A number of committees are involved in the conduct and oversight of a clinical trial. These committees are set-up in consultation with the sponsor, and are responsible for:
- The overall conduct of the trial (Trial Management Group, also referred to as project management group)
- Day-to-day management of the trial at a site (Site Trial Management Team)
- Independent evaluation of unblinded data to ensure that the trial is safe to continue (Data Safety Monitoring Board)
- Independent oversight of the trial (Trial Steering Committee)
- Independent assessment of clinical events that might be the trial endpoints or outcome (Endpoint Review Committee).
Trial Management Group (TMG)
The Trial Management Group is responsible for the overall conduct of the trial. This group essentially comprises of those who are responsible for the day-to-day management of the trial and includes the Coordinating-Principal Investigator (PI), Site PI, the trial statistician, trial/project manager, data manager and other applicable personnel. In academic trials, it often includes the site PIs.
The main responsibilities of this group are to ensure that the trial is conducted in accordance to the trial documents that have been approved for example, Protocol, Trial Management Plan, Quality Management Plan, Risk Management Plan, Monitoring Plan, Data Management Plan. The safety of participants is protected throughout the trial and complete, reliable and accurate data is generated. They need to oversee effective resource allocation and ensure that the trial is conducted as per agreed timelines and budget.
It is recommended that a charter is developed for the Trial Management Group, detailing the specific roles and responsibilities of each member, composition of the group, schedule of the meetings etc.
Site Trial Management Team (STMT)
The Site Trial Management Team (STMT) is the operational group that is responsible for day-to-day management of the trial at a site. This group generally comprises of the Site PI, Co- I, clinical research/site coordinator, study nurse, technicians, data entry operators and others as applicable. It is the responsibility of the STMT to ensure that that activities are conducted at the site in accordance to the approved trial documents. The site PI is required to ensure effective resource allocation.
Data Safety Monitoring Board (DSMB)
The National Ethical Guidelines for Biomedical and Health Research involving Human Participants, 2017 specify that Institutes or agencies involved in the conduct of clinical trials have policies and established mechanisms to ensure data quality and safety of the intervention. This includes adequate provisions for monitoring and auditing the conduct of a clinical trial and constitution of a Data Safety Monitoring Board (DSMB) as part of the requirement.
Data Safety Monitoring Board (DSMB), also known as the Independent Data Monitoring Committee (IDMC), is key to patient safety. It comprises of a panel of independent experts who review and evaluate the safety data and critical efficacy endpoints at various intervals in the trial. The members of the DSMB review the data according to the randomised groups, to ensure that there is no evidence to suggest harm or benefit to the participants, such that the trial should be stopped.
The DSMB considers the differences between randomised groups in primary endpoint(s). They also take into account factors such as: multiple testing issues or chance variation, biological plausibility of differences, differences in other secondary endpoints, and whether these differences would change clinical practice if the trial was to be stopped.
The DSMB then makes recommendations to the Trial Steering Committee (if it has been set up) or directly to the sponsor whether to continue or modify or stop the trial. The DSMB may also raise concerns regarding the management of the trial (example, SAE reporting), that could have an impact on the comparison of randomised groups.
The DSMB should be formed before the trial commences. It should have a Charter and Terms of Reference, so that the roles and responsibilities of the members, scope and format and schedule of meetings are clearly defined. The members should review and agree to the terms specified in the Charter. A critical aspect of the charter is confidentiality. Members should be aware that maintaining the confidentiality of trial participants, is of paramount importance. In order to ensure this, DSMB members are required to sign Non-Disclosure or Confidentiality Agreements, prior to their participation in any meeting.
In addition to above, the voting procedure, events that might cause an unscheduled meeting, documents and processes under its purview should be clearly specified in the Charter and agreed upon by the members. This document is a suggestive template for the development of a DSMB Charter.
It is also recommended that the Sponsor and DSMB agree on how the data will be presented for the DSMB review. For instance, the data might be coded for some trials, while for others the DSMB may need information that includes unblinding of treatment allocation.
The members of the DSMB should be experts in specific areas related to the trial, so that they have the knowledge and experience required to interpret the data. Examples include:
- Clinical expert(s): for the diseases or population under study
- Biostatistician(s) (independent of the trial)
- Investigators with relevant experience and expertise: to evaluate the conduct and methodology
- Ad-Hoc specialists: they may be invited to be a part of the deliberations if required i.e. permanent members of the DSMB may invite subject experts on ad-hoc basis.
- Bioethicists (if required)
- The trial statistician (or biostatistician) who prepares the statistical report for the DSMB are also invited to be a part of the meetings.
It is imperative that the Sponsor ensures that none of the members of the DSMB are directly involved in the conduct of the trial to ensure there is no conflict of interest. Moreover, membership to the board should not be influenced/result in a financial or personal or professional gain. The Sponsor must ensure that there are no conflicts of interest.
Once the DSMB members have been selected, all relevant information and documents, pertaining to the trial must be sent to the DSMB. It is also essential that all subsequent revisions and amendments are sent to the DSMB. All documents, reports, or any other material discussed and/or circulated for these meetings are highly restricted and confidential.
The DSMB reports should be made available to the Ethics Committee(s) that has provided an approval for the trial.
Trial Steering Committee (TSC)
The Trial Steering Committee (TSC) is the executive committee that provides overall supervision of the clinical trial and advises on its scientific credibility. TSC ensures that the main objectives of the trial are not compromised, and that the trial participants are protected at all times. It considers the recommendations of the independent Data Safety Monitoring Board (DSMB) and makes appropriate decisions. For example, changes in the trial design or protocol, abstracts, manuscripts, and approval of any sub-studies. It is ultimately responsible for deciding whether a trial needs to be stopped on grounds of safety or efficacy and provides recommendations to the funding agency and/or Sponsor of the trial.
The TSC must include, independent members who are independent of the investigators, their employing organisations, funders and sponsors and members who are a part of the trial (the PI, trial statistician and other representatives of the Trial Management Group). Independent experts usually include a biostatistician, senior investigator with experience in trials methodology and a clinician or disease specific expert. The TSC should be constituted while the trial is being set-up, prior to initiation of the trial sites and start of recruitment.
A TSC charter or terms of reference document, detailing proposed composition of the TSC, the roles and responsibilities of the individual members, details of the meeting schedule, voting procedures should be made available.
The committee ensures that the trial is conducted in compliance with the applicable regulations, Good Clinical Practices guidelines and is quality driven. Some of the roles of the TSC include monitoring of:
- Progress of the trial
- Adherence to the protocol, and applicable regulations
- Safety of the trial participants
- Recruitment rates across sites
- Follow-up rates
- Publication of trial results
Documents that should be submitted for review by the TSC include trial protocol, statistical analysis plan, protocol amendments, agreements for data sharing, risk assessment and management plans, plans for publication of trial results. To facilitate oversight, trial progress reports should be submitted in a timely manner to the TSC.
Endpoint Review Committee (ERC)
The sponsor of a clinical trial may opt to establish an Endpoint Review Committee (ERC), also known as Endpoint Assessment or Adjudication Committee. An ERC reviews important endpoints that are reported by the investigators, to determine whether these endpoints meet the criteria specified in the protocol. Ideally, the members of the ERC should be masked to the study arm, while performing this review. The ERC reviews all reported events, which might potentially be key clinical endpoints; and decide which endpoints are to be included in randomised comparison. The information reviewed by the ERC on each potential endpoint may include laboratory data, autopsy reports, pathology data, imaging results, and any other data that may be considered relevant to the endpoint.
It is important to know that the ERC does not share DSMBs responsibility. However, ERCs review helps ensure that the data provided to DSMB is free of bias and as accurate as possible. Typically, an ERC has 3 to 4 members, comprising of an independent chair, project lead of each site or the coordinating (main) site (or a member of the trial management group), and other independent members who are experts in the therapeutic area.
In addition to reviewing data specific to the endpoints of the trial, the ERC might also assess participant data. For example, serious adverse events, unexpected adverse drug reactions, etc.
ERCs are recommended when:
- There is extreme variability in outcomes across the sites
- Endpoints are complex
- Higher rates of enrolment or longer duration are expected for a trial
- Study cannot be blinded (open trials) in open label clinical trials, the investigators may be more or less likely to report events in an arm. This may be due to their prior beliefs about the efficacy, and also the allocated arm the participant is in. This might lead to under or over reporting of an event in a trial, leading to false results.
The Trial Management Group usually drafts a scope of work or terms of reference for the ERC which is reviewed and endorsed by the Trial Steering Committee. This document must specify the schedule and frequency of the ERC meetings, and data that will be provided to the ERC for review.
References and further reading:
- Good Clinical Practices for Clinical Research in India, Central Drugs Standard Control Organization, 2001, available online (last accessed on 26.02.2019).
- National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, Indian Council of Medical Research, 2017, available online (last accessed on 26.02.2019).
- International Council for Harmonization, Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), 2016, available online (last accessed on 26.02.2019).
- Guidance for Clinical Trial Sponsors, Establishment and Operation of Clinical Trial Data Monitoring Committees, U.S. Department of Health and Human Services, FDA, 2006, available online (last accessed on 26.02.2019).
- Harman et al., 2015, Exploring the role and function of trial steering committees: results of an expert panel meeting, BMC (link to access the article) (last accessed on 26.02.2019).
- Green, L.A., et al., Experience with a cross-study endpoint review committee for AIDS clinical trial. Terry Beirn Community Programs for Clinical Research on AIDS, AIDS, 1998, 12(15), page 1983 – 90.