1. THE ROLE OF DSMB’s in CLINICAL RESEARCH Data and Safety Monitoring Monitoring

2. Data and Safety Monitoring NIH Policy NIH Policy Each Institute/Center should have a system for the appropriate oversight and monitoring of the conduct of clinical trials Each Institute/Center should have a system for the appropriate oversight and monitoring of the conduct of clinical trials Must ensure the safety of participants and Must ensure the safety of participants and Should protect the validity and integrity of the data for all NIH-supported/conducted trials Should protect the validity and integrity of the data for all NIH-supported/conducted trials

3. DATA and SAFETY MONITORING Clinical Trials have a relationship between participants and investigators Clinical Trials have a relationship between participants and investigators Both must fulfill certain obligations Both must fulfill certain obligations

4. Data and Safety Monitoring Participants: Participants: Must be fully informed of the study requirements throughout the study Must be fully informed of the study requirements throughout the study Should comply with the rigors of the research protocol or be allowed to withdraw from participation Should comply with the rigors of the research protocol or be allowed to withdraw from participation

5. Data and Safety Monitoring Investigators: Investigators: Must protect the health and safety of participants Must protect the health and safety of participants Inform participants of information relevant to their continued participation Inform participants of information relevant to their continued participation Pursue the research objectives with scientific diligence Pursue the research objectives with scientific diligence

6. Data and Safety Monitoring 1979 1979 Every clinical trial should have provision for data and safety monitoring Every clinical trial should have provision for data and safety monitoring The size of the monitoring committee depends upon the nature, size, and complexity of the clinical trial The size of the monitoring committee depends upon the nature, size, and complexity of the clinical trial The Principal Investigator was expected to perform the monitoring function but may have had others to help The Principal Investigator was expected to perform the monitoring function but may have had others to help

7. Data and Safety Monitoring 1994 1994 It was recommended that every clinical trial, even those that pose little likelihood of harm have an external monitoring body It was recommended that every clinical trial, even those that pose little likelihood of harm have an external monitoring body

8. Data Safety Monitoring Boards 1998 1998 Establishment of Data Safety Monitoring Board (DSMB) is required for multi-site clinical trials involving interventions that entail potential risk to the participants Establishment of Data Safety Monitoring Board (DSMB) is required for multi-site clinical trials involving interventions that entail potential risk to the participants The functions and oversight of such activities are distinct from the requirement for study review and approval by an IRB The functions and oversight of such activities are distinct from the requirement for study review and approval by an IRB

9. Data and Safety Monitoring Principles of monitoring data and safety in studies include: Principles of monitoring data and safety in studies include: Physiologic, toxicity, and dose-finding studies—Phase I Physiologic, toxicity, and dose-finding studies—Phase I Efficacy studies—Phase II Efficacy studies—Phase II Efficacy, effectiveness and comparative trials—Phase III Efficacy, effectiveness and comparative trials—Phase III

10. Data and Safety Monitoring Monitoring should be commensurate with the degree of risk involved Monitoring should be commensurate with the degree of risk involved A data and safety monitoring committee should determine safe and effective conduct and A data and safety monitoring committee should determine safe and effective conduct and Recommend conclusion of the trial when significant benefits or risks have developed or Recommend conclusion of the trial when significant benefits or risks have developed or The trial is unlikely to be concluded successfully The trial is unlikely to be concluded successfully

11. Data and Safety Monitoring Risk associated with participation in research must be minimized to the extent practical Risk associated with participation in research must be minimized to the extent practical Size and complexity will determine if a single person or a committee is needed to oversee the study Size and complexity will determine if a single person or a committee is needed to oversee the study

12. Data and Safety Monitoring Performance of Data and Safety Monitoring Performance of Data and Safety Monitoring 1. Is to protect the integrity of the system for monitoring trial data and participant safety 2. Monitoring must be performed on a regular basis 3. Conclusions of the monitoring must be reported to the IRB and the Research Subject Advocate Committee (RSA) on the GCRC

