Exploring Barriers to Clinical Trial Readiness Among the Myotonic Dystrophy Community: A Mixed-Methods Study

Exploring Barriers to Clinical Trial Readiness Among the Myotonic Dystrophy Community: A Mixed-Methods Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exploring Barriers to Clinical Trial Readiness Among the Myotonic Dystrophy Community: A Mixed-Methods Study Julia Stellmann Wrenn, Ali Ryan-Mosley, Jonah Watt, Erin Hellthaler, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8961613/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Myotonic dystrophy (DM) is a multisystemic disorder characterized by significant heterogeneity in symptom manifestation, progression, and severity. This variability complicates clinical trial design and implementation, thereby affecting therapeutic development. This study aimed to identify barriers to clinical trial readiness in DM and explore actionable solutions by incorporating perspectives from pharmaceutical partners, clinical trial site staff, people living with DM (PLDM), and caregivers. Focus groups, surveys, and interviews were conducted with pharmaceutical partners (n = 65), PLDM and caregivers (n = 35), principal investigators (n = 12), and clinical research coordinators (n = 12). Qualitative findings were thematically analyzed and triangulated with survey data to enhance validity. Three major barriers consistently emerged: (1) a lack of comprehensive, validated endpoints that capture outcomes meaningful to patients; (2) insufficient data sharing and coordination across industry; and (3) challenges in trial design, recruitment, and participant burden. PLDM emphasized under-studied but debilitating symptoms—such as dysphagia, fatigue, and cognitive impairment—that are rarely prioritized in clinical trials. Pharmaceutical partners cited regulatory uncertainty surrounding composite outcome measures as well as the value of quantitative myotonia indicators as informative holistic disease indicators. Limited access to natural history data, often prohibitively costly for smaller companies, reinforces competitive rather than collaborative dynamics. PLDM and caregivers also highlighted substantial financial, logistical, and accessibility challenges associated with trial participation. Participants favored several strategies to address these barriers: (1) convening a multi-stakeholder scientific session with the U.S. Food and Drug Administration (FDA) and establishing a working group to define and standardize patient-centered, clinically relevant endpoints; (2) developing a comprehensive, coordinated registry that integrates existing data sources, longitudinal health and study data, genetic diagnostic data, supports recruitment and refinement of study inclusion criteria, and enables post-market surveillance; (3) strengthening trial site preparedness and anticipating recruitment needs, including biomarker-driven cohorts; and (4) adopting patient-centered trial designs that minimize burden, with patient advocacy groups (PAGs) serving a central convening and advocacy role by bringing various groups together to discuss these topics. While barriers to DM clinical trial readiness are significant, they are addressable. Coordinated action among industry, regulators, clinicians, and advocacy groups—guided by patient priorities—will be essential. Implementing these strategies could accelerate therapeutic development, improve trial inclusivity, and ultimately enhance quality of life for individuals living with DM. Myotonic Dystrophy clinical trial barriers mixed-methods patient advocacy groups registry rare disease Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Myotonic dystrophy (DM) is a rare, autosomal-dominant, multisystemic, and progressive disease affecting up to 1 in 2,100 people [ 1 ]. It is the most common form of muscular dystrophy in adults, and given its wide spectrum of severity, symptoms, and age of onset, is considered one of the most variable diseases in medicine [[ 2 ], [ 3 ], [ 4 ], [ 5 ]]. Disease manifestations include myotonia, muscle weakness, fatigue, excessive daytime sleepiness, apathy, and cognitive difficulties. DM also frequently causes cardiac, gastrointestinal, vision, and endocrine complications [ 5 ]. As a repeat expansion disorder, DM demonstrates genetic anticipation, with disease severity worsening across successive generations [[ 6 ], [ 7 ]]. DM occurs in two distinct genetic forms: (1) Myotonic dystrophy type 1 or DM1, caused by a repeat expansion in the DMPK gene. DM1 is the more common type and can affect individuals of all ages. Subtypes include congenital DM (CDM), where symptoms present at birth and are linked to longer repeat lengths, and childhood/juvenile-onset DM, typically presenting before age 18 [ 8 ]. (2) Myotonic Dystrophy Type 2 or DM2 is caused by a repeat expansion in the CNBP gene, and it generally presents in adulthood [[ 5 ], [ 9 ], [ 10 ], [ 11 ]]. The variability and multisystemic nature of DM present major challenges. For patients and caregivers, symptoms generate physical, cognitive, emotional, and logistical burdens [ 12 ]. Many caregivers are themselves affected, further complicating care dynamics. For clinicians, variability hinders timely recognition and diagnosis of the disease, and for those planning, designing and running clinical trials, it complicates guidance on meaningful selection of clinical trial endpoints. For the industry, it creates obstacles in trial design, patient stratification, and endpoint selection. For regulatory agencies, matching clinical trial endpoints with true and meaningful patient impact is a logical concern. Currently, no