When to Stop a Clinical Trial Early for Benefit: Lessons Learned and Future Approaches
- clinical trial
- clinical trials data monitoring committees
- data interpretation
- statistical stopping rules for benefit
Early stopping of a clinical trial for evidence of benefit has been widely debated in the medical literature.1–13 This practice has important implications from many viewpoints: clinicians who practice evidence-based medicine; future patients to whom the results of research studies apply; patients who voluntarily agree to participate in clinical trials; and scientists, investigators, and regulators who strive to balance conducting scientifically rigorous studies with disseminating data that support therapeutic advances as quickly as is reasonable.
During the 7th Global Cardiovascular Clinical Trialists Forum held in Paris, France, in December 2010, cardiovascular clinical trialists, biostatisticians, National Institutes of Health scientists, regulators, and pharmaceutical industry scientists met to discuss current issues related to cardiovascular clinical trials, including the topic of stopping a clinical trial early for benefit. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) is a recent trial that was stopped early for benefit14 and was used as a stimulus for discussion. This report summarizes the results of the group's discussion on the scientific, statistical, and practical issues regarding the topic of stopping a clinical trial early for benefit.
The EMPHASIS-HF Experience
EMPHASIS-HF was a randomized, double-blind, clinical trial of eplerenone compared with placebo, in addition to maximally tolerated doses of an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and β-blocker (unless contraindicated) in patients with mild (New York Heart Association class II) heart failure symptoms and left ventricular ejection fraction ≤30% (≤35% was allowed for patients with QRS duration >130 ms).14 The primary end point was death from cardiovascular causes or hospitalization for heart failure. This trial was of particular clinical relevance because it was the first trial of a mineralocorticoid receptor antagonist in heart failure patients with mild symptoms.
EMPHASIS-HF was monitored by an independent data monitoring committee (DMC) with 2 prespecified interim …