Regulatory Requirements and Guidelines for DSMB’s

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Regulatory Requirements and Guidelines for DSMB’s. ….Or ‘who-advises-what’ in regard to DSMB’s. Regulatory Requirements and Guidelines for DSMB’s. All sorts of trials …academic, product development, industry, governments…. All sorts of regulators …. NIH, EMEA, MHRA, MRC - PowerPoint PPT Presentation

Text of Regulatory Requirements and Guidelines for DSMB’s

  • Regulatory Requirements and Guidelines for DSMBs.Or who-advises-what in regard to DSMBs

  • Regulatory Requirements and Guidelines for DSMBsAll 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 isthen summarise how this relates for trials conducted in Africa.

  • Regulatory Requirements and Guidelines for DSMBsDocuments 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 DSMBsfor Vaccine Trials (RC)

  • Regulatory Requirements and Guidelines for DSMBsWHO/TDR : 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

    Based on various national and international guidelines

  • Regulatory Requirements and Guidelines for DSMBsWHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards.

    DSMBs 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

  • Regulatory Requirements and Guidelines for DSMBsWHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards.

    DSMBs 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

  • Regulatory Requirements and Guidelines for DSMBsWHO/TDR : 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. 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

  • Regulatory Requirements and Guidelines for DSMBsWHO/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

  • Regulatory Requirements and Guidelines for DSMBsWHO/TDR : Operational Guidelines for Establishment and Function of Data Safety and Monitoring Boards.

    All DSMBs 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

  • Regulatory Requirements and Guidelines for DSMBsNHS R&D Health Technology Assessment: Issue in Data Management and Interim Analysis of Trials

    RCT increasingly have DMCs. 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

  • Regulatory Requirements and Guidelines for DSMBsNHS R&D Health Technology Assessment: Issue in Data Management and Interim Analysis of Trials

    - Advantages with both large and small DMCs dependant on protocol

    Consumer or ethicists on DMCs 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

    DMCs should comment on draft and final reports

  • Regulatory Requirements and Guidelines for DSMBsEMEA : 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 questionDSMB needed in many trials but not all.

    . A group of independent experts to assess progress, safety data and efficacy end-points of a CT

  • Regulatory Requirements and Guidelines for DSMBsEMEA : 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?)

  • Regulatory Requirements and Guidelines for DSMBsEMEA : 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 DMCs in mind. May influence decision on whether appropriate or not

  • Regulatory Requirements and Guidelines for DSMBsNIH :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.

  • Regulatory Requirements and Guidelines for DSMBsMRC Clinical Trial ToolKit Trial Monitoring Procedureswww.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!!!

  • Regulatory Requirements and Guidelines for DSMBs(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."3/19/2007PharMed GCP, SOP' s and Audits PharMed GCP, SOP' s and Audits M. Podoor, MDRoles and ResponsibilitiesThe SponsorClinical 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 theapplicable regulatory requirements to the investigator and takinapplicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detecteappropriate action designed to prevent recurrence of the detected deviations.deviations.[GCP ICH 5.18.4 (e)]...Verifying that written informed consent was obtained before each subject's participation in the trial.3/19/2007PharMed GCP, SOP' s and Audits PharMed GCP, SOP' s and Audits M. Podoor, MDSponsor and ResponsibilitiesThe SponsorNon 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 theregulatory authorities

  • Regulatory Requirements and Guidelines for DSMBsRelevance 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.