Regulatory Requirements and Guidelines for DSMB’s

1. Regulatory Requirements and Guidelines for DSMB’s ….Or ‘who-advises-what’ in regard to DSMB’s

2. Regulatory Requirements and Guidelines for DSMB’s All sorts of trials …academic, product development, industry, governments…. All sorts of regulators …. NIH, EMEA, MHRA, MRC All sorts of research groups suggesting guidelines… TDR/WHO, Universities, Funding agencies, NHS Aim of this session is to discuss an overview of what is being requested and recommended … what the difference is…then summarise how this relates for trials conducted in Africa.

3. Regulatory Requirements and Guidelines for DSMB’s Documents used in this overview: WHO/TDR: Operational Guidelines for Establishment and Functioning of Data Safety and Monitoring Boards NHS R&D Health Technology Assessment: Issue in Data Management and Interim Analysis of Trials EMEA: Committee for Medicinal Products for Human Use, Guidelines on Data Monitoring Committees. NIH: further guidance on a data and safety monitoring for phase i and phase ii trials MRC Toolkit: MRC/DH Joint project codify good practice in publicly funded UK trials with medicines AMANET; Terms of Reference DSMB’sfor Vaccine Trials (RC)

4. Regulatory Requirements and Guidelines for DSMB’s • WHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards. • DSMB’s 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 • Based on various national and international guidelines

5. Regulatory Requirements and Guidelines for DSMB’s • WHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards. • DSMB’s might also need 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

6. Regulatory Requirements and Guidelines for DSMB’s • WHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards. • DSMB’s role: • Maintain the scientific integrity of the trial • Protect the welfare of the subjects • Maintain the credibility of the data • Interim analysis – conduct/review/recommend

7. Regulatory Requirements and Guidelines for DSMB’s • WHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards. • All trials need safety monitoring and many BUT NOT ALL need DSMB’s. Definitely needed if; • Controlled CT with mortality or severe morbidity as primary or secondary endpoint. • 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 • Entry or exclusion criteria • Sample size • recruitment rate

8. Regulatory Requirements and Guidelines for DSMB’s • WHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards. • Role of DSMB. Review, Evaluate and then Recommend. • Need to be: Independent, Competent and Timely and properly constituted. • Sponsor must select and appoint and write the charter. • Membership should be multi-disciplinary, relevant and representative of participating countries

9. Regulatory Requirements and Guidelines for DSMB’s • WHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards. • All DSMB’s need a charter. • Description of board • Objective • Meetings • Data management and security • Documents • Conditions of appointment • Quorum • reporting and communicating recommendations • document management and archiving

10. Regulatory Requirements and Guidelines for DSMB’s • NHS R&D Health Technology Assessment: Issue in Data Management and Interim Analysis of Trials • RCT increasingly have DMC’s. Important but not always. • Criteria for NOT having a DMC; • 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

11. Regulatory Requirements and Guidelines for DSMB’s • NHS R&D Health Technology Assessment: Issue in Data Management and Interim Analysis of Trials • - Advantages with both large and small DMC’s – dependant on protocol • Consumer or ethicists on DMC’s is controversial • Costs should be covered but any further reward should be minimal • Meetings should be face to face when possible. First meeting then teleconferences? • Disadvantages of blinded data outweigh un-blinding • DMC’s should comment on draft and final reports

12. Regulatory Requirements and Guidelines for DSMB’s EMEA : title Role of DSMB is to strike the important balance: No Unavoidable risk vs. Allow to continue for an adequate period and not stopped too early to answer the question DSMB needed in many trials – but not all. …. A group of independent experts to assess progress, safety data and efficacy end-points of a CT

13. Regulatory Requirements and Guidelines for DSMB’s • EMEA : title • Assessing need: • Life-threatening, for example, almost always would need a DSMB. • Weigh up the risk to the participant versus answering the question • DSMB Not Useful When; • Not practical as CT is so short (so may apply even if life-threatening) • Known drugs used within the licence • Non-critical conditions (mild pain trials?)

14. Regulatory Requirements and Guidelines for DSMB’s • EMEA : title • Methodological implications of DMC analysis on CT final analysis: • Inflation of type I error (false positive, i.e.. treatment better than other when there was no difference). • Possible bias on future conduct of a CT • Important to keep these major methodological problems in connection with DMC’s in mind. May influence decision on whether appropriate or not

15. Regulatory Requirements and Guidelines for DSMB’s • NIH :Regulatory requirements: • 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-centred • Blinded • High risk • vulnerable population • Need to provide justification if no DSMB required. • Not necessarily appropriate if intervention is low risk. In this case close monitoring by investigator is adequate.

16. Regulatory Requirements and Guidelines for DSMB’s • MRC – Clinical Trial ToolKit ‘Trial Monitoring Procedures’ • www.ct-toolkit.ac.uk • Explains ICH-GCP requirements • Defines type of monitoring • Trial Oversight committees • Trial Management group • Trial Steering committee • Data monitoring committee • Coordinating Centre ‘good housekeeping • Central Monitoring • On-Site Monitoring • ……. Helpful context of whole trial and not only form of monitoring!!!

17. (GCP ICH 5.18.3) ... In general there is a need for on-site monitoring, before, during and after the trial; however in exceptional circumstances the sponsor may determine... Statistically controlled sampling may be an acceptable method for selecting the data to be verified." Roles and Responsibilities The Sponsor Clinical Monitor responsibilities [GCP ICH 5.18.4 (q)] ...Communicating deviations from the protocol, SOPs, GCP and the ...Communicating deviations from the protocol, SOPs, GCP and the applicable regulatory requirements to the investigator and taking applicable regulatory requirements to the investigator and takin appropriate action designed to prevent recurrence of the detected appropriate action designed to prevent recurrence of the detecte deviations. deviations. [GCP ICH 5.18.4 (e)] ...Verifying that written informed consent was obtained before each subject's participation in the trial. PharMed GCP, SOP' s and Audits PharMed GCP, SOP' s and Audits 3/19/2007 M. Podoor, MD Sponsor and Responsibilities The Sponsor Non Compliance (GCP ICH 5.20.2) If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution's participation in the trial. When an investigator's /institution's participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authorities PharMed GCP, SOP' s and Audits PharMed GCP, SOP' s and Audits 3/19/2007 M. Podoor, MD ICH-GCP 5.18.3 Page 25 The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size and endpoints of the trial. In general there is a need for on-site monitoring, before, during and after the trial; however …central monitoring in conjunction with procedures such as investigators’ training and meetings and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified Page 26 Page 27 Regulatory Requirements and Guidelines for DSMB’s

18. Regulatory Requirements and Guidelines for DSMB’s • Relevance to African Trials? • - All aiming to work to ICH-GCP...right? • Registration, funding and publishing • Need to be ethical and gain ethics approval • Product development trials • Academic / locally led • Practicalities …. Back to assessing need.