13. Data and Safety Monitoring IRB/RSA responsibilities IRB/RSA responsibilities May direct who shall perform the monitoring activities May direct who shall perform the monitoring activities May direct the composition of the monitoring group including that: May direct the composition of the monitoring group including that: the PI is not to chair the Data and Safety Monitoring Board nor be the single person doing the monitoring the PI is not to chair the Data and Safety Monitoring Board nor be the single person doing the monitoring

14. Data and Safety Monitoring Plan All protocols receiving GCRC support are required to have a Data and Safety Monitoring Plan which All protocols receiving GCRC support are required to have a Data and Safety Monitoring Plan which 1. Monitors the progress of the research study and the safety of participants 2. Plans for assuring compliance with requirements for reporting adverse events

15. Data and Safety Monitoring Plan 3. Plans for assuring that any action resulting in a temporary or permanent suspension of the clinical trial is reported to all responsible parties 4. Plans for assuring protocol compliance and data accuracy

16. Data and Safety Monitoring Plan The plan should include the following: The plan should include the following: 1. Committee chair and members 2. Frequency of evaluation 3. Method of detecting adverse events 4. How adverse events will be scored

17. Data and Safety Monitoring Plan Adverse event reporting requirements Adverse event reporting requirements A description of interim efficacy analysis if appropriate A description of interim efficacy analysis if appropriate Distribution of Data and Safety Monitoring Board (DSMB) reports—must go to GCRC RSA for review Distribution of Data and Safety Monitoring Board (DSMB) reports—must go to GCRC RSA for review

18. Data and Safety Monitoring Plan Specifics of the plan will depend upon the nature, size, complexity and risk of the clinical trial Specifics of the plan will depend upon the nature, size, complexity and risk of the clinical trial A monitoring committee is required to determine safe and effective conduct A monitoring committee is required to determine safe and effective conduct Or to recommend conclusion of the trial when significant benefits or risks have developed Or to recommend conclusion of the trial when significant benefits or risks have developed

19. Data and Safety Monitoring Plan and Board Single individual—if trial is small with little risk Single individual—if trial is small with little risk IU GCRC has decided that the Principal Investigator cannot be the chair of the DSMB and cannot be the only monitor of a research study in order to eliminate any potential conflict IU GCRC has decided that the Principal Investigator cannot be the chair of the DSMB and cannot be the only monitor of a research study in order to eliminate any potential conflict

20. Data and Safety Monitoring Plan and Board A description of the plan and the composition of the monitoring board are required at the time of the GCRC submission. A description of the plan and the composition of the monitoring board are required at the time of the GCRC submission. This description should be included in Section G of the GCRC application This description should be included in Section G of the GCRC application

21. Data and Safety Monitoring Plan and Board Description should include: Description should include: 1. DSMB chair and members 2. How frequently the study will be evaluated 3. The method of detecting adverse events 4. How events will be scored

22. Data and Safety Monitoring Plan and Board 5. Adverse event reporting requirements 6. A description of interim efficacy analysis if appropriate 7. The distribution of DSMB reports

23. Significant Risk Protocols Definition of Risk is a complex sum of individual contributors to the overall risk of participation in the study Definition of Risk is a complex sum of individual contributors to the overall risk of participation in the study

24. Significant Risk Protocols Risk to study subjects may be thought of as encompassing aspects of: Risk to study subjects may be thought of as encompassing aspects of: 1. Study design 2. Potential for loss of confidentiality 3. And the nature of the study population involved

25. Significant Risk Protocols The risk of the intervention is a function of the potential for adverse events (AE) and the severity of adverse events The risk of the intervention is a function of the potential for adverse events (AE) and the severity of adverse events 1. The potential for adverse events includes the expected frequency of adverse events 2. When the frequency of AEs is unknown or identifying the frequency of AEs is one of the endpoints of the trial such as Phase I trials, the risk is higher

26. Significant Risk Protocols The severity of adverse events should also be considered independent of the frequency of AEs The severity of adverse events should also be considered independent of the frequency of AEs 1. Study procedures which are not expected to lead to frequent AEs, but include the possibility of severe AEs, confer higher risk

27. Significant Risk Protocols The amount of experience with the study intervention also affects the risk, since the risk of AEs may not be fully defined. The amount of experience with the study intervention also affects the risk, since the risk of AEs may not be fully defined.

