The Evolution of DSMBs in Clinical Research
The Greenberg Report of 1967 (not published until 1988) recommended DSMBs for large clinical trials.2 DSMBs have since become an essential component of safety surveillance in clinical trials.3
The scope of DSMBs’ responsibilities has drastically expanded over the past 20 years. At the beginning of the “DSMB era,” these bodies exclusively focused on safety. Today, the function of DSMBs has broadened, and they must increasingly review all parts of a clinical trial, from study design and protocols before initiation to evaluation of the continuation or stopping of a trial due to efficacy, futility, or ethical considerations.
Because DSMBs oversee safety during clinical trials, they add another layer of vigilance and provide a periodic independent review during a clinical trial. Such reviews are often a condition for continuing a trial. The DSMB functions as a safeguard for any potentially unsafe reactions, side effects, or otherwise potentially life-threatening complications due to the treatment course.
DSMBs also provide crucial independent reviews of blinded and unblinded data throughout the study to protect subjects' safety. More than simply a facet of patient protection, investigators and sponsors require blinded access to data and ongoing trial results to prevent biased decisions. Having a neutral party with unblinded access is important for understanding the full scope of relevant trial data.
To answer the question of when a clinical trial requires a DSMB, one must first clarify what one expects from a DSMB. The DSMB recommendations issued after each DSMB meeting reflect such expectations, with the most common being to help determine whether to continue a study (either unmodified or with changes), halt enrollment, or even stop the study. The main task or responsibility of a DSMB is to detect the critical turning point when it may be necessary to halt enrollment or stop a study early.
There are three reasons for stopping a trial early:
1. Major safety concerns
Trials may be stopped early for safety reasons, particularly when unexpected adverse events significantly threaten patients. The ALTITUDE trial, designed to determine whether the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both, is one example.4 The sponsor prematurely stopped the study because patients treated with aliskiren had a higher occurrence of cardiovascular morbidity endpoints, resulting in an increased number of adverse events – particularly hyperkalemia with
serum potassium level ≥6 mmol/L and hypotension – than the placebo control group.
2. Lack of efficacy, even in the absence of safety issues
This is called stopping for futility and may occur when the early data suggests that a significant treatment effect is unlikely to be found, even if the study continues to its full planned sample size. The sponsor discontinued the Phase 3 Mosaico study of the human immunodeficiency virus (HIV) vaccine as the DSMB determined that the regimen was not effective in preventing HIV infection compared to placebo among study participants, even though there were no identified safety issues with the vaccine regimen.5
3. Significant clinical benefit demonstrated early in the study
The Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) study was a multi-center randomized controlled trial in patients with hypertension with at least three other cardiovascular risk factors. Patients were assigned either amlodipine, adding perindopril as needed, or atenolol, adding bendroflumethiazide and potassium as needed. The primary endpoint was non-fatal myocardial infarction (including silent myocardial infarction) and fatal congestive heart failure. After 5.5 years, the DSMB found a therapeutic advantage of amlodipine/perindopril versus atenolol/thiazide in preventing cardiovascular disease and lowering the risk of developing diabetes in patients with hypertension.6
One of the most significant challenges sponsors face when establishing and setting up Data and Safety Monitoring Boards is the lack of comprehensive guidelines for managing DSMBs. While the current Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines outline the various functions of DSMBs, they fall short in providing answers to all potential questions and challenges for sponsors.7,8 As a result, many sponsors need additional guidance on whether their new clinical trial requires a DSMB, where to start, and how to proceed after establishing one.
Another challenge with managing DSMBs is the lack of a uniform approach for data presentation and review. This results in inconsistencies, affecting the scientific integrity and safety of clinical trials conducted in the same therapeutic area.
Next up: When is a DSMB Needed?
