The primary function of the Data Monitoring Core Committee (HRC DMCC) is to ensure that HRC-funded trials that require data and safety monitoring are adequately monitored.
Criteria for trials that require data and safety monitoring:
- early trials of high-risk treatments
- trials in vulnerable populations
- trials with a potentially large public health impact
- trials where study integrity could be enhanced by the independence of the DMC
- trials with risk of potentially life-threatening or disabling complications
- the intervention is novel and there is very limited information on clinical safety
- where prior information of the trial raises concern regarding potential serious adverse events
- studies carried out in emergency settings, and
- other trials where independent monitoring is international best practice.
- Professor Thomas Lumley - chair, Department of Statistics, the University of Auckland
- Dr Philip Adamson – Christchurch Heart Institute, University of Otago, Christchurch
- Professor Tim Dare - Department of Philosophy, the University of Auckland
- Dr Ben Hudson - Department of Primary Care and Clinical Simulation, University of Otago Christchurch
- Professor Suetonia Palmer – Department of Medicine, University of Otago, Christchurch
- Dr Yalu Wen - Department of Statistics, the University of Auckland.
- Dr Conroy Wong - Department of Respiratory Medicine, Middlemore Hospital.
Committee Secretary: Lana Lon
Responsibilities of the Data Monitoring Core Committee (DMCC)
Responsibilities of the HRC DMCC include:
- If requested by the HRC's Chief Executive, independently review grant applications of clinical trials, innovative treatment evaluation or community intervention studies submitted to the HRC and make recommendations regarding issues relevant to monitoring that may include comments on trial design and organisation.
- Reviewing the monitoring plans for trials funded by the HRC and provide advice to the HRC on whether the plans meet best international practice.
- Constituting a trial-specific Data Monitoring Committee (DMC) for any trial funded by the HRC where this is appropriate and is requested/agreed by the investigators.
- Evaluating, advising, and contributing to independent or international data monitoring committees on those trials funded or co-funded by the HRC. This may be particularly appropriate where there is:
- a large New Zealand cohort, and/or
- significant contribution to funding by the HRC, and/or
- minor New Zealand representation on the DMC, and/or
- inexperience in monitoring data and safety in the proposed data monitoring committee.
- Contributing to the current field of knowledge in monitoring and protocol review by:
- apprenticeship and mentoring of DMCC members with appropriate expertise but without monitoring experience, and
- providing information and education regarding protocol development, current data and safety monitoring processes, and good clinical practice.
For investigators submitting a proposal for funding for a clinical trial
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 being monitored. Membership is therefore limited to those individuals free of any significant conflict of interest in relation to the study, 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 healthcare 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/or 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 has been completed. This confidentiality protects the trial from inappropriate early termination, which can be caused by premature judgement based on potentially misleading early results.
Guidance on 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.
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, such as 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)
What are the implications of this for my grant application?
For the grant application, it is recommended you provide a brief description of the planned approach to monitoring including planned interim analyses, statistical guidelines for early termination, and whether an independent DMC will be used.
It is recommended that all trials have some form of monitoring, therefore periodic production of reports will be required for most trials. As such, statistician and trial management time should be allowed for in the budget.
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?
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 (see templates for two different statistical analysis plans (SAPs): template 1 and template 2), and draft charter and templates for the open and closed reports (see Frank Harrell’s example of a closed report and open report) 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 six months. 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 DMCC at least 14 days before the 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 recommendations on aspects of trial conduct that would improve the integrity and credibility of the trial.
How and when do I request the HRC DMCC set up a DMC for my trial?
The HRC DMCC reviews all applications for clinical trials, and will confirm whether or not they can monitor your trial after this process has been completed. You can also request that the HRC DMCC monitors your trial by emailing Lana Lon, the secretary of DMCC. The HRC DMCC will then consider if they can provide monitoring.