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Data Support Placebo Group Alternatives in Rare Disease Trials

DNA puzzle

(Arek Socha, Pixabay)

8 Feb. 2023. Findings from a review of medical data and records indicate matched genetic control groups may not be needed in clinical trials testing treatments for Duchenne muscular dystrophy. Results of the review, conducted by the Collaborative Trajectory Analysis Project or cTAP, appear in the 1 Feb. 2023 issue of the journal Neurology.

cTAP seeks to streamline the conduct of clinical trials to help find effective treatments for Duchenne muscular dystrophy, but the group says its results can be extrapolated to studies of other rare diseases. Duchenne muscular dystrophy is a rare genetic disorder that causes worsening muscle weakness and degeneration, mainly in the arms, shoulders, thighs, and hips. The disease affects primarily boys from age 3 to 5, and is traced to a defective gene that does not produce a protein called dystrophin for strengthening muscle fiber and protecting muscles from injury. Life expectancy for people with Duchenne muscular dystrophy can vary, but people with the disease do not often live past their 20s or 30s.

Duchenne muscular dystrophy is not traced to a single genetic mutation, but a collection of related deletions in the dystrophin gene. Randomized clinical trials of new treatments for Duchenne muscular dystrophy need to match the precise genotype of a patient, with the exact same genetic variation pattern in the dystrophin gene, in another control-group patient receiving a placebo. Finding these precise matches in this conventional trial design is often difficult, particularly for a rare disease.

Data analyzed from 700 patients

In this review, a cTAP team led by James Signorovitch, co-founder of cTAP and managing principal at the economics consulting firm Analysis Group in Boston, analyzed six real-world and natural history databases from Europe, the U.S. and U.K. Real-world data come from patients’ health records and insurance claims, while natural history data are records tracking the course of a disease without intervention, from onset to resolution of patient death. The team analyzed data from 700 patients, representing some 1,600 years of follow-up evaluation by clinicians.

In assessing those data, the researchers looked particularly at variations in key genetic sequences of Duchenne muscular dystrophy patients. The team then matched those specific variations to changes in motor functions over one year, in scores on standard rating scales of ambulatory skills and time needed to run or walk 10 meters. The researchers find that among people with Duchenne muscular dystrophy, genetic variations account for only about two percent of change in motor functions over one year, and are better explained by other factors, such as initial motor function levels.

The authors conclude that because of the small effects of genetic variations, clinical trials for Duchenne muscular dystrophy or DMD treatments, can be designed without strict genetic matching between treatment and placebo groups. Instead, study teams can design trials that mix genetic status, allowing for smaller placebo groups, and focus more on changes in motor functions over time compared to initial baselines.

“Our findings have significant implications for drug development,” says Signorovitch in a cTAP statement. “Most importantly, clinical trials in DMD should consider patients’ initial levels of motor function at least as carefully as their genotypes.” Signorovitch adds, “Our findings also open the door to multi-genotype approaches, including mixed-genotype controls and platform trials, that can more efficiently test new therapies.”

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