Recommendations offer guidance for CMT clinical trial design
Coalition develops framework to advance treatment development
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A new set of recommendations offers guidance on how to design clinical trials for potential treatments for Charcot-Marie-Tooth disease (CMT), emphasizing a need for flexible approaches that can accommodate the disease’s many subtypes and the importance of incorporating input from the CMT community.
The recommendations were developed by a coalition of physicians, scientists, representatives from the pharmaceutical industry, and CMT-focused advocacy organizations including the Charcot-Marie-Tooth Association and the Muscular Dystrophy Association (MDA).
They were published in the Journal of the Peripheral Nervous System in a paper titled, “Clinical Development of Therapies for Charcot–Marie–Tooth Disease: Recommendations for Trial Design, Endpoints, and Regulatory Pathways.”
“For the first time, patient advocacy organizations, clinicians, and industry have aligned on a common framework for CMT clinical trials,” Brian Lin, PhD, senior director of research at the MDA, said in a press release from the group. “These recommendations provide greater clarity for sponsors developing therapies while keeping the needs and experiences of people living with CMT at the center of the process. This type of collaboration helps reduce barriers to development and brings us closer to delivering effective treatments for the CMT community.”
CMT encompasses a group of inherited disorders that cause problems with the peripheral nerves, which connect the brain and spinal cord with muscles and sensory organs throughout the body. There are no therapies that can cure CMT or address its underlying cause, so CMT treatment focuses largely on interventions such as physical and occupational therapy that help to maintain function.
Flexible trial design
Developing disease-modifying treatments for CMT has been challenging in part because of the disease’s genetic diversity. CMT has many subtypes, each caused by different genetic changes, and individual subtypes can be rare. This can make it difficult for clinical trials to recruit enough participants to reliably determine whether an experimental treatment is effective.
The new recommendations encourage trial designs that are flexible enough to address these challenges.
Because many CMT subtypes share similar disease courses, the guidance recommends that, when appropriate, trials consider enrolling people with multiple subtypes rather than focusing on a single one. This could help researchers recruit enough participants to generate meaningful results, particularly for treatments expected to work across different forms of the disease.
Alternative trial designs could reduce reliance on placebo groups, the researchers noted. For example, external-control trials allow outcomes in people receiving an experimental treatment to be compared with data from matched patients who were treated or observed in other settings. Another possible approach is a single-participant design, in which outcomes are compared before and after treatment is initiated, allowing participants to serve as their own controls.
The guidelines also support efforts, where ethically and scientifically appropriate, to enroll young people with CMT and treat them proactively, with the goal of preventing long-term damage.
Another consideration is how researchers measure the effects of an experimental treatment in clinical trials. The researchers highlighted several CMT-specific assessments of physical function and patient-reported outcomes that have already been developed and might be useful as trial endpoints. They also called for continued development of sensitive measures that accurately capture facets of disease progression meaningful to people living with CMT.
The guidelines also note a need to test for biomarkers that can provide objective insight into the underlying disease processes driving CMT. In some cases, promising biomarker data can be used to secure conditional regulatory approvals, allowing therapies to be commercially available while definitive tests of clinical efficacy are conducted.
Beyond trial design, the framework provides recommendations on safety assessment, gene therapies, and regulatory evaluation of potential CMT treatments.
Above all, the guidelines stress that CMT treatment should be designed with the community’s needs front and center.
“Regulatory flexibility, informed by patient input and natural history data, can facilitate efficient development while maintaining assurance of safety and effectiveness,” the team wrote.
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