Within-Trial Decisions

4. Data Safety Monitoring Boards (DSMB)

4.1. Function of Data Safety Monitoring Boards (DSMB)

Although DSMB members are selected and appointed by the sponsor, all members should be completely independent of any ties to the trial that may affect their objectivity. Possible conflicts of interest (e.g. political, market, financial influences) should be taken into account. Any compensation paid to DSMB members should be reasonable to ensure there is no conflict of interest for members. Thus, any recommendation made by the DSMB should be free from bias.

DSMB operating procedures (how it works and communicates with other study participants – data centres, sponsor, etc.) must be established and described before the start of the trial. Operating procedures should also describe how the integrity of the study with respect to preventing dissemination of unblinded study information is ensured. The size and composition of the DSMB depends on the type of trial to be executed. Members with clinical and statistical experience must alwaysbe included, and additional expertise in ethics and the specific disease area is often required. This is where community or patient representatives might be invited. Terms and conditions of appointment should be transparent and procedures should be clearly defined and well documented.

Although it seems a very logical step in protecting the participants’ or patients’ best interest, the inclusion of expert patients or other representatives of patient organisations in DSMB’s is a relatively recent development. E.g. the European Community Advisory Board (on HIV/AIDS) has been dispatching members into DSMBs regularly since 2010. Patient representatives are equal participants of DSMBs, their work is also bound by strict confidentiality, however, they will import their experience of living with the given disease from a very special aspect – that of the patient themselves.

While in general, safety monitoring is the major task for a DSMB, other aspects of a clinical trial (e.g. trial integrity, design aspects) might also be assessed.

The DSMB will convene both open and closed meetings on a frequency laid out in the operating procedures at the start of the trial; this can be time based or when the pre-determined analysis points have been met, e.g. 50% patients reaching six months treatment. Usually only a sub-set of data that is most pertinent to the question being asked of the DSMB is analysed and often still in blinded fashion, if the study is blinded. The operating procedures will contain rules that detail when the DSMB may request further data to be analysed or the blind to be broken.

A report by the sponsor to the DSMB, (along with the full safety and efficacy data) may contain an open and a closed section, containing blinded and non-confidential data, and unblinded confidential data, respectively. The operating procedures should also clearly state the parties allowed to have access to any unblinded data.

Finally, the process of how the DSMB will arrive at a recommendation, must be documented. Ideally, recommendations should be made after reaching consensus, wherever possible, otherwise by vote. A recommendation that will result in modification, suspension or termination of a trial must be clearly supported by the reasons why the DSMB reached such a decision.

The proper communication of its recommendations is a major responsibility for a DSMB. If changes in the study conduct are recommended by a DSMB, sufficient information should be provided to allow the sponsor to decide whether and how to implement these recommendations. The implementation of any DSMB recommendation is solely the responsibility of the sponsor who has no obligation to follow them (in whole or in part).

Safety monitoring is an essential and integral part of any trial; nevertheless, not all clinical studies require a DSMB. DSMBs may be critical for studies intended to save lives, prevent serious disease progression or reduce the risk of a major adverse health outcome.

EMA Guideline on data monitoring committees Doc. Ref. EMEA/CHMP/EWP/5872/03 (1) describes the process for assessing the need for a DSMB. DSMBs are particularly important in studies where interim data analysis is required to ensure the safety of research participants.

As there are currently no accepted standards on what constitutes conclusive evidence, transparency in the decision-making process is paramount. A way to achieve this would be for the DSMB, after the trial has been completed, to publicly disclose the full rationale for their recommendations (2).