Clinical research studies may require one or more different oversight committees to ensure that the study is able to answer the question, that the data is accurate and that the study is safe.

All clinical trials need some form of safety oversight and safety monitoring, but the type of committees and extent of the oversight will depend on the risk and complexity of the study. Straightforward and safe studies should not put all committees in place if they are not required, because this would add unnecessarily to the cost and administration of the study.

The committees discussed in this document, and the following steps in this process map, are:

• Study (or Trial) Steering Committee

• Protocol Review Committees (PRC)

• Data Monitoring Committees (DMC)

• End Point adjudication Committees

Steering Committees
Steering Committees are often set up in large multicentre clinical trials by the sponsor, and comprise clinical experts who take responsibility for the scientific integrity of the research by reviewing the scientific validity of the study protocol, and assessing the study quality. It is also the role of the steering committee to monitor the progress of the study and to maximise the chances of completing the study within the agreed time scale and allocated budget.
The steering committee can sometimes take on the role of the Protocol Review committee, as their role can be all encompassing.

Protocol Review Committee
In most institutions, clinical research study protocols will need to be approved by an independent panel of experts; typically set up by the sponsor, a clinical site, a research organisation or academic institution.

The PRC is charged with responsibility of reviewing the scientific rationale, study design, adequacy of statistical input, prioritization in terms of scientific merit and patient availability. The PRC usually has the final authority regarding protocol review and approval, prior to regulatory and ethics committee submissions.
The frequency of reviews and the type of protocol to be reviewed should be specified in the organisation’s SOPs but typically should involve all protocols - especially those involving vulnerable subjects such as children, the elderly, or critically ill subjects, as well as significant amendments to the protocol such as those that affect the safety, efficacy or risk benefit ratio of the study. Administrative amendments to the protocols do not affect the outcome of the study or the safety of patients and are often exempt from PRC review.

Data Monitoring Committee (DMC)/Data Safety and Monitoring Board (DSMB)
The terms DSMB and DMC are synonymous and can be used interchangeably to describe an independent group of experts external to a study that reviews accumulating data from an ongoing clinical trial; primarily to ensure the safety of subjects enrolled to the trial.

The DSMB may be involved in the review of the initial protocol to assess that it will capture the information necessary to evaluate the safety and efficacy of the study and to provide recommendations that may improve the conduct of the study.
To define the role of the DSMB, the DSMB charter/plan will need to be in place. The plan is prepared by the sponsor and reviewed by DSMB members and should include: the DSMB's composition, operating procedures, frequency of meetings based on anticipated recruitment, and identified safety concerns. Along with monitoring Serious Adverse Events (SAEs), the DSMB may request to review events which may not necessarily be serious but of special interest to the sponsor or/and members of the committee - such as perceived risk of the drug or the incidence of certain risks already identified.

The DMC has the capacity to make recommendations that might impact the future conduct of the research, such as “continue”, “amend” or “terminate” a study based on the data reviewed. However, it is ultimately the sponsor’s responsibility to make the final decision.

In studies where a DSMB is not needed, which is typically when the interventions are known to be very safe or the trial is very short, then other forms of safety monitoring are appropriate and recommended.

Appointing a local safety monitor is a good alternative and often put in place in addition to a DSMB. The Local Safety Monitor is a clinician experienced in the field of study. They are independent from the trial and their role is to review any adverse events and give an independent review of the causal relationship to the trial intervention.

Roles of the DSMB:
- Monitoring the safety of subjects as pre-specified in the DSMB plan by accessing data to perform a risk/benefit assessment in order to weigh possible disadvantages against a possible gain in efficacy. Though the main part of the DSMB’s role can be performed with blinded data, it is important that the DSMB is allowed access to unblinded data if necessary for safety – but without unblinding the study team.

- Review the efficacy of the treatments being tested and independently make recommendations to researchers e.g., terminate a clinical trial because the analyses indicate the study is having a negative effect, the intervention is not adequately implemented or there is no evidence of a treatment effect after the prescribed level of power is reached.

