Thursday, March 31, 2022

Safety Assessment Committee (SAC), Data Monitoring Committee (DMC), Steering Committee (SC), Clinical Event Committee (CEC)

In clinical trials, there are usually different committees established to ensure the study protocol is executable, to ensure the integrity of the study, to monitor the safety of the clinical trial participants. The most common one is the Data Monitoring Committee (DMC) - previously called Data Safety Monitoring Board (DSMB), which is critical for conducting the interim analysis for safety or for efficacy (whether the interim results are too good (overwhelming efficacy) or futility (unlikely to achieve the statistical significance if the trial continues)). In FDA's Guidance for Clinical Trial Sponsors "Establishment and Operation of Clinical Trial Data MonitoringCommittees", DMC was defined as the following: 

A clinical trial DMC is a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials. The DMC advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial. When a single DMC is responsible for monitoring multiple trials, the considerations for establishment and operation of the DMC are generally similar to those for a DMC monitoring a single trial, but the logistics may be more complex. For example, multiple conflict of interest determinations may be needed for each DMC member.

In this same guidance, two other clinical trial committees were mentioned to be compared with the DMC: Steering Committee (SC) and Endpoint Adjudication Committee (EAC). EAC may be called Clinical Endpoint Committee (CEC). 

Clinical Trial Steering Committees In some clinical trials the sponsor may choose to appoint a steering committee; this committee may include investigators, other experts not otherwise involved in the trial, and, usually, representatives of the sponsor. A sponsor may delegate to a steering committee the primary responsibility for designing the study, maintaining the quality of Contains Nonbinding Recommendations 7 study conduct, ongoing monitoring of individual toxicities and adverse events, and, in many cases, writing study publications. When there is a steering committee, the sponsor may elect to have the DMC communicate with this committee rather than directly with the sponsor. Interactions between the steering committee and the DMC consist primarily of discussions during "open sessions" (see Section 4.3) of DMC meetings and the communication of recommendations following each DMC review of the trial. More extensive interactions might occur when early termination is being considered, or when external forces (e.g., announcement of results of related studies) impact the ongoing trial.

Endpoint Assessment/Adjudication Committees Sponsors may also choose to establish an endpoint assessment/adjudication committee (these may also be known as clinical events committees) in certain trials to review important endpoints reported by trial investigators to determine whether the endpoints meet protocol-specified criteria. Information reviewed on each presumptive endpoint may include laboratory, pathology and/or imaging data, autopsy reports, physical descriptions, and any other data deemed relevant. These committees are typically masked to the assigned study arm when performing their assessments regardless of whether the trial itself is conducted in a blinded manner. Such committees are particularly valuable when endpoints are subjective and/or require the application of a complex definition, and when the intervention is not delivered in a blinded fashion. Although such committees do not share responsibility with DMCs for evaluating interim comparisons, their assessments (if performed at frequent intervals throughout the trial with results incorporated into the database in a timely manner) help to ensure that the data reviewed by DMCs are as accurate and free of bias as possible.

In FDA guidance for Industry "Safety Assessment for IND Safety ReportingGuidance for Industry", a separate committee, Safety Assessment Committee or SAC, in short, was proposed. The SAC was defined as 

"... a group of individuals chosen by the sponsor to review safety information in a development program and tasked with making a recommendation to the sponsor regarding whether the safety information must be reported in an IND safety report"

In a separate Guidance for Industry, "Sponsor Responsibilities— Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies", the term 'Safety Assessment Committee" was not used, but the responsibility of a 'safety assessment team' was discussed. 

All of these committees can be established to ensure patient safety and study integrity. The responsibilities across these committees are sometimes overlapped. The table below is created to compare these committees side by side:

 

Data Monitoring Committee (DMC)

Steering Committee (SC)

Clinical Event Committee (CEC)

Safety Assessment Committee (SAC)

Alternative names

Data Safety Monitoring Board (DSMB)

Data Safety Monitoring Committee (DSMC)

 

Event Assessment Committee (EAC)

Event Adjudication Committee (EAC)

 

Responsibilities

Monitoring for effectiveness, safety, study conduct; Executing the adaptation rules for adaptive designs; making recommendations for study modification, pause, termination

Designing the study, maintaining the quality of study conduct, ongoing monitoring of individual toxicities and adverse events, and, Helping the sponsor to execute the study (for example enrollment); Writing study publications.

Reviewing important endpoints reported by trial investigators to determine whether the endpoints meet protocol-specified criteria

Reviewing safety information in a development program; Performing aggregate safety analyses; and making recommendations regarding whether the safety information must be reported in an IND safety report

Participating in study design and protocol development

May provide the comments on the protocols

Yes

May provide inputs related to the clinical events to be adjudicated

Limited to the safety reporting section of the study protocol

External

Usually external

External

External

Usually internal within the sponsor

Independent

Usually independent

Usually not    independent

Independent

Independent of the study team

Review aggregate data

Safety and maybe also Efficacy

Secondary review

Usually not

Safety data only

Blinding

Unblinded to the treatment assignments. DMC can review fully unblinded data

Blinded

Usually blinded

Blinded

Participating in clinical trial result reporting/publication

Usually not

Yes

Usually not

Usually not

Documents

DMC Charter

DMC Statistical Analysis Plan

SC Charter is optional

CEC Charter, Operational Manual, May employ a computer system to facilitate the adjudication

Safety Surveillance Plan

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