disease-modifying therapies exist, and treatment remains limited to symptom management. Nonetheless, drug development efforts are progressing, indicated by a robust and expanding development pipeline, with more than 12 therapies in preclinical stages and over 10 in clinical trials [ 13 ]. Still, substantial barriers remain. Ensuring clinical trial readiness or the community overall being best prepared to conduct, engage, and succeed with clinical trials operations and outcomes requires coordinated action to address challenges faced by industry sponsors, trial sites, clinicians, patients, and families, while also anticipating barriers to treatment access once therapies become available. Patient advocacy groups (PAGs) are central to this process. PAGs often serve as the first point of contact for disease-specific information and are recognized advocates for rare disease drug development. Yet DM’s rarity and variability complicate progress in drug development and clinical trials. Key challenges include small patient populations, insufficient natural history data, evolving regulatory frameworks, and difficulty defining consistent endpoints and biomarkers [[ 14 ], [ 15 ]]. Prior research has shown how muscular dystrophy PAGs have mitigated these hurdles. Huml et al. (2020) identified five effective strategies: establishing national registries, reducing barriers to patient participation, partnering with biopharmaceutical companies, collaborating with regulators on disease-specific guidance, and integrating market access considerations early in development. Humel et al. also emphasized the importance of direct patient engagement to identify needs, evaluate registries, and strengthen collaboration across stakeholders. To accelerate progress toward effective therapies, continuous information exchange among patients, caregivers, clinicians, regulators, and industry is critical. People living with DM, as the true experts of their condition, must play a central role in shaping trial design and research priorities [[ 16 ], [ 17 ]]. This study builds on previous work by systematically assessing barriers to clinical trial readiness. The first phase captured challenges reported by industry partners, patients, and caregivers. These findings then informed further assessments with clinical and non-clinical trial site leaders. Together, results highlighted both organizational and systemic gaps, underscoring the need for targeted solutions and coordinated, ecosystem-wide action. 2. Methods To understand the gaps, barriers, and needs of myotonic dystrophy (DM) community members and industry partners as they relate to clinical trial readiness, the following thematic questions were explored: 1. What are the current challenges and barriers to clinical trial readiness among industry partners, patients, the DM community, and the clinical trial sites? 2. What potential solutions to the challenges and barriers exist? a. How do potential solutions align or not within and across these groups? b. Which potential solutions are acceptable to the three groups? We employed a mixed-methods approach by gathering, analyzing, and reporting findings that included both qualitative and quantitative data. The qualitative data informed the quantitative survey method. Each form of data collection included a consent process outlining confidentiality, data privacy, and potential harms of participation. This study was determined to be exempt by the Advarra Institutional Review Board (IRB) as Pro00081721. 2.1 Qualitative Data Collection We directly engaged 75 individuals through interviews and focus groups, contacted through the Myotonic Dystrophy Foundation’s extensive network. This process included: • 11 focus groups with different pharmaceutical companies (40 participants); • 11 individual interviews with people living with DM (PLDM); • 4 caregiver focus groups (24 participants). Written and verbal consent were obtained for PLDM and caregivers, while verbal consent only was obtained for pharmaceutical partners due to privacy concerns. The pharmaceutical companies involved in this research all have active drug development programs for DM, but they are in various stages, including discovery, preclinical, and clinical trial phases. PLDM and caregivers also represented people at various stages of disease and with a range of symptoms and experiences with prior interventional and/or natural history trials. 2.2 Quantitative Data Collection In the second phase, we distributed two confidential surveys, one to pharmaceutical industry partners and another to representatives at current and potential interventional and/or natural history study sites. For simplicity, these sites are collectively referred to as Clinical Trial Sites, although they might not be currently running interventional drug trials. Written consent was included in the survey prior to any questions. The Pharmaceutical Partners Questionnaire was distributed to each focus group participant, and 27 complete responses were received. Because participants were able to share the survey with other colleagues outside of the focus group and the survey was not required, we cannot calculate the response rate because we do not know the total distribution volume. Participants were not asked to report their names or the names of their companies. The Clinical Trial & Study Site Survey consisted of two versions, one tailored to the clinical trial principal investigators (PIs) and another tailored to trial site research coordinators. Participants were invited to participate in the survey via email based on their role at current DM clinical trial sites and DM clinics, which may be selected as future clinical trial sites. All known sites were included in the sampling pool. The Clinical Trial Site Survey received 24 complete responses, including 12 from clinical research coordinators at the clinical trial sites and 12 from principal investigators (PIs) who are running DM studies and trials. This represents response rates of 16% and 41%, respectively. These responses represent many different sites, though not all unique. 