- Check for the presence of early unanticipated therapeutic results, side effects or adverse consequences and independently make recommendations to the sponsor e.g., terminate a clinical trial because it would be unethical to continue the non-treatment/ treatment as usual arm.

- Review the performance of the trial e.g., protocol violations, improper entry criteria, slow accrual rate, low participation rate, inadequate treatment adherence, inadequate follow-up rate, and to independently make recommendations for improvement or termination if the trial would be unable to prove anything meaningful, regardless of modifications. Early withdrawals or protocol adherence may indicate of possible problems with efficacy or safety.

Not all studies will need a DMC. To decide if a study needs a DMC or not, the study endpoint(s), duration and the study population should be taken into. Also, where there is insufficient data about the intervention or where the sponsor intends to use the intervention for a new indication, it may be prudent to set up a DMC.
A DMC has to be fully functional prior to study enrolment to enable them respond to any safety signal.

Establishing a DMC
There are three major aspects to establishing membership of the DMC - The composition, qualifications and independence of the DMC. As the work of the DMC is multidisciplinary in nature, a DMC needs expertise from different scientific areas to arrive at their decision. Clearly there is a need for qualified clinicians to assess the clinical aspects of safety and/or efficacy monitoring but, as often statistical methods will be applied in the monitoring process, biostatistical expertise should also form part of a DMC, as well as an ethicist. For practical reasons, members of a DMC should be limited and ideally should be an uneven number.

DMC members should not only have scientific expertise relevant to the indication being studied, but they should also have practical experience in conducting clinical trials and a good understanding of the problems and limitations of conducting clinical research.

The DMC should ideally be completely independent from the study sponsor, but this is not always possible as DMC members can sometimes be appointed by the sponsor or by the principal investigator (for investigator-led studies), and can be paid an honorarium, meaning that total independence is not possible. However, conflicts of interest should be taken into account when appointing DMC members. Potential candidates for DMC membership should have no financial interest in the outcome of the study. Also, planned authorship of DMC members in publications on study results might impact the independence of the DMC. Additionally, problems could arise where a potential DMC member serves in parallel on the DMC of a clinical trial in the same indication area but with a different sponsor, so this constitutes another conflict of interest that should be avoided.

Whilst there is usually a single DSMB per study, there is a growing request for DSMB members to share experiences for similar studies being conducted concurrently, such as in meta analysis studies. This would need to be agreed up front by the sponsors and members of the DMC. The remit of what can be shared should also be discussed and documented where applicable in the DSMB charter. Studies have shown that efficient protection of study participants in trials requires that data monitoring committees have access to all relevant research, including unpublished and interim data, and it is also scientifically and ethically desirable to have this information to hand for DMC members to make an informed decision. However, this may only be practical in collaborative studies or within institutions where there is already an agreement to share data.
You can read more about DSMBs in the next step [link to step].

For the DSMB charter and regulatory requirements guidelines for DSMBs please see the article in resources in this step.

Endpoint Adjudication Committees
Endpoint adjudication committees are set up in complex clinical studies, where components of the end points are subjective or where a study cannot be blinded. As with the DMC committee, members should consist of clinical experts in a specific clinical area and are charged with centrally reviewing and classifying suspected efficacy and/or safety endpoints in a blinded and unbiased manner. Their roles can also include providing standardised endpoint outcomes for statistical analysis.

In order to allow for an unbiased endpoint assessment, members of the committee should be blinded to treatment assignment regardless of whether or not the study is blinded. Endpoint Adjudication Committees are, for example, widely used in the assessment of radiological endpoints, incidence of infection or disease; disease severity and progression; cardiovascular events; and determination of cause of death.

Methods of adjudication
Adjudication is usually performed by using the locally reported outcome as a surrogate for a subject’s endpoint status. By using data reported by the investigator, data analyses can be performed promptly but there is a risk of the DMC making a decision about the future of the trial on the basis of unadjudicated data. Further, if the results of the data barely meet study stopping criteria, the DMC may be hesitant to recommend halting the study. Another option is to use the available adjudicated data for data analyses while adjusting for any unadjudicated data, using predictive values and weighting unadjudicated events as true events. These statistical methods of adjudication rely on assumptions about future endpoint adjudications that cannot be verified until after all data have been adjudicated.

