1. An agency of the European Union Presented by: Paolo Tomasi Data Safety Monitoring Boards / Data Monitoring Committees in paediatric studies Paolo Tomasi, M.D. Ph.D. Head of Paediatric Medicines European Medicines Agency

2. Current EMA/PDCO position for PIPs Opinion template (published on website) contains limited guidance: (independent) DSMB: Should be foreseen in all studies in neonates, in safety/efficacy studies in other age groups. If inserted in PIP opinion, this becomes a key element = obligation for the applicant (if not created: non-compliance  non-validation)

3. Regulatory Requirements and Guidelines for DSMBs All sorts of trials: academic, product development, industry, governments… All sorts of regulators: FDA, EMA, MHRA, MRC… All sorts of groups suggesting guidelines: TDR/WHO, European Commission, universities, funding agencies, NHS…

4. Why are DSMBs needed? WHO: Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards. DSMBs are needed: because trials should not continue if the design is no longer appropriate as a trial might reach its objective earlier than predicted, or the primary objective may never be achievable a positive trend to do harm within trials might become apparent trials may need modifying if accumulated data is not in-line with the original trial design assumptions DSMBs might also need to recommend protocol amendments such as: -Change in dosage of trial or concomitant medications -Treatment duration of trial of concomitant medications -Entry or exclusion criteria -Sample size -Recruitment rate In red: amendments potentially requiring a modification of the agreed PIP

5. When are DSMBs needed? WHO: Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards. All trials need safety monitoring and many BUT NOT ALL need DSMBs. Definitely needed if: -Controlled CT with mortality or severe morbidity as primary or secondary endpoint (life-threatening condition). -RCT evaluating clinical efficacy and safety of an investigational new product -Early studies of a high risk new intervention -CT design or data accrual is complex -If there is uncertainty about whether the data will impact the trial design -Vulnerable populations (Paediatrics, Neonates…) -Entry or exclusion criteria -Sample size -Recruitment rate

6. When are DSMBs needed? NIH Need to submit a data safety and monitoring plan for all phase I – III trials. This may or may not include a DSMB. Usually require a DSMB if: multi-centered blinded high risk vulnerable population Need to provide justification if no DSMB proposed/required.

7. When are DSMBs needed? EMA/CHMP DMC guideline Usually required if: Life-threatening disease (any case) Potentially harmful treatment (even if highly effective) Preplanned interim analysis/complex designs vulnerable population such as children Responsibility for trial lies with sponsor/investigators, not DSMB.

8. When are DSMBs NOT needed? UK NHS: Issue in Data Management and Interim Analysis of Trials: Not possible for a DMC to make a contribution Where any observed differences would not prompt a protocol change (i.e.. stop the trial) Where there is no reason why a DMC decision would differ from internal monitoring (open-label studies?) Criteria for NOT having a DSMB: EMA/CHMP guideline: Not practical if CT is too short (may apply even if life-threatening) Known drugs used within the license Non-critical conditions (mild pain trials?) DSMB may be even counterproductive in some situations

9. Questions for the participants 1.Are there any recent/additional views of the CHMP on the requirements/indications for a DSMB? 2.Is the EMA/PDCO guidance sufficient? 3.Should there always be an explicit justification if a DSMB is not proposed/mentioned in the opinion for any paediatric study?