Regulatory Requirements and Guidelines for DSMB’s

Regulatory Requirements and Guidelines for DSMB’sRegulatory Requirements and Guidelines for DSMB’s

….Or ‘who-advises-what’ in regard to 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.


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)


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



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



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



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



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



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



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



- 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


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


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?)


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


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.

-


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!!!


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

ICH-GCP 5.18.3


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.