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Adaptive Design

As both the complexity and cost of clinical research have expanded in recent years, the benefits of a structured and inflexible clinical trial design have diminished. Increasingly, sponsors are incorporating elements of adaptive design in clinical research, allowing researchers to analyze data mid-stream and then use that information to refine research strategy and modify trial design as necessary without compromising the scientific integrity of the trial. This approach, while more complex, can work to keep a clinical research effort on track while having a potentially positive impact on factors including cost, patient safety or trial duration.

The use of adaptive design in clinical research programs requires an enhanced focus on many critical elements including clinical monitoring, statistical analysis, regulatory compliance and investigator education and support. With extensive experience in the planning and execution of clinical trials incorporating adaptive design elements, PROMETRIKA is able to help sponsors access the benefits of this option while minimizing risk. We provide the statistical knowledge and expertise necessary to evaluate data from ongoing studies. Our evaluations provide the insights necessary to make important decisions related to stopping a study based on outstanding efficacy or futility, sample size re-estimation, and outcome-adaptive randomization. We can also coordinate services as necessary under the auspices of a DMC.

PROMETRIKA's adaptive design experience in clinical research includes:

• A Phase 3 double-blind study in patients with acute myeloid leukemia, where our planning included an opportunity to stop the study mid-stream based on a futility-analysis. Using the LAN-Simon-Halperin approach, conditional power was calculated under the assumption that treatment differences in the second half of the study would be consistent with the alternative hypothesis.
• Sample size recalculation using conditional power in a Phase 2 study of patients with type 2 diabetes.
• Sample size re-estimation in a Phase 4 study of patients with asthma.
• Blinded interim analysis for sample size re-estimation in a Phase 2 study in patients undergoing cardio-pulmonary bypass surgery. The analysis involved the use of methods that do not affect the type 1 error rate (Gould, Stat in Med, 1992).
• Interim futility analysis in a Phase 2 study of patients with peripheral T-cell lymphoma.
• Interim futility analysis for sample size in a Phase 1 imaging study.
• Significance testing based on the O'Brien-Fleming/Lan-DeMets Alpha spending function in a Phase 2 study in patients with rare malignancies. The study is designed based on an adaptive strategy with significance testing used to support early cessation based on evidence of efficacy.
• The use of a sequential testing procedure in a Phase 2 study in colorectal cancer, where non-inferiority and superiority of the test product versus the comparator were assessed in the same complex study.
• PROMETRIKA President and CEO Miganush Stepanians, PhD, is a member of a Data Safety Monitoring Board for two large adaptive design trials that involve complex study designs and interim analyses.