2.3 Qualitative Analysis The data was analyzed in phases, as insights from certain data informed the design of other parts of the study. During the preliminary analysis process, we conducted a rapid qualitative data analysis process that elevated the key themes and findings across interviews and focus groups. Once key themes were identified, the preliminary findings were used to conduct an in-depth analysis, coding each transcript using a mix of deductive and inductive codes. This process was conducted in NVivo (Lumivero, Denver, CO), a qualitative coding software. From this, a qualitative coding matrix was created to explore patterns within and among key themes and various participant groups. These findings, in addition to analysis of the Pharmaceutical Partners Questionnaire, guided and informed the design of the Clinical Trial Site Survey. 2.4 Quantitative Analysis The survey was distributed through Qualtrics (Qualtrics, Provo, UT), a survey distribution software. To analyze the quantitative survey data, both Qualtrics and Excel’s descriptive statistics tools were used. The key themes and patterns from the qualitative data were triangulated with data from the two surveys. Data from the surveys was given more depth and nuance by pairing it with individual perspectives from the focus groups and interviews. Additional context and information were provided. The mixed-methods process is outlined in Figure 1. 3. Results Tables 1–3 summarize participant characteristics. The study engaged four primary groups: pharmaceutical partners, people living with DM (PLDM), caregivers, and clinical trial site principal investigators (PIs) and research coordinators. Table 1: Number of Participants in Interviews and Focus Groups by Type of DM Conversations with Patient and Caregiver Community Type of DM Participants Form of Involvement DM1 DM1 Adults 17 Caregiver focus group (n=7) Interviews with PLDM (n=10) Juvenile-onset DM 8 Caregiver focus group (n=8) Congenital DM 4 Caregiver focus group (n=4) DM2 6 Caregiver focus groups (n=5) Interview with PLDM (n=1) Table 2: Breakdown of Engagements with Pharmaceutical Partners Engagement with Pharmaceutical Partners Method Participants Form of Involvement Focus group 40 11 focus groups with 11 different companies Pharmaceutical Partners Questionnaire 25 25 questionnaire responses from focus group participants Table 3: Clinical Trial Site Survey Participants by Role Clinical Trial Site Survey Participants Survey Type Number of Responses Clinical Trial Site Research Coordinator Survey 12 Clinical Trial Site Principal Investigator Survey 12 From these data, three major categories of barriers to trial readiness emerged: 1. Lack of Comprehensive and Meaningful Endpoints a. Current Endpoints Do Not Reflect the Multi-system Nature of the Disease b. Importance of Patient Input for Endpoints c. Need for Further Research on Endpoints 2. Industry Need for Data Sharing and Coordination a. Importance and Cost of Natural History Study Data b. Competition Instead of Collaboration c. Potential Solution of a Centralized Registry 3. Challenges with Trial Design and Participation a. Prioritization of Known Participants in Recruitment while avoiding selection bias b. Issues with Finding and Enrolling in Trials c. Trial Accessibility and Burden of Participation Each theme is examined in detail below, with triangulation from the Clinical Trial Site Survey and Pharmaceutical Partners Questionnaire. Figure 2 maps and summarizes barriers along the trajectory of interventional trial design and execution. 3.1 Lack of Comprehensive and Meaningful Endpoints 3.1.1 Current Endpoints Do Not Reflect the Multi-system Nature of the Disease Across groups, participants emphasized the absence of standardized, validated, and patient-centered trial endpoints. DM’s hallmark symptom is myotonia, but the disorder affects multiple organ systems and varies widely, even within families. In most cases, PLDM and caregivers described years-long diagnostic delays due to heterogeneous symptoms and limited clinical awareness. PIs and pharmaceutical partners acknowledged the challenge of controlling for disease variability in trial design, underscoring the need for endpoints that capture DM’s multisystemic presentation. Most pharmaceutical partners reported incorporating Video Hand Opening Time (vHOT) in their designs, but noted high variability in both vHOT and other outcome measures. Several cited disagreements with regulators, particularly the FDA, regarding acceptable endpoints and what constitutes and defines meaningful change for patients. “I don't think we're so interested in producing a statistically significant improvement in the relaxation in the muscle on the index finger on one hand, and saying we've got a successful drug. We're trying to find methodologies to assess the whole of the phenotype, and we invested a massive amount to try and develop an outcome measure that didn't work, to do that.” - Pharmaceutical Partner “We've had long debates with the [regulatory agency] about composite outcome measures that allow you to have a measure of brain function, a measure of muscle function and then collapse