28. Significant Risk Protocols Study Population Study Population Participation of vulnerable subjects confers greater risk than non vulnerable populations Participation of vulnerable subjects confers greater risk than non vulnerable populations 1. Examples include children under 18, prisoners, and employees of the workplace

29. Significant Risk Protocols Normal volunteer populations require special consideration since any intervention confers greater risk than would be experienced by subjects not participating in a study Normal volunteer populations require special consideration since any intervention confers greater risk than would be experienced by subjects not participating in a study

30. Significant Risk Protocols The gravity of loss of confidentiality The gravity of loss of confidentiality Loss of confidentiality for study participants in genetic studies, studies of stigmatized conditions, or studies where loss of confidentiality could lead to social harms may be considered high risk Loss of confidentiality for study participants in genetic studies, studies of stigmatized conditions, or studies where loss of confidentiality could lead to social harms may be considered high risk

31. Significant Risk Protocols Physical, emotional and psychosocial harms Physical, emotional and psychosocial harms Example: a genetic study which might lead to a diagnosis of or identify a predisposition for a serious disease in study participants would be considered high risk such as Huntington’s disease Example: a genetic study which might lead to a diagnosis of or identify a predisposition for a serious disease in study participants would be considered high risk such as Huntington’s disease A study including known illegal drug users could be considered high risk since loss of confidentiality of study participants could lead to great social harm A study including known illegal drug users could be considered high risk since loss of confidentiality of study participants could lead to great social harm

32. Significant Risk Protocols Significant Risk may be conferred by the degree of severity of a single consideration or the combined weight of several considerations Significant Risk may be conferred by the degree of severity of a single consideration or the combined weight of several considerations By mandate, all studies using GCRC facilities or resources which are considered to be of significant risk will be required to establish an independent data safety monitoring board By mandate, all studies using GCRC facilities or resources which are considered to be of significant risk will be required to establish an independent data safety monitoring board

33. Significant Risk Protocols Independent Data and Safety Monitoring Board Independent Data and Safety Monitoring Board Is made up of at least one member who is not directly involved with the study Is made up of at least one member who is not directly involved with the study Should not be a member of the PIs or co-PIs division within a given department Should not be a member of the PIs or co-PIs division within a given department If the PI is a division director, then the DSMB cannot be made up of more junior members of his or her division If the PI is a division director, then the DSMB cannot be made up of more junior members of his or her division

34. Significant Risk Protocols Studies requiring an Independent DSMB Studies requiring an Independent DSMB Early clinical trials Early clinical trials All Phase I studies All Phase I studies Phase II studies unless they involve low risk interventions Phase II studies unless they involve low risk interventions Studies of devices or invasive techniques with which the PI or the community has little experience Studies of devices or invasive techniques with which the PI or the community has little experience Gene Therapy trials Gene Therapy trials

35. Significant Risk Protocols Genetic Studies Genetic Studies Studies that examine more than 20 genetic loci Studies that examine more than 20 genetic loci Studies which seek to examine stigmatized conditions Studies which seek to examine stigmatized conditions Lethal or disabling diseases for which no treatment is available Lethal or disabling diseases for which no treatment is available Or conditions where loss of confidentiality within the study could lead to serious emotional, psychological, or social consequences. Or conditions where loss of confidentiality within the study could lead to serious emotional, psychological, or social consequences.

36. Significant Risk Protocols Studies in vulnerable populations Studies in vulnerable populations Children under 18 Children under 18 Prisoners Prisoners Decisional-impaired subjects involving more than minimal risk Decisional-impaired subjects involving more than minimal risk Studies that involve administering agents manufactured on campus Studies that involve administering agents manufactured on campus

37. The Role of DSMB’s in Clinical Research Produced and Presented by Carole Weir, RN, MSN cweir@iupui.edu Directors Edward Liechty, MD eliecht@iupui.edu Peter Schwartz, MD phschwar@iupui.edu The Research Subject Advocate Committee