In studies involving a large number of investigative sites with considerable degree of variability, it can be difficult to determine the end point of a clinical trial study. While both methods provide some sort of adjudication, there have been disparities between locally reported and centrally adjudicated end points documented in studies.

Regulatory agencies are increasingly expecting, and in some cases requiring, centralised adjudication to assess clinical endpoints to control the impact of this variability and to produce data for use in statistical analyses that are as standardised as possible. Centralised adjudication process can be applied to both efficacy and safety endpoints. In efficacy studies, conducted for instance for cardiovascular drugs, the objective is to evaluate whether there is compelling statistical evidence that fewer events occur in the test drug treatment group than in the control group, i.e., prove that the test drug is effective. Conversely, in safety studies, the objective is to evaluate whether the number of events occurring in the test drug treatment group is statistically significantly lower than in the control group. In both cases, the validity and integrity of the study’s results and interpretation are enhanced by the acquisition of optimal quality endpoint data which has been centrally adjudicated.

Endpoint adjudication can now be done via the web, and there are several advantages to performing adjudication through this method. Since the system is automated and utilizes electronic data capture, the EAC process can occur throughout the course of the study. The reviews are immediately incorporated into the database and are readily available for use in data analyses. The automated nature of this system also reduces errors that can be introduced while organizing EAC materials, assigning cases and tracking reviews.

Additionally, similar to electronic data capture (EDC) systems for capturing clinical data; the system has built-in edit checks and dynamic control logic to reduce errors introduced during the data entry process, all of which lead to higher quality EAC review data. These features work together to allow the analyses of data and DMC reviews use data that are both current and adjudicated. The Web-based adjudication process also allows for monitoring of EAC performance as the web based reports can be used to ensure that members complete all assigned reviews promptly. It also tracks trends to determine if any of the EAC members are consistently interpreting cases differently from other members. Since all data related to the reviews are captured in the database in real time, up-to-date reports can be created to manage the endpoint adjudication. Obviously the efficiency of the web-based adjudication process is predicated on the fact that data review takes place on an ongoing basis and is therefore limited by inefficient data collection and verification processes. Also in circumstances where additional source documentation is required, obtaining this information in a timely manner can be challenging.

Conclusion
Not all of these committees will be necessary for all studies and the number or types of committees to be formed is dependent on the sponsor, phase of the study, the complexity of the study and whether or not vulnerable subjects are to be enrolled. Some committees have overlapping roles and it may be sufficient to have committees that are pertinent to the study requirements.

References

- Meyskens l Frank “Clinical Trials Oversight Plan” University of California - A National cancer Institute-designated comprehensive cancer centre 2012
http://www.cancer.uci.edu/clinical_trials.asp

- “Draft Guidelines for establishing and operating a data and safety monitoring board” National Institute on Drug abuse. 2002
http://www.drugabuse.gov/funding/clinical-research/draft-guidelines-establishing-operating-data-safety-monitoring-board

- Committee for Medicinal Products for Human Use (CHMP) “Guideline on data monitoring committees” 2005
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003635.pdf

- Chalmers I, Altman D G, Mchaffie H, Owens N and Cooke R W “Data Sharing among data Monitoring Committees and responsibilities to patients and science” Trials 2013 14 (102)
http://www.trialsjournal.com/content/14/1/102

- Medical Research Council “Trial Steering Committee
http://www.eme.ac.uk/investigators/pdfs/TSCGuidelines.pdf

- Nolen T.L, Dimmick B.F, Ostrosky-Zeichner L, Kendrick A.S, Sable C, Ngaii A and wallace D “A Web-based endpoint adjudication system for interim analysis in Clinical Trials” Clinical Trials 2009 6 (1) 60-66
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000902/

- Turner R.J, Somaratne R, Cabell C.H, Tyner C.A. “Centralised Endpoint Adjudication in cardiovascular outcomes studies” Journals for clinical studies 3 (2) 46-49
http://www.quintiles.com/library/experts/centralized-endpoint-adjudication-cardiovascular-outcome-studies#pdf