PREP #16: Data and Safety Monitoring Plans. Presented by: Hallie Kassan, Director, IRB Dorean Flores, Manager, IRB

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1 PREP #16: Data and Safety Monitoring Plans Presented by: Hallie Kassan, Director, IRB Dorean Flores, Manager, IRB

2 CME Disclosure Statement The North Shore LIJ Health System adheres to the ACCME s new Standards for Commercial Support. Any individuals in a position to control the content of a CME activity, including faculty, planners, and managers, are required to disclose all financial relationships with commercial interests. All identified potential conflicts of interest are thoroughly vetted by the North Shore-LIJ for fair balance and scientific objectivity and to ensure appropriateness of patient care recommendations. Course Director and Course Planners, Kevin Tracey, MD, Cynthia Hahn, Emmelyn Kim, MPH, Tina Chuck, MPH have nothing to disclose. Hallie Kassan and Dorean Flores have nothing to disclose

3 Learning Objectives Define Data and Safety Monitoring Plan (DSMP) Define Data and Safety Monitoring Board. (DSMB) Identify components of an adequate data and safety monitoring plan Identify when a DSMB is needed

4 Why is the IRB concerned with safety monitoring?

5 Regulations Criteria for IRB approval of research When appropriate, the research plan makes adequate provision for monitoring data collected to ensure the safety of participants 45 CFR (a)(6); 21 CFR (a)(6)

6 Regulations Criteria for IRB approval of research Risks to subjects are minimized : (i) by using procedures which are consistent with sound research design and do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed 45 CFR (a)(1); 21 CFR (a)(1)

7 AAHRPP Element II.3.B. The IRB has and follows written policies and procedures for reviewing the plans for data and safety and monitoring, when applicable, and determines that the data and safety monitoring plan provides adequate protection for participants

8 Local Policies From HRPP Manual, Section 10.4 The IRB will review the data and safety monitoring plan for protocols during initial review and at continuing reviews.

9 What type of monitoring is appropriate? Type of monitoring should be commensurate with the risk of the study, population being studied and size and complexity of the research

10 What is a Data & Safety Monitoring Plan (DSMP)? A DSMP describes how the study investigators plan to oversee the safety of research subjects and how adverse events will be characterized and reported.

11 Data & Safety Monitoring Plans Not required when the only study procedure involves the use of materials (data, documents, records, or specimens) that have been collected, or will be collected solely for nonresearch purposes.

12 What information is required in a DSMP? 1. Types of data or events that are to be captured under the monitoring plan and frequency of analysis 2. Responsibilities and roles for gathering, evaluating and monitoring the data. 3. Information about the monitoring entity (the person or group monitoring the data). 4. Time frames from reporting adverse events and unanticipated problems to the reporting entity. 5. Any plans for interim analysis and stopping rules

13 Details of the Data and Safety Monitoring Plan should be in the Protocol

14 Example DSMP Subjects will be monitored for adverse event of serum calcium: Monitoring: Whole blood ICal will be performed at every visit, including screening. Actions: If 1.4 mmol/l at any study visit, subject will be taken off therapy, but will continue to be followed until end of study. If 1.3 and <1.4 mmol/l at any study visit, dose will be reduced to 2000 IU dailyheld for 7 days and ionized calcium rechecked in 1 week. If unchanged or higher at that time, subject will be taken off therapy and followed until end of study period. If <1.3, subject will continue onresume at a reduced dose of 2000 IU and with regular study follow-up.

15 Example DSMP The PI will identify an independent Safety Officer/Medical Monitor with expertise in [TOPIC/CONDITION/DISEASE BEING STUDIED] who does not have any scientific, financial, or other conflict of interest related to the study and who is not responsible for patient care at any of the participating sites. Safety will be formerly monitored [FREQUENCY] by the study team and the Safety Officer/Medical Monitor throughout the duration of the study. [ ] will prepare a safety report for these regular reviews comprised of anticipated safety events and actions taken. The PI will contact the Safety Officer/Medical Monitor for ad hoc reviews of any unanticipated safety events. The study protocol will be carried out in accordance with OHRP/FDA/NIH guidelines and requirements. In the event of a serious adverse event during the study protocol, it will be reported immediately to the PI, the co-investigators, and the Safety Officer/Medical Monitor. It will also be reported to the [IRB s FOR THE STUDY, SPONSORS, ETC.] and to all members of the research team.

16 What is a Data & Safety Monitoring Board (DSMB)? A DSMB is an independent group of experts that review on a regular basis accumulating data from an ongoing clinical trial.

17 What are the responsibilities of a DSMB? 1. Review the research protocol and plans for data safety and monitoring 2. Evaluate the progress of the trial with periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, and reports from related studies 3. Make recommendations to the IRB and investigators concerning continuation or conclusion of the trial

18 What is the composition of a DSMB? members 2. Usually consist of clinicians who are experts in the particular clinical area under study, and biostatisticians who understand the statistical methods used to analyze the study data and are able to draw a conclusion based on the information. 3. Members cannot be directly involved in the study

19 What are the basic elements of a DSMP when there is a DSMB? 1. Description of the chair and members 2. Meeting structure (closed vs open, frequency) 3. Adverse event reporting requirements 4. Description of interim analyses, if applicable 5. Study stopping rules, if applicable 6. How and to whom DSMB reports will be distributed

20 How do I know if my study needs a DSMB 1. Is the trial intended to provide definitive information about the effectiveness and/or safety of a medical intervention? 2. Are there prior data to suggest that the intervention being studied has a potential to induce potentially unacceptable toxicity?

21 How do I know if my study needs a DSMB 1. Is the trial evaluating mortality or another major endpoint, such that inferiority of one treatment arm has safety as well as effectiveness implications? 2. Would it be ethically important for the trial to stop early if the primary question addressed has been definitively answered, even if secondary questions or complete safety information were not fully addressed?

22 Clinical Research? Yes No Phase III or Multicenter Yes No Blinded, high-risk intervention, or vulnerable population? Yes No IRB + DSMP + DSMB IRB + DSMP

23 Conduct of a DSMB meeting Initially an open session is conducted members of the clinical trial may be present may focus on accrual, protocol compliance, and general toxicity issues no outcome results discussed during this session Followed by a closed session DSMB members only outcome results discussed statistical reports (if necessary)

24 Conduct of a DSMB meeting Finally an executive session DSMB members only discuss the general conduct of the trial all outcomes (including toxicities and AE) develop recommendations and vote if necessary

25 Investigator Responsibilities Tell the IRB what is actually happening (not what you think the IRB wants to hear) Ensuring that the Data and Safety Monitoring Plan is implemented Informing the IRB if the DSMP changes after IRB approval has been granted

26 Does this study require a DSMP? An investigator would like to use some blood samples for research. The blood is being collected for clinical care. The investigator will take left over blood for his research.

27 Does this study require a DSMB? An investigator is studying an approved medication for an off-label indication, in a small Phase I study (30 participants)

28 Does this study require a DSMB? An investigator is studying an investigational drug (never approved by the FDA) in a Phase III, randomized, multicenter study

29 What is missing from this DSMP? Each arm will be monitored for toxicities that cause a patient to go permanently off protocol therapy. If an arm is determined to have an excessive number of patients who go permanently off-protocol therapy due to toxicity, then the data will be carefully reviewed with an eye to modifying the therapy, or, at worst, closing the arm.

30 Further Guidance NSLIJ HRPP Website DSMP Guidance DSMP Templates NIH : FDA: mation/guidances/ucm pdf

31 Questions??? Office of the Human Research Protection Program 3333 New Hyde Park Road New Hyde Park, NY Phone: Fax: