37 Reporting Safety Information - SUSAR Example: A subject with extrapulmonary small-cell carcinoma receiving an investigational chemotherapy agent experiences a bowel perforation during his second cycle of chemotherapy. Is this reportable to the IRB as one occurrence? NO 37

38 Reporting Safety Information - SUSAR Aggregate Analysis of Specific Events An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group. 38

39 Reporting Safety Information - SUSAR Example: 17 oncology sites are participating in a research study comparing an investigational chemotherapy agent to standard therapy in subjects ages Of those subjects receiving the investigational drug, an average of 35% of subjects across the 17 sites experience deep vein thrombosis. Is this reportable as an aggregate analysis? 39

40 Reporting Safety Information - SUSAR Example: 17 oncology sites are participating in a research study comparing an investigational chemotherapy agent to standard therapy in subjects ages Of those subjects receiving the investigational drug, an average of 35% of subjects across the 17 sites experience deep vein thrombosis. Is this reportable as an aggregate analysis? YES 40

41 Reporting Safety Information - SUSAR Critical to understand the definition of Suspected Adverse Reaction coupled with the examples the FDA provides: o Individual occurrence o One or more occurrences o Aggregate analysis 41

42 Reporting Safety Information - SUSAR Without this understanding, the FDA explains that the following problem occurs: Reporting of individual events even though unlikely that the event was caused by the drug. Examples include: Serious adverse experiences (e.g. mortality or major morbidity) that are unlikely to have been manifestations of the underlying disease Serious adverse experiences that commonly occurred in the study population independent of drug exposure (e.g. strokes or acute myocardial infarction in an elderly population) Serious adverse experiences that were study endpoints (i.e. the study was evaluating whether the drug reduced the rate of these events) Such reporting causes a drain on resources when the FDA, and IRBs are inundated with generally uninformative Safety Information especially when reported as single events without any context. 42

43 Reporting Safety Information - UADE Unanticipated Adverse Device Effect (UADE) originates from 21 CFR 812 and is designed to guide sponsors on when to submit reports to the FDA and investigators Must report to the IRB all UADEs that satisfy the following criteria: Serious (death, life-threatening, serious problem) Not previously identified (an effect not previously identified in nature, severity, or degree of incidence in the investigational plan or application) Caused by, or associated with, a device 43

44 Reporting Safety Information - UADE FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009) Essentially states that reporting UADEs to the IRB should be treated the same as reporting SUSARs to the IRB While not in the device regulations like the drug regulations and while there are different considerations between safety information for drugs and devices, take into account whether the effect is a: Individual occurrence One or more occurrences Multiple occurrences determined through an aggregate analysis 44

45 Recommended Practices for Reporting Safety Information to the IRB 45

46 Recommended Practices for Reporting Safety Information For Multi-center studies: Even though the FDA regulations indicate it is the investigator s responsibility to notify the IRB of unanticipated problems (21 CFR ) FDA guidance states: Investigators must rely on the sponsor to provide them information about AEs occurring at other study sites The sponsor is in a better position to process and analyze the significant of AE information from multiple sites and to make a determination about whether an AE is an unanticipated problem. FDA supports an arrangement in which the sponsor prepares UP reports and submits to the IRB when the sponsor, investigator, and IRB have made an explicit agreement for the sponsor to report directly to the IRB. Although the investigator s view of the causal relationship between an adverse event and the investigational drug is important, FDA believes that the sponsor is better positioned than the individual investigator to assess the overall safety of the investigational drug because the sponsor has access to serious adverse event reports from multiple study sites and is able to aggregate and analyze these reports. FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009); Draft FDA Guidance for Industry and Investigators, Safety Reporting Requirements for INDs and BA/BE Studies (September 2010) 46

47 Recommended Practices for Reporting Safety Information (continued) While Investigators may report SUSARs and UADEs to the IRB, Quorum recommends that Sponsors/CROs submit SUSAR and UADE information to the IRB on behalf of investigators. This means... The Sponsor/CRO should inform investigators and arrange with the IRB that it will report on behalf of investigators (arrangement with IRB should include in what format to report) The protocol should not state generally that all adverse events require reporting the IRB or include similar language because then if all adverse events are subsequently not reported, investigators run the risk of being out of compliance with the protocol Also it is not appropriate to submit all AEs to the IRB, just AEs that are SUSARs or UADEs! 47

48 Recommended Practices for Reporting Safety Information For single-center or investigator initiated studies: Obviously, the investigator is likely the one reporting to the IRB. This still means: The investigator can arrange with IRB in what format to report The protocol should still not state generally that all adverse events require reporting the IRB or include similar language because then if all adverse events are subsequently not reported, investigators run the risk of being out of compliance with the protocol. Also it is not appropriate to submit all AEs to the IRB, just AEs that are SUSARs or UADEs! 48

49 Recommended Practices for Reporting Safety Information TIMING of Reporting to the IRB (continued) Report SUSARs and UADEs promptly to the IRB Promptly is generally considered 10 days, which is supported in the FDA s guidance on reporting AEs to the IRB This 10-day timeframe exists whether there is an arrangement for the sponsor to submit on behalf of the IRB or whether the investigator is responsible for submitting to the IRB 49

50 Recommended Practices for Reporting Safety Information What to report (continued) QUESTION ABOUT Whether to report How to report When to report Contact the IRB! 50

51 Obligations for Reporting Non-Safety Information to the IRB 51

52 Reporting Non-Safety Information to the IRB Unanticipated Problems and Adverse Events Safety Related: Do not report adverse events that are not UPs Safety Related: Must report adverse events that are UPs Non-Safety Related: Must report UPs that are not adverse events Adapted from HHS Guidance, Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (January 15, 2007); See also FDA Guidance, Adverse Event Reporting to IRBs Improving Human Subject Protection (January 2009) 52

53 Reporting Non-Safety Information to the IRB Unexpected Related or Possibly Related UP Unanticipated Problem Must report all UPs to the IRB IRB Greater Risk of Harm 53

54 Reporting Non-Safety Information Unanticipated Problems Examples: Failure to obtain informed consent Omitting study procedure(s) required by the approved protocol Study personnel misconduct that adversely impacts the study Adverse findings by a regulatory agency, medical board, or other relevant body Are these UPs? * Whether these are UPs depends on the type of study and the specific factors surrounding each event or incident. 54

55 Reporting Non-Safety Information Unanticipated Problems Example: An investigator is conducting behavioral research and collects individually identifiable sensitive information about illicit drug use by surveying college students. The data is stored on a laptop computer that is password protected. The laptop is stolen from the investigator s car. Is this reportable to the IRB as a UP? 55

56 Reporting Non-Safety Information Unanticipated Problems Example: An investigator is conducting behavioral research and collects individually identifiable sensitive information about illicit drug use by surveying college students. The data is stored on a laptop computer that is password protected. The laptop is stolen from the investigator s car. Is this reportable to the IRB as a UP? YES 56

57 Reporting Non-Safety Information Unanticipated Problems Example: An Investigator is conducting a psychology study evaluating decision making and response times when persons are listening to music at various decibel levels. In order to perform the study, participants are placed in a small, windowless, soundproof booth. The IRB-approved protocol and consent form describe claustrophobic reactions as one of the research risks. The 12 th subject enrolled in the research experiences significant claustrophobia, resulting in the subject withdrawing from the study. Is this event reportable to the IRB as a UP? 57

58 Reporting Non-Safety Information Unanticipated Problems Example: An Investigator is conducting a psychology study evaluating decision making and response times when persons are listening to music at various decibel levels. In order to perform the study, participants are placed in a small, windowless, soundproof booth. The IRB-approved protocol and consent form describe claustrophobic reactions as one of the research risks. The 12 th subject enrolled in the research experiences significant claustrophobia, resulting in the subject withdrawing from the study. Is this event reportable to the IRB as a UP? NO 58

59 Reporting Non-Safety Information Unanticipated Problems Example: As a result of a processing error by a pharmacy technician, a subject enrolled in a multi-center clinical trial receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB-approved protocol. While the dosing error increased the risk of toxic manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after an appropriate period of careful observation. Is this error reportable to the IRB as a UP? 59

60 Reporting Non-Safety Information Unanticipated Problems Example: As a result of a processing error by a pharmacy technician, a subject enrolled in a multi-center clinical trial receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB-approved protocol. While the dosing error increased the risk of toxic manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after an appropriate period of careful observation. Is this error reportable to the IRB as a UP? YES 60

61 Recommended Practices for Reporting Non-Safety Information to the IRB 61

62 Recommended Practices for Reporting Non-Safety Information For multi-center or single-center: Generally, UPs that are not an adverse event (i.e. nonsafety related) are typically site or investigator specific Therefore, it makes more sense for the investigator, not the sponsor, to report the UP to the IRB The investigator can arrange with IRB in what format to report 62

63 Recommended Practices for Reporting Non-Safety Information (continued) TIMING of Reporting to the IRB Report UPs promptly to the IRB Promptly is generally considered 10 days, which is supported in the FDA s guidance on reporting to the IRB This 10-day timeframe exists whether there is an arrangement for the sponsor to submit on behalf of the IRB or whether the investigator is responsible for submitting to the IRB 63

64 Recommended Practices for Reporting Safety Information What to report (continued) QUESTION ABOUT Whether to report How to report When to report Contact the IRB! 64

65 Key Take Aways Know where the obligations to report to the IRB originate Understand the term Unanticipated Problem (UP) and its three criteria: Unexpected, Related, Greater Risk of Harm Understand the terms SUSAR and UADE, know their criteria, and know that these are UPs that require reporting to the IRB Understand that there are UPs that are not safety-related that must be reported to the IRB Know how and in what timeframe to report to the IRB If there are ever any questions relating to reporting to the IRB, talk to your IRB. The IRB is a resource! 65

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70 Making Sense of Reporting Obligations to the IRB fully accredited since 2006