Coalition Takes Guesswork Out Of Charcot-Marie-Tooth Disease Research With New Guidance

A conversation between CMT Research Foundation Chief Mission Officer Susan Ruediger and Clinical Leader Executive Editor Abby Proch

Drug developers for Charcot-Marie-Tooth disease used to have a trial design problem. Patient heterogeneity, limited patient population, patient willingness to participate, and variable endpoints have long led to wavering confidence in researchers who were trying to design trials that regulators would accept and patients would agree to.

Now, thanks to the work of the CMT Research Foundation and its partners, there’s a much clearer path to trial execution and, hopefully, success.

In this Q&A, CMTRF Founder and Chief Mission Officer Susan Ruediger explains how a coalition of patient advocates, clinicians, and industry partners came together to develop a CMT trial design framework, first with regulatory input, then on their own. She also shares what this patient-led effort may offer other rare disease communities seeking to clarify the path from promising science to practical, regulator-ready trials.

Clinical Leader: How did the need for the CMT framework arise? What was the catalyzing moment?

Susan Ruediger: At the 2023 Global CMT Research Convention, Dr. Shannon Strom, who is both a patient and an expert who works in regulatory affairs, approached me to discuss a clear gap that wasn’t mentioned in the meeting: regulatory guidance about how to design clinical trials for CMT.

Without published guidance specific to CMT, companies are responsible for proposing designs to the FDA. Designing a clinical trial that enrolls the optimal participants, operates in an acceptable timeframe, and measures meaningful endpoints — all in a disease not well understood by the FDA — leaves a lot to chance.

A company can invest significant work to design a trial well only to see it rejected in a single regulatory meeting. For drug developers, an indication becomes daunting when the clinical path isn't clear, as it leaves open questions: Will key opinion leaders and regulators support this trial? Will patients participate?

I imagine the framework contains information that is already widely accepted, while some might be new. What points within the guidance stand out to you as being new and/or critical?  

Because CMT is a heterogeneous disease, it can be thought of as a class of a disease rather than one disease itself. But there are common disease mechanisms that cause the symptoms of CMT, like the loss of the neuromuscular junction or the deterioration of the axon. We encourage the regulators to assess non-genetic therapies for CMT using common therapeutic pathways instead of dividing the disease into segments by the genetic cause, giving more options to more patients, even those with ultra-rare genetic mutations.  

CMT is a length-dependent progressive disease.  Some people experience nerve deterioration early in life; others see their first symptoms as adults. In all people with CMT, the nerves continue to deteriorate unless it is disrupted. Therefore, the earlier the intervention, the better. This framework encourages the regulators to consider pediatric trials and intervention with the hope of preventing children from ever experiencing the kind of disability that many adults today live with.

Who led the charge, what stakeholders supported the effort, and what insights did they lend?

I, along with Dr. Strom, contacted key clinicians, specifically neurologists with CMT expertise, to assess their interest. We invited other patient advocacy groups working in CMT to join the endeavor. We also invited industry partners from Big Pharma and biotech, which to our knowledge is the first time industry partners were included in these discussions. In all, Dr. Strom and I coordinated more than 30 experts from the three sectors in a coalition we named ToPIC: CMT (Together Patients, Industry and Clinicians) to draft guidance for designing clinical trials.

The working group included former FDA employees to help frame the language in line with FDA expectations, clinicians who have been designing ways to measure CMT progression, and drug developers who have worked with the FDA to understand the regulatory challenges of CMT trials. Most importantly, patient advocacy representatives led the development of each section of the guidance to keep the patient voice at the center.

How were patient and caregiver perspectives incorporated, and did any recommendations change because of their input?

Patients and their families ensured the guidance included the huge variety of CMT symptoms that patients experience. Patients and caregivers also shared which risks were worth taking and which were too great to bear for potential improvement. Patients as well as drug developers want regulators to talk with them before they dismiss a program for its safety profile. We do not have any approved treatments, and the impact of living with a progressing debilitating disease is profound — maybe in immeasurable ways.  So, patients also want a voice in the decision.

In addition, patients and families pushed for streamlined trial approaches that make the best use of limited patient populations to get treatments approved across the widest set of CMT subtypes possible.

What do you hope this framework will resolve? What are the biggest takeaways?

The published paper in the Journal of the Peripheral Nervous System provides a consensus from the clinical, pharmaceutical, and patient communities about considerations when designing a clinical trial for CMT, removing much of the guesswork and reducing wasted resources. It aims to prevent the development of drugs and trials that won't be approved by regulators, conducted by clinicians, or joined by patients because of design. The hope is that the guidance gives companies with investigational therapies for CMT a clearer clinical path they can commit to.

How do you expect regulators to respond, and what evidence would help build confidence in nontraditional trial designs for CMT?

The committee initially engaged the FDA about the guidance document, but the 2025 reduction in force across the Department of Health and Human Services left the FDA unable to participate in the guidance development any longer. So, the committee pivoted to publishing the recommendations in a journal to still make this important regulatory framework publicly available.

If given another chance, what feedback would you like to request from the FDA?

Ultimately, it’s the regulators who approve trials and therapeutics. ToPIC can only make recommendations. We would like to hear the FDA’s perspective to ensure our guidance will help sponsors design trials that are acceptable and avoid potential delays or denials that waste significant time and money — two resources the CMT community doesn’t have. If not for this framework, what would be the fate of this type of research?

Without this guidance, drug developers face an uncertain and risky path in CMT. Without published clinical trial guidance, companies remain responsible for proposing their own trial designs to the FDA, with no clear sense of what regulators, KOLs, or patients will accept. That uncertainty might discourage some developers from pursuing CMT as an indication at all.

What concepts developed here might translate to other disease areas or inspire other researchers?

The CMT community was inspired by the patient communities for Duchenne muscular dystrophy and ALS, who previously wrote similar drafts of guidance documents. They submitted these drafts to the FDA to be reviewed, edited, and eventually published, enabling more companies to understand clinical trial designs for these diseases. With this published CMT guidance, we hope to inspire others who work in advocacy for rare diseases to fill this gap for their diseases. If not you, then who? If not now, then when?

Editor’s note: This transcript has been edited for clarity.

About The Expert:

Susan Ruediger has CMT1A that she can trace back five generations in her mother’s family. Since 2007, she has been deeply engaged with the patient and research communities, building connections to fund efficient and effective research leading toward drug delivery. From CMTRF's launch in 2018, she was the Foundation’s CEO. In January 2022, she became the organization’s first chief mission officer while continuing to serve on the board of directors, helping support CMTRF’s rapid financial growth and serving as the primary spokesperson for the Foundation.