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Data Monitoring Core Committee
The Data Monitoring Core Committee (DMCC) was established to provide objective, independent monitoring of clinical trials funded by the HRC. The DMCC has two main functions:
- to review the monitoring plans for trials funded by the HRC and provide advice to the HRC on whether the plans meet best international practice
- to constitute a Trial-Specific Data Monitoring Committee for any trial funded by the HRC where this is appropriate and is requested by the investigators. Trial-Specific Data Monitoring Committees are formed from the DMCC membership, plus additional co-opted members who have expertise specific to the trial.
A third function of the HRC DMCC is to provide apprenticeship style training in the data monitoring committee role to leading clinical researchers and biostatisticians from New Zealand. This approach is recommended internationally as the optimal way of maintaining an experienced data monitoring committee workforce.
For investigators submitting a proposal for funding for a clinical trial:
- What is a Data Monitoring Committee?
- What is the purpose of a Data Monitoring Committee?
- What does a Data Monitoring Committee do?
- What is the appropriate form of monitoring for my trial?
- What are the implications of this for my application?
For people considering asking the HRC DMCC to provide the data monitoring committee for their trial:
- How does the HRC DMCC choose the membership for my trial?
- What is involved in using an HRC data monitoring committee for my trial?
- How and when do I request the HRC DMCC set up a data monitoring committee for my trial?
The DMCC is administered by the HRC Ethics Committee. Submission of trials to be monitored by the DMCC should be made to the HRC.
Dr Katrina Sharples ̶ Chair
Department of Preventive and Social Medicine, University of Otago, Dunedin
Dr Mark Jeffery
Department of Oncology, Christchurch Hospital
Professor Ngaire Kerse
School of Population Health, The University of Auckland
Professor Thomas Lumley
Department of Statistics, The University of Auckland
Dr Andrew Moore
Department of Philosophy, University of Otago, Dunedin
Dr Mark Webster
Department of Cardiology, Auckland City Hospital
Dr Conroy Wong
Department of Respiratory Medicine, Middlemore Hospital
Committee Secretary: Lana Lon
Terms of Reference for DMCC
What is a Data Monitoring Committee?
An independent Data Monitoring Committee (DMC) is an advisory body responsible for monitoring emerging safety and efficacy data, reviewing trial conduct and making recommendations to the trial steering committee and study sponsor(s). Normally, this DMC should have sole access to the data emerging in the study. The DMC makes recommendations on early termination of the study if there is convincing evidence of benefit, unfavourable results ruling out benefit, safety concerns, or a low probability of the trial achieving its objectives.
An independent DMC is independent of those conducting the study the DMC is monitoring. Membership is therefore limited to those individuals free of any significant conflict of interest in relation to the study being monitored, whether financial, intellectual, professional or regulatory in nature. It has a multidisciplinary membership, including physicians from relevant medical specialties and biostatisticians. In many cases its membership also includes others with relevant expertise, including ethicists, epidemiologists and basic scientists. All clinical and biostatistical members of the DMC should have experience in clinical trials, and at least some members, especially the chair and the biostatistician, should have prior DMC experience.
All intervention studies need monitoring, but not all studies need an independent DMC (Ellenberg et al 2003: 153–6). Where an independent DMC is not required, a Trial Steering Committee may set up an "internal" Data Monitoring Committee to carry out the monitoring functions.
What is the purpose of a Data Monitoring Committee?
The primary responsibilities of a DMC are to safeguard the interests of the study participants, to preserve the integrity and credibility of the study so that future patients may be treated optimally and to ensure definitive and reliable results are available in a timely way to the health care community.
What does a Data Monitoring Committee do?
A DMC meets regularly to review reports containing current trial data on safety, efficacy and trial conduct. On the basis of this information, and any external information, the DMC makes recommendations to the Trial Steering Committee regarding early termination and any changes to trial conduct to improve the integrity of the data.
Where the trial has an independent DMC the trial statistician prepares two DMC reports. The first of these, the open report, contains information on trial conduct and is made available to the Trial Steering Committee. The second, the closed report, contains comparative data on safety and efficacy, including the results of any planned interim analyses. The closed report remains confidential to the DMC until the trial is complete. This confidentiality protects the trial from inappropriate early termination, which can be caused by premature judgement based on potentially misleading early results.
Guidance on DMCs describing international best practice:
USA Food and Drug Administration Guidance document on the establishment and operation of clinical trial Data Monitoring Committees:
In the UK, a report was commissioned by the Health Technology Assessment programme: Data Monitoring Committees: Lessons, Ethics and Statistics (DAMOCLES). Their report provides a systematic review of DMC practices and their recommendations for DMC processes. An executive summary and the full report can be found here:
What is the appropriate form of monitoring for my trial?
An independent DMC is most needed for an intervention study that aims to provide definitive data on treatments intended to save lives or prevent serious disease (Ellenberg et al 2003: 153–6). An independent DMC should also be considered in other settings:
Earlier phase studies, whether or not randomised, of a high-risk intervention. For example:
- where there is risk of non-preventable, potentially life-threatening complications
- where the intervention is novel and there is very limited information on clinical safety, or
- where prior information raises concern regarding potential serious adverse events
- where professional or financial goals may be perceived to unduly influence the sponsor and/or investigators
- where interim analyses of efficacy (allowing planning for the possibility of early study termination) and safety are considered essential to ensure patients' safety
- where vulnerable populations, such as children or people with mental illness, are studied
- where there is potential for a large public health impact
- where studies are carried out in emergency settings (Ellenberg et al 2003: 153–6).
Where an independent DMC is not required, some aspects of the oversight provided by a DMC will generally still be valuable, and could be carried out by a group that is not fully independent of the study, sometimes termed an 'internal' DMC (Ellenberg et al 2003: 157–8). An internal DMC can significantly improve patient safety and trial integrity through regular meetings to review data on study conduct and relative efficacy and safety. Its membership should be multidisciplinary, and may include the principal (clinical) investigator for the study and the study statistician.
The table below gives an indication of the most appropriate form of DMC monitoring for an intervention study (Ellenberg et al 2003: 160). For advice regarding your particular trial please contact Lana Lon or the chair of the HRC DMCC.
Appropriate form of DMC monitoring (Ellenberg et al 2003: 160 Table 9.1)
|Type of setting1||Imperatives||Need for DMC|
|Ethical integrity||Credibility||Independent DMC||Internal DMC|
|Randomised trials (phases IIb, III, IV)||Yes||Yes||Yes||-|
|Randomised trials (phases I, IIa)||Yes||Likely||Maybe||Likely2|
|Randomised (any phase trial)||Unlikely||Likely||Unlikely3||Maybe2|
1 Setting 1 includes: life-threatening diseases (treatment, palliation and prevention); diseases causing irreversible serious morbidity (treatment, palliation and prevention); novel treatments for life-threatening diseases (treatment, palliation and prevention) with potential for significant adverse events; and vulnerable populations. Setting 2 includes trials not included in setting 1.
2 An internal DMC would be advised if an independent DMC is not established.
3 Integrity/credibility issues could motivate use of an independent DMC (for example, if a trial in this setting were to impose interim monitoring of comparative data).
What are the implications of this for my grant application?
For the grant application it is recommendend you provide a brief description of the planned approach to monitoring including planned interim analyses, statistical guidelines for early termination, and whether or not an independent DMC will be used. The application form asks you to indicate whether or not you plan to use an HRC DMC; this is useful for our planning purposes as well as indicating to the Clinical Trials Assessing Committee that international best practice will be followed.
It is recommended that all trials have some form of monitoring, therefore periodic production of reports will be required for most trials, and this should be allowed for in statistician and trial management time. International best practice requires periodic in-person meetings of the DMC and the Trial Steering Committee; therefore the budget should allow for travel to an annual meeting in Auckland for the principal investigator, the trial statistician and any other key personnel.
How does the HRC DMCC choose the membership for my trial?
Each Data Monitoring Committee set up by the HRC DMCC includes the members of the HRC DMCC who are free of conflict of interest for that trial. In addition principal investigators are asked to provide names of one or two researchers, independent of the trial, who can provide the necessary trial-specific expertise. Final choice of the additional DMC members is made jointly between the DMC and the trial investigators, based on review of their experience relevant to the trial and any prior DMC experience. The HRC approves appointments.
What is involved in using an HRC Data Monitoring Committee for my trial?
The DMC Charter template describes the contract between the Trial Steering Committee and the HRC DMC for the monitoring of the trial.
An initial organisational meeting is held when a near final version of the trial protocol is available, and before recruitment begins. At this meeting the protocol, statistical analysis plan, draft charter and templates for the open and closed reports (see Example of DMC closed report, Frank Harrell closed report and open report, and Coding of adverse events) are reviewed and any questions the DMC may have about these documents are discussed. Any questions about the monitoring process will also be addressed at this meeting.
Data review meetings generally take place every 6 months, with at least one of these meetings being in person in Auckland at the HRC office. Open and closed reports are prepared by the trial statistician for each meeting, using data current to within two months of the meeting, and must be received by the HRC 14 days before the DMC meeting. The data review meetings consist of two sessions: a closed session attended only by the statistician who prepared the DMC reports; and an open session where the principal investigator provides the DMC with an update on the trial and any other relevant information, and answers any questions that were raised by the reports. At the end of the meeting, the DMC formulates recommendations to the Trial Steering Committee regarding trial continuation or early termination, and also provides recommendation on aspects of trial conduct which would improve the integrity and credibility of the trial. Further details are provided in the DMC Charter template.
The following links may provide useful information for monitoring.
- SPIRIT Guidance for Protocols of Clinical Trials
- Example DMC closed report
- Example of closed report and open report from Frank Harrell at Vanderbilt University
- Coding of adverse events by body system and severity is required for aggregating and comparing event rates in intervention and control groups during monitoring. The Common Terminology Criteria for Coding Adverse Events (CTCAE) is a freely available system that can be used.
How and when do I request the HRC DMCC set up a DMC for my trial?
You can request that an HRC DMC monitor your trial ether by emailing Lana Lon or by ticking the box on the grant application form indicating you wish to use the HRC DMCC. The HRC DMCC reviews all applications for clinical trials, and will confirm whether or not they can monitor your trial after this process is complete. The HRC DMCC will always agree to provide monitoring where an independent DMC is necessary.
Search terms: DMCC, DMC, Data Monitoring Committee, DSMB, Data Monitoring Board, SDMC, Safety and Data Monitoring Committee, data monitoring, trial monitoring, safety monitoring.