DATA MONITORING COMMITTEE CHARTER FOR THE XXXXXXXTRIAL
Full trial title:
Acronym:
EUDRACT number:
Trial sponsor:
Chief Investigator:
1. INTRODUCTION
This document describes the roles and responsibilities of the independent Data Monitoring Committee (DMC) for the ______study, including the timing of meetings, methods of providing information to and from the DMC, frequency and format of meetings, statistical issues and relationships with other committees.
This charter has been based on the Damocles Charter and thanks to the University of Nottingham Clinical Trials Unit for their template document.
2. COMPOSITION
The DMC for this study comprises:
______(Chair)
______(Clincial Specialist)
______(Statistician)
Statistical programming support will be provided by ______(Statistician to the ______trial).
3. ROLES AND RESPONSIBILITIES
General aims of the committee
- To safeguard the interests of trial participants (with particular reference to safety and its relation to the efficacy of the interventions).
- Monitor the overall progress and conduct of the trial.
- Assist and advise the Investigators so as to protect the validity and credibility of the trial.
The DMC will be provided on a planned basis with data as required covering:
a) Trial progress & conduct, eg
- Patient disposition
- External Validity
- Deviations from Protocol
- Data completeness
- Losses to follow-up/ post-randomisation withdrawals
b) Evidence of safety & tolerability, eg
- Non-serious adverse reactions (non-serious ARs)
- Serious Unexpected Serious Adverse Reactions (SUSARs)
- Non-SUSAR Serious adverse reactions (SARs)
- Compliance
In addition, any SUSARs arising at any time will be reported to the DMC, within seven days of their occurrence, if not explained on the basis of the known pharmacology of the two trial drugs
c) Evidence of efficacy, eg
- ______
The DMC will not makedecisions about the trial, but will make recommendations to the Trial Steering Committee, its Chair or the Co-ordinating Centre over the course of the trial and where necessary or indicated, the trial funder, sponsor or regulator if they believe the safety and interests of trial participants are in question. In particular, the DMC should inform the Chair of the steering committee if, in their view:
(i) the results are likely to convince a broad range of clinicians, including those supporting the trial and the general clinical community, that one trial arm is clearly indicated or contraindicated, and there was a reasonable expectation that this new evidence would materially influence patient management; or
(ii) it becomes evident that no clear outcome would be obtained.
If in the opinion of the DMC no meeting is necessary, then none will be held, and a statement on safety and adverse events will be prepared by the Chair for submission to the Chair of the Trial Steering Committee.
In addition the DMC may also suggest additional data analyses, advise on protocol modifications suggested by investigators or funders (e.g. to inclusion criteria, trial endpoints, or sample size), review sample size assumptions, appropriateness of patient information, compliance with previous DMC recommendations and assess the impact and relevance of external evidence.
The responsibilities of the DMC statistician
The DMC statistician, ______, will provide independent statistical expertise to the DMC, aiding in the interpretation of the results and directing additional analyses if required.
The responsibilities of the DMC statistical programmer
The statistical programs for the DMC will be run by a statistician outwith the trial – with unblinded treatment assignments if necessary - who will produce the report, participate in the DMC meetings and may be asked to take notes, but will not be a formal, voting member of the DMC.
The responsibilities of the trial statistician
The trial statistician, ______, will produce draft statistical programs to provide tables for the DMC using dummy treatment assignments. He will participate in the confidential sections of the DMC meetings.
The responsibilities of the trial office team
The Trial Office team (Trial Manager and Data Manager) will only input to the production of the non-confidential sections of the DMC report.
The responsibilities of the CI and other members of the Trial Management Group (TMG)
The CI, may be asked, and should be available, to attend open sessions of the DMC meeting. The other TMG members will not usually be expected to attend but can attend open sessions when necessary.
4. BEFORE OR EARLY IN THE TRIAL
All potential DMC members will have had sight of the protocol/outline before agreeing to join the committee. While DMC members should be independent and constructively critical of the ongoing trial, they should also be supportive of the aims and methods of the trial, therefore, if a DMC member subsequently has major reservations about the trial (e.g. the protocol or the logistics) these should be reported to the trial office and the member may then decide to stand down from the DMC.
The DMC will meet within X months of the trial starting, to discuss the protocol, the trial, any analysis plan for the DMC, future meetings, and to have the opportunity to clarify any aspects with the Chief and Principal investigators. The DMC should meet either in person or via teleconference within XX months of recruitment commencing, depending on recruitment rates.
Consideration should be given to provision of an initial “dummy” report, including the use of shell (empty) tables, to familiarise the DMC members with the format that will be used in the reports.
Relevant issues specific to the disease and treatment under study should be described and noted in the minutes of the first DMC meeting.
The DMC should be aware of any regulatory implications of their recommendations.
DMC members must formally register their assent by confirming (1) that they have agreed to be on the DMC and (2) that they agree with the contents of this Charter
5. RELATIONSHIPS
Other Trial committees and Groups
1. The Trial Steering Committee (TSC)
The TSC has the overall responsibility for ensuring a scientifically sound study design, a well executed trial, and accurate reporting of the study results.
It is composed of representatives from the academic and medical communities, a consumer representative, and from the Trial Management Group (TMG). Members from the TMG will not have voting privileges on the TSC.
The TSC must address and resolve scientific, medical, and practical issues encountered during the trial. The TSC will draw up its own guidelines, and will review the criteria and guidelines of the other committees in order to provide advice and suggestions if necessary. The TSC will convene, either in person or via teleconference, as often as deemed necessary to carry out its responsibilities, but at least once per year.
The CTU will provide statistical support to the TSC to investigate any additional database questions that the TSC raises, which may include possible additional analyses to those outlined prospectively in the trial protocol. However these will not be undertaken without an appropriate protocol amendment or justified variation to the Final Statistical Analysis Plan.
The TSC will have administrative support from the Trial Coordinating Centre staff including the Trial Manager, based at the University of Nottingham.
2. The Trial Management Group
This group will oversee the “operational” aspects of the trial, which include the processes and procedures employed, and the day-to-day activities involved in study conduct.
Day to day management of the trial will be undertaken by the trial Coordinating Centre at the ______. The TMG will meet regularly, in person or by conference call to review the progress of the trial and to address any urgent issues. The TMG will provide recommendations and helpful suggestions to the TSC.
The ______, will employ its own systems and procedures in the conduct of this trial, using the ______and ______personnel such as database builder, trial statistician, and senior manager, Project Manager, Trial Coordinator and Data Entry Administrator, in liaison with the Chief Investigator.
Payments to DMC members
DMC members will be reimbursed for reasonable travel, subsistence and accommodation expenses for attending DMC meetings. No other payments or rewards are planned.
Competing interests
These should be disclosed at the first DMC meeting and notified to the TSC. These are not restricted to financial matters – involvement in other trials or intellectual investment could be relevant and complete disclosure enhances credibility (See Annex 1).
DMC members will not use interim results to inform trading in pharmaceutical shares, and careful consideration should be given to trading in stock of companies with competing products.
6. ORGANISATION OF DMC MEETINGS
Frequency
The DMC will consider the appropriate timeframe for reviewing the data as the study progresses.
The DMC will meet within XX months of the first patient being recruited and then once a year after this for the duration of the trial data collection period provided there is sufficient business for such a meeting to be necessary. Ideally the DMC meetings will precede the TSC by no more than a month.
Mode
The first meeting will be face-to-face to facilitate full discussion and allow members to get to know each other. Subsequent meetings should be face-to-face if possible, with teleconference as an alternative.
Format
These will consist of an open and closed session. Only DMC members and others whom they specifically invite will attend closed sessions. In the open sessions, all those attending the closed session may be joined by the PI(s), members of the TMG, and as relevant possibly also representatives of the sponsor, funder, or regulator.
7. TRIAL DOCUMENTATION AND PROCEDURES TO ENSURE CONFIDENTIALITY AND PROPER COMMUNICATION
Intended content of material to be available in open sessions:
- Accumulating information relating to recruitment and data quality (e.g. data return rates, protocol compliance).
- Toxicity details based on pooled data of all enrolled patients and total numbers of events (with total numbers recruited for comparison) for the primary outcome measure.
- Other pooled outcome measures, at the discretion of the DMC.
Intended content of material to be available in closed sessions
In addition to all the material available in the open session, the closed session material will include efficacy and safety data by treatment group.
The DMC will have access to all trial data. It may request and will be provided with whatever additional data it deems necessary or useful for it to carry out its duties.
The initial data provided to the DMC will have the treatment allocation blinded. However, the DMC may also wish to have unblinded data and in these circumstances the data will be provided by treatment group blinded initially. Unblinded data will be examined only if necessary.
Access to accumulating efficacy data and interim analyses
This will be restricted to the DMC members and supporting statistical programmer. DMC members do not have the right to share confidential information with anyone outside the DMC, including the Chief Investigator (CI).
Responsibility for Identification and circulation of external evidence
This will be primarily the responsibility of the CI and will be collated and distributed to the DMC by the trial manager. The annual safety report should include any updates to SmPCs and any new information from a PubMed or similar search. It should be sent to the DMC by email as soon as it is available: if necessary the DMC will meet to discuss the annual safety report.
Communication
Interim analysis results will be saved by the DMC statistical programmer in a password -protected zipped .pdf file. This will be distributed by e-mail to each member of the DMC not later than 10 working days prior to the date of the DMC meeting. The password will be distributed in a separate e-mail.
The DMC will report its recommendations in writing to the Trial Steering Committee. This will be copied to the CI, trial statistician and trial manager, and if possible should be sent via the trials office in time for consideration at a TSC meeting.
If the trial is to continue largely unchanged then the report from the DMC should include a summary paragraph suitable for trial promotion purposes.
All SARs will be reported to the DMC, by email, as they occur (or within 7 days).
Communication between the DMC and the other trial committees (e.g. TSC) will be via the DMC chair in the first instance.
Handling of confidential material
The DMC members should store the papers safely after each meeting so they may check the next report against them. After the trial is reported, the DMC membersshould destroy all interim reports.
8. DECISION MAKING
Possible recommendations by the DMC may include:-
•No action needed, trial continues as planned;
•Early stopping due, for example, to clear benefit or harm of a treatment
futility, or external evidence;
•Stopping recruitment within a subgroup or centre;
•Extending recruitment (based on actual control arm response rates being different to predicted rather than on emerging differences) or extending follow-up;
•Stopping a single arm of a multi-arm trial;
•Sanctioning and/or proposing protocol changes.
Statistical methods
No interim analyses for efficacy are planned by the TMG. However the DMC may informally assess efficacy, as well as safety, during the trial in accordance with their charter, e.g. at 1 and 2 years from the start of recruitment.
For these “administrative” analyses, informal Haybittle-Peto type boundaries will be adopted as a guideline for efficacy assessment to permit the DMC to break the blind with negligible effect on the properties of the final analysis.
How decisions or recommendations will be reached within the DMC
The DMC will aim to reach decisions by consensus. Every effort will be made for the DMC to reach a unanimous decision. If the DMC cannot achieve this, a vote may be taken, although details of the vote should not be routinely included in the report to the TSC as these may inappropriately convey information about the state of the trial data.
It is important that the implications (e.g. ethical, statistical, practical, financial) for the trial be considered before any recommendation is made.
The default position for the DMC is that all three members should be present, in person or by teleconference, before the DMC is quorate for decision-making.
In an emergency (due to sudden illness or incapacity of a DMC member), the two remaining members can meet, at their discretion, and be quorate for decision making.
DMC members should make every effort to attend every DMC meeting. If a DMC member cannot commit themselves to attending regular DMC meetings then they should resign from the DMC by informing the CI in writing. The CI would then arrange a replacement in consultation with the other remaining DMC members.
9. REPORTING
To whom will the DMC report their recommendations/decisions, and in what form?
In the first instance the DMC (via the Chair) will report their recommendations/decisions to the Chair of the TSC and the CI in the form of a letter/email within 3 weeks of any recommendation/decision being made. A copy of the letter would be sent to the Trials Office. The DMC reserves the right to report recommendations/decisions directly to the funder, sponsor or regulator in exceptional circumstances.
Whether minutes of the meeting be made and, if so, by whom and where they will be kept
Minutes of the DMC meetings will be made, with separate records for the open and closed sessions. The DMC statistical programmer will take the minutes and keep a record. The DMC Chair should sign off any draft minutes or notes, after a DMC meeting, with the minutes formally approved at the next DMC meeting.
What will be done if there is disagreement between the DMC and the body to which it reports?
If there is disagreement between the DMC and the TSC/CI then attempts should be made to resolve this at a meeting between the parties. If the disagreement cannot be resolved, then the DMC reserves the right to inform other interested parties (for example, the funder, trial sponsor, MCRA, RECs) with their recommendations.
The information about the DMC that will be included in published trial reports
DMC members will be named and their affiliations listed in the main report, unless they explicitly request otherwise. A brief summary of the timings and conclusions of DMC meetings may be included in the body of this paper.
Whether the DMC will have the opportunity to approve publications, especially with respect to reporting of any DMC recommendation regarding termination of a trial
The DMC will be given the opportunity to read and comment on any publications before submission.
There will be no constraints on DMC members divulging information about their deliberations after the primary efficacy results of the trial have been published
Signature
I confirm that I am happy to sit on the Data Monitoring Committee for the ______trial and agree to abide by this charter whilst sitting on the committee.
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