them into one measure, and the [regulatory agency] won't agree to that. So it's difficult when you've got a population where almost any organ system of the body can be compromised, but isn't necessarily compromised in any one patient, how do you come up with an outcome measure?” - Pharmaceutical Partner Participants noted that these regulatory uncertainties make it difficult to identify which outcomes are meaningful, what endpoints might demonstrate improvement across DM’s diverse spectrum of symptoms, and whether an identified trial endpoint is truly a proxy for patients’ experiences and ultimately an indicator of meaningful change or improvement. This uncertainty reflects the fundamental issue of how to define “meaningful change” in clinical trial settings that also translates into real improvements in patients’ quality of life. Not surprisingly, this issue also transcends and manifests in the lack of regulatory clarity. 3.1.2 Importance of Patient Input for Endpoints PLDM and caregivers valued vHOT but stressed the need for broader endpoints, including measures of GI function, cardiac function, cognitive decline, daytime sleepiness, and apathy. These symptoms profoundly affect daily life but are rarely assessed beyond questionnaires. Concerns extended to other muscles, such as cardiac and pharyngeal. “There's no biomarkers for speech or for swallowing. Swallowing is a big deal. I’ve choked four times. I needed the Heimlich three times, the fourth I did to myself.” - PLDM “You know, there are muscle treatments, studies are going on, but the key is going to be getting a brain treatment. The executive function loss of kids needs to be reversed. Too many of them are robbed of their futures and their dreams because they just don't have the executive functions.” - PLDM Participants criticized patient-reported surveys as inconsistent, yet noted their regulatory endorsement. “The [regulatory agency] has pointed us to certain patient reported outcomes, like the DM1-Activ. And then when you take that to adult onset patients, they hate it, and it's a standard … You can see that the [regulatory agency] has been giving the same advice to all of the pharma companies in the space. And it's now a running joke of the ‘soup questionnaire,’ because the first question is, can you eat soup?” - Pharmaceutical Partner 3.1.3 Need for Further Research on Endpoints Less than half of pharmaceutical partners (45%) felt moderately ready to assess non-muscular endpoints; 20% reported being not very ready. Thirty-five percent judged the broader field as not very or not at all ready, with cost and regulatory hurdles cited as key barriers. Survey data corroborated and confirmed these concerns: 90% of PIs agreed that more research is needed on endpoints, and 90% supported a structured forum to advance consensus. “So this is where there is still a lot of discussion and also no agreement between the community and the [regulatory agency]…. We were quite convinced with our study design … yet we've confronted some, I don't want to call it criticism, but further clarifications needed for what is clinically meaningful for these patients. If myotonia gets improved … What does it mean in terms of the disease progression? What does it mean in terms of patients’ perception of improved quality of life, and how should we measure it? So, there is a battery of validated tools as of today, and yet we hear different opinions of acceptance by the regulators, by [regulatory agency] … there is no consensus on that. So it makes it really difficult to talk about the study designs that would kind of accommodate all these different needs.” - Pharmaceutical Partner 3.2 Industry Need for Data Sharing and Coordination Natural history data, patient experience data, as well as–when available–genetic diagnostic data are considered foundational for the drug development process. In DM, the identification of comprehensive and meaningful endpoints is still limited and hindered by the fact that DM natural history and clinical trial data are not yet freely accessible. In general, participants identified the siloed and competitive culture among trial sponsors and research organizations as a deterrent to data sharing, trial design, and collaboration, and criticized the lack of a central, free database containing natural history data, disease progression data, and genetic information. 3.2.1 Importance and Cost of Natural History Study Data Participants identified siloed data and a lack of coordination as barriers. Natural history data, while critical, is largely restricted to a “pay-to-play” model. The Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1(END-DM1) study by the DMCRN is the most comprehensive resource, but sponsorship is costly. While the END-DM1 study has been enabled and its expansion funded by early entrants in the DM drug development space, these early funders receive regular “data-cuts” serving as reference points for general disease progression, prior to clearly outlined publication plans and milestones of the entire study. This arrangement acts as a perceived major barrier for smaller pharmaceutical companies with limited budgets who are trying to enter the space. “… I've never worked [on a disease] where you've had to pay. … I've worked in places where you have to pay, but it's just to cover costs, it's not to make money … I think other advocacy groups for rare diseases, they also charge based on the company's size and revenue. There's another way of doing it. And I think the DMCRN actually do not bother if you're like a top 10 pharma or a small, tiny biotech, they charge you the same flat rate, which is kind of really, really uneven playing ground here.” - Pharmaceutical Partner Participants criticized the lack of public dissemination despite FDA and advocacy group funding for the study. Many acknowledged willingness to share data but cited competitive barriers. Suggestions included advocacy groups convening sponsors to coordinate. Industry representatives pointed to opportunities for sharing placebo or failed trial data, noting success in ALS. Yet most stressed the need for collective agreements to reduce individual risk. “[Placebo data] is of great use to patient groups who are setting up a database establishing a natural history where you have such a frequent collection of data in a very systemic fashion … I would not want to give [data] to a patient group upfront unless I am pushed. And I'm not only me. If other sponsors are pushed too, I would say, ‘well, I'm happy to do it, would [company name] do it? Would [company name] do it, would [company name] do it? Would [company name] do it?’ And MDF tells them ‘look guys we want to set this consortium. This will be an anonymized data set but will support your … efforts if you commit to submission of this data.’” - Pharmaceutical Partner Some large pharma partners expressed less concern, viewing DM as relatively advanced in terms of available data. “I think myotonic dystrophy is actually ahead, and that through the DMCRN, most companies do have access to that data. Do we pay for it? Of course we pay for it. But most of us do have access to a good chunk of reasonably well-collected natural history data.” - Pharmaceutical Partner 3.2.2 Competition Instead of Collaboration Despite shared concerns, many companies reported siloed approaches. The lack of a standardized assay for DMPK gene repeat lengths was particularly noted, with larger firms developing in-house tools without wider dissemination. “This is a disease caused by the presence of CUG repeat RNA, right? There is no assay for CUG repeat RNA, so … there is no way of measuring whether you're treating the disease. That's like trying to do HIV research without a way of measuring HIV virus or anti-infective research, without a way of measuring whether you can remove infections. And we're having to build our own assay. And when I've asked all of the academics that we speak to, why is there no assay, I get no good answer.” - Pharmaceutical Partner Pharmaceutical partners and PIs also expressed growing interest in genetic modifiers and CTG repeat length, though few current trials incorporate them. Eighty percent of PIs judged repeat composition and modifier loci as likely to influence disease severity. While promising, this could complicate recruitment if the infrastructure for genetic stratification is lacking. 3.2.3 Potential Solution of a Centralized Registry When asked about registries, participants generally supported the idea of a centralized natural history registry, either through the coordination of existing registries or the development of a new resource. No such registry currently exists for DM, although there are several registries currently operating. Desired data include demographics, natural history data, natural history study data (e.g. END-DM1), comprehensive and inclusive clinical data from the patient’s electronic health record (EHR), genetic testing data, all clinical visit data, reference to available biospecimens, and consent for trial eligibility testing. “… Collecting [data on symptoms] and then constantly kind of looking in [the registry] and saying like, ‘what are the key symptoms’ so that you could eventually go to a physician and say ‘you see people with diarrhea, you see people with exhaustion, you see people with hand cramping. But if you see all three of those things together … you should thank DM1.’” - Pharmaceutical Partner Registries were also viewed as tools for patient education and awareness. “Not every patient out there knows everything about their disease … so having the resources available to them is fantastic because that allows them to understand more about themselves, more about the opportunities that are open to them and their family. And that is where I think a patient registry becomes very helpful. So it's not necessarily a recruitment tool … [but] the patients become more educated as well because they have outreach from other patient advocacy groups.” - Pharmaceutical Partner Sixty percent of PIs (6 out of 10 participants) judged a comprehensive registry as helpful for trial planning, though fewer currently use registries for recruitment. This is likely due to the fact that most centers draw on their own pools of patients for study recruitment. Some participants cautioned against duplicative registries, stressing consolidation and core data sharing. “There already are other registries that are bigger, and what I don't like to see … is all these little registries, and I think it's better to have one central registry …. I don’t like rival registries. … It’s almost better if a lot of these organizations came together and just decided, ‘okay, well, we're going to have one registry. We're going to share core data.’ And then, yes, each [registry] will have the flexibility … [to] add other things depending on what they think they need. But it would be nice to have one core registry, or at least not the 100 that we have.” - Pharmaceutical Partner Others expressed skepticism about the feasibility, citing reluctance to share and potential sensitivities around global access. Still, PLDM and caregivers were generally eager to contribute, though some raised concerns about privacy and insurance. 3.3 Challenges with Trial Design and Participation For PLDM and caregivers, a major barrier to clinical trial readiness in the DM community is the actual design of trials and their ability to participate. Despite a willingness to volunteer for clinical trials, many participants discussed how the process of screening and being selected for trials requires much more than offering to be part of the study. 3.3.1 Prioritization of Known Participants in Recruitment Recruitment was perceived by PLDM and caregivers as heavily dependent on clinic affiliation. Many felt proximity to selected sites increased access, prompting some to travel interstate for care. Survey data confirmed that recruitment is largely through prior clinic or study connections rather than patient-initiated contact, with almost all PIs and research coordinators (90%, n=10, of PIs and 89%, n=9, of research coordinators) indicating that the participants are known from the clinic. Furthermore, the majority responded that potential interventional trial participants are known from being registered in a “registry” (50% of PIs and 56% of research coordinators) or from a natural history study (50% of PIs and 44% of research coordinators, Table 4). The term registry here also implies “study record structures”. Patient-initiated contact in the clinical trial enrollment process played only a very minor role, cited by only 10% (n=10) of responding PIs and less than a quarter of responding research coordinators (22%, n=9). Table 4: PI and Research Coordinator Responses by Answer Choice. This data originates from the Clinical Trial & Study Site Survey. Answer Choice (Participants Could Select Multiple Options) PIs (n=10) Coordinators (n=9) Participant is known from clinic 90% 88.9% Participant is registered in a registry 50% 55.6% Participant is known from other natural history study 50% 44.4% Participant is known from END-DM1 natural history study 40% 33.3% Participant initiated contact 10% 22.2% Other (please describe) 10% 11.1% None 0% 0.0% 3.3.2 Issues with Finding and Enrolling in Trials Participants frequently noted difficulty identifying trial opportunities. PLDM described reliance on clinicaltrials.gov, which they found challenging to navigate. Consistent with a lack of interventional trials for juvenile and pediatric-onset disease forms as well as DM2, caregivers emphasized limited opportunities for DM2 and adults with juvenile-onset DM. Many PLDM reported educating their own physicians about DM, raising concerns about clinicians' capacity to inform patients of trial options. "It's not a disease that … I would say a lot of doctors are familiar with. And so there's a lot of misinformation or just no information. Like my dad, when he first was diagnosed, his doctor was like ‘oh well, you're like his repeats are low, so you're not really going to have any other symptoms.’ And then he had to have an emergency pacemaker placed in. And he would have died. … I'm very confident in the team of doctors I have, but I also have a wealth of medical knowledge to fall back on, whereas I think a lot of people don't. And so, you know … You try to trust your doctor, but if your doctor isn't putting in any effort to understand your disease then … They’re not really doing their job." - PLDM Both PLDM and caregivers requested more proactive dissemination of trial opportunities from advocacy groups. “I think just helping to … make us more aware of what's out there, at least until we get to a point where maybe we're stable enough that we can take the time to do that. I don't know if and when that'll happen. But it would be nice to know, to be alerted of those types of things. And if there's something that we're interested in, we can research it more. But, you know, something that's just say, ‘hey, you know, this is what's out there.’” - Caregiver Participants also highlighted frustrations with trial pacing and regulatory delays. Pharmaceutical partners expressed interest in discussing accelerated approval pathways with regulatory agencies, like the FDA. “So from a regulatory policy standpoint, I think the [regulatory agency] has been very open to defining and discussing, I guess, accelerated approval pathways for other neuromuscular disorders. So I think it's important to have a discussion with them around, what is the path to accelerated approval for myotonic dystrophy and that it should be a priority for them, you know? And how do we get to a place where the [regulatory agency] is having a discussion with companies right in terms of, are they willing to think about this as a regulatory pathway for myotonic dystrophy drugs?” - Pharmaceutical Partner Exclusion criteria were another major concern. PLDM reported being excluded for DM-related comorbidities, age, or concomitant medications, which they perceived as contradictory. While such perception indicates a lack of understanding of the trial process per se, it also highlights education opportunities. “When they're looking for individuals with certain symptoms, finding the individuals within DM that don't have other symptoms that are very characteristic of the disease. That's very hard. So it really limits that pool of individuals that they have to draw from." - PLDM “Some of [the trials] you have to be off your meds. And if I didn't take my Ritalin and my Nuvigil this morning, I wouldn't be sitting up here talking to you. I'd be a dish rag. I was in one [study] where I had to be off them for I think it was two weeks. And I was still working full time. And it was hard. I had a lot of caffeine to get me through the day … So a lot of people have to be off certain meds they can't really function without. So that's a big issue I have.” - PLDM PLDM participants also expressed disappointment with the screening process for trial participation. Disappointed when finding out they are excluded, PLDM felt the inclusion/exclusion criteria were at times conservative, and the screening process unclear and burdensome. "So far, I haven't [participated in a trial]. I did screen for one clinical trial. But … I didn't fit the criteria because one of my blood works was off. So I did spend a whole day at [site] screening for the [company] clinical trial. It's a phase three clinical trial. I would have loved to take part, but I didn't qualify.” - PLDM 3.3.3 Trial Accessibility and Burden of Participation For clinical trial sites, staffing emerged as the top barrier (Table 5). Table 5: Top 1-3 challenges in getting clinical trials for myotonic dystrophy up and running, according to PIs and Research Coordinators. This data originates from the Clinical Trial & Study Site Survey. Answer Option PIs (n=10) Coordinators (n=9) Staffing (number of staff) 70.0% 44.4% Extensiveness of the assessment protocols 30.0% 33.3% Navigating regulations/requirements 30.0% 44.4% Finances 30.0% 11.1% Other (please describe) 30.0% 11.1% Competing with other neuromuscular disease clinical trials 20.0% 22.2% Communication with sponsors 10.0% 11.1% Equipment (e.g., purchasing, set up, function) 10.0% 0.0% Participant retention 10.0% 0.0% Participant enrollment 10.0% 0.0% Participant recruitment 10.0% 11.1% Staffing (staff expertise) 10.0% 11.1% Participant education 0.0% 0.0% Belief in the success of the intervention 0.0% 0.0% Unsure 0.0% 33.3% Interestingly and in contrast, 50% (5 of 10 respondents) of PIs also indicated that their site was prepared to start three or more trials in the next year, and 40% (4 of 10 respondents) indicated that they were prepared for 1-2 trials to start in the next year. With surveying sites that were and were not currently conducting interventional trials, staffing shortages point towards a potential bottleneck in trial execution, especially at a time when we expect more trials for DM to begin. PLDM participants highlighted perceived variable site readiness. “What we've learned from all this is all centers aren't created equal. Some have great infrastructure. Some have great admin, some have great coordinators. And others are missing that piece or that center doesn't have the support of their own faculty to cheer you on and say, okay, let's go.” -Caregiver The logistical burden of remembering appointments and appointment details is high and particularly challenging for PLDM who experience brain fog, anosognosia, apathy, and fatigue. Clinical trial site research coordinators flagged this issue, some even naming it as the greatest challenge for participants in an interventional trial. Site research coordinators unanimously (100%, n=9) indicated that they currently send multiple follow-ups and reminders about appointments. The symptoms of DM uniquely require this type of extra attention and follow-up for retention, even though PLDM are willing to participate in trials. However, caregivers and PLDM alike noted that most of the logistical burden still falls on the caregiver, who might be taking care of multiple family members with DM and some of whom might also have DM. PLDM and caregivers frequently described burdens of travel, site accessibility, and cognitive/financial stress. “One of the things that gets talked about in our group a lot is just the actual physical hands-on challenges of flying. Getting on and off of a plane, the amount of equipment that it takes just to go to a hotel for a night because you have to have a certain level of surface to get off of for the bed, for the toilet, for all those things.” - Caregiver The travel burden is high for many clinical trials, which might require multiple days of travel for relatively simple and quick but frequently occurring procedures, like a blood sample collection. “We're currently traveling … to be in a study. And it is really tiring when you go for a five-minute blood draw. And then you go home. You know, because [closer study site] wasn't up and running yet. And it just was months and months and months of waiting.” - Caregiver Financial barriers include upfront costs and delayed reimbursement, as well as reimbursements in less usable formats, like a prepaid debit card. “DM1 is associated with difficulty keeping a job. There's a lot of poverty there. So if you're on your own, it would be impossible to participate. Really, if you barely have enough money for food and rent, you can't necessarily pay for something and wait a month to get it back. If you're even going to get it back because maybe the systems are just too complicated to follow … And you can't pay rent with a charge card … So there's probably a lot of people who just can't do it.” - PLDM Caregivers described the compounded burden of supporting multiple affected relatives. The logistical burden of being in a study also emerged as a barrier to participation. Frequently, the time commitment to participate is not limited to the person participating but extends to caregivers or even whole families, as they may have to travel together. Some caregivers also discussed the burden placed on them due to the cognitive impairment of the people they care for. “The obstacle to getting any of [my family members] into clinical trials is that I would be the one doing it because they don't have the executive function to follow through and be looking to think to themselves, ‘oh, let me initiate this task, oh, let me maintain this task. Oh, let me finish this task.’ None of those skills exist for any of them. And so I would be the one doing it and I'm the one doing everything.” - Caregiver “And in my case, my wife is dealing with all of it, and the follow-up and everything. If I was single I would not be able to handle it. …Because of the fatigue you get from DM1 and then you get a lot of cognitive issues, brain fog, inability to focus for long periods of time.” - PLDM Despite the concerns from the perspective of patients and caregivers, few pharmaceutical partners or PIs see participant recruitment as a current barrier to clinical trial success, with most indicating that study recruitment is going really well. According to the Clinical Trial Site Survey, 80% (n=10) of PIs agree or strongly agree with the statement, “patient recruitment for upcoming clinical drug trials is not a concern–we have enough participants that meet eligibility criteria,” and the other two responded neutrally. However, when asked about future levels of recruitment, multiple pharmaceutical partners expressed concerns, particularly considering the number of upcoming trials. “We have lots of interest and lots of potential patients, so I think we're feeling as of now, generally pretty good about [patient recruitment]. That may, of course, change as more studies start in the area. But right now, finding participants has not been the problem. We will see as more and more studies get up and going, particularly larger ones.” - Pharmaceutical Partner 4. Discussion 4.1 Barriers and Potential Solutions This study identified three major barriers to clinical trial readiness in DM, reported consistently by pharmaceutical partners, people living with DM (PLDM), caregivers, and clinical trial site staff: Lack of comprehensive and meaningful endpoints; Insufficient data sharing and coordination across the industry; and Challenges in trial design, recruitment, and site and participant burden. Figure 3 provides a visual summary of the primary concerns identified by each participant group. Although all groups discussed every barrier, the figure highlights only the most frequent concerns. Primary concerns were determined based on data richness, frequency with which participants raised them, and the level of consensus across groups. [Figure 3 ] These findings align with prior landscape assessment research by the Myotonic Dystrophy Foundation (MDF) [ 18 ] and build on it by incorporating PLDM and caregiver perspectives. Our findings also echo other research exploring the role of patient advocacy groups for rare disease research [ 15 ]. The study also highlights potential solutions to address these barriers and move the DM community closer to effective treatments. Figure 4 illustrates these solutions. [Figure 4 ] 4.2 Exploring Solutions 4.2.1 A Process To Investigate, Explore, and Establish Endpoints; Hosting a Scientific Session Developing treatments is impossible without standardized, validated endpoints that reflect outcomes meaningful to patients. Current measures like vHOT capture hand myotonia but fail to represent the full DM experience. To establish a broader spectrum of informative endpoints that capture the patient experience within the relatively short duration of interventional studies, stakeholders emphasized the need for a scientific session with the FDA and a dedicated working group to establish multiple clinically relevant, patient-centered endpoints. Action steps include: Hosting a multi-stakeholder session with the FDA (i.e., patients, caregivers, pharma, researchers). Expanding research into outcomes meaningful to patients (e.g., GI, cognition, fatigue). Exploring accelerated approval pathways. Promoting industry collaboration and open data sharing. A strong alliance across all stakeholders, including regulatory agencies, would create continuous processes to find consensus, integrate advances in knowledge, and support targeted efforts to overcome delays. Most importantly, such concerted efforts could also positively influence reimbursement decisions for DM at large or for defined subgroups. PAGs, as trusted conveners, can ensure patient perspectives remain central in convening such forums and defining endpoints. A central barrier remains the lack of knowledge and consensus regarding how to assess, measure and prioritize the full spectrum of DM manifestations. PLDM and caregivers stressed that outcomes most relevant to daily functioning—such as swallowing safety, fatigue, and executive function—are rarely prioritized. Pharmaceutical partners also reported persistent uncertainty regarding regulatory acceptance of limited (e.g. myotonia specific) but quantifiable endpoints and their generalizability capturing or reflecting broad disease impact and improvement thereof. As one partner noted, We invested a massive amount to try and develop an outcome measure that didn’t work, and we are still struggling with how to demonstrate what matters to patients in a way that regulators will accept. Endpoint development must be dynamic, not static. Iterative processes that incorporate emerging evidence, patient-reported outcomes, biomarker discovery, and lessons from ongoing trials are needed. Standing multi-stakeholder groups with regulators, advocacy organizations, and experts would enable continuous refinement of endpoints in real time. Such dynamic processes are essential to move beyond reliance on limited measures like vHOT and toward tools that reflect the heterogeneity of DM. They would also facilitate the adoption of innovative digital endpoints, wearable technologies, and advanced imaging modalities. Expanding knowledge in a structