Hybrid Controlled Clinical Trials Using Concurrent Registries in Amyotrophic Lateral Sclerosis: A Feasibility Study.

Area of Science:

• Clinical Trial Design
• Biostatistics
• Neurodegenerative Diseases

Background:

• Hybrid trial designs combine randomized arms with external controls.
• Concurrent patient registries offer high-quality data for augmenting clinical trials.
• Amyotrophic lateral sclerosis (ALS) drug development faces challenges in trial efficiency.

Purpose of the Study:

• To leverage patient-level data from concurrent registries to enhance clinical trials.
• To evaluate the impact of external controls on treatment effect estimates, precision, and trial duration.
• To illustrate the application in amyotrophic lateral sclerosis (ALS) trial design.

Main Methods:

• Utilized a well-defined, population-based registry running parallel to a randomized, placebo-controlled trial.
• Identified and matched concurrently nonparticipating, eligible registry patients with trial participants.
• Integrated external controls into the statistical analysis to assess their impact.

Main Results:

• A matched external control population was identified from nonparticipating registry patients.
• Augmenting with external controls could have reduced randomization by 12.8% (17 patients).
• Study duration could have been shortened by 25.0% (from 30.1 to 22.6 months).

Conclusions:

• Hybrid designs using concurrent registries and rigorous matching can accelerate new treatment development.
• Careful matching minimizes bias from calendar time and standard of care differences.
• This approach enhances clinical trial efficiency and reduces the need for unnecessary randomization.