Research Horizons


Borrowing Historical Controls Could Accelerate Rare Disease Research

Biostatistics and Epidemiology | Top Scientific Achievement
2023 Research Discoveries In a re-analyisis of the MILES trial, researchers at Cincinnati Children’s found that using historical controls could have shortened the study by five months and still produced the same results.

Rare disease research faces challenges due to limited patient populations, making randomized controlled trials slow and costly. However, clinical trials could be accelerated through the use of historical controls alongside concurrent controls, according to researchers from Cincinnati Children’s.

The study, led by first author Nusrat Harun, PhD, and senior author Maurizio Macaluso, MD, DrPH, re-analyzed data from the MILES trial led by Francis McCormack, MD, at the University of Cincinnati, which resulted in the FDA’s approval of sirolimus for treating lymphangioleiomyomatosis (LAM). They used propensity score matching to identify comparable historical controls from a registry, allowing for more new patients to be assigned to the sirolimus arm. Statistical simulations indicated that borrowing information from historical controls would have led to the same trial conclusions with fewer concurrent controls, without compromising statistical performance.

The MILES trial needed 964 days to enroll 89 patients and conduct the final analysis. In an efficient alternative design, however, the trial would have needed 34 fewer participants and could have been completed five months sooner in part by replacing a placebo arm with matched historical controls. The comparison between active treatment (sirolimus) and control would have yielded almost identical results as observed in the actual trial, leading to the same conclusion earlier and with lower costs.

“Our findings suggest that augmenting the design of a trial by incorporating high-quality historical control data (from previous clinical trials or natural history studies) can reduce the number of new patients needed in the control arm and accelerate patient enrollment,” Macaluso says. “It requires case-by-case consideration to assure the quality and rigor of the historical data and other factors, but this innovative approach could significantly benefit the field of rare disease research and expedite the development and evaluation of new treatments for these conditions.”


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Publication Information
Original title: Dynamic use of historical controls in clinical trials for rare disease research: A re-evaluation of the MILES trial
Published in: Clinical Trials
Publish date: Mar. 17, 2023
Read the study

Research By

Nusrat Harun, PhD
Nusrat Harun, PhD
Division of Biostatistics and Epidemiology
Maurizio Macaluso, MD, DPH
Maurizio Macaluso, MD, DPH
Director, Division of Biostatistics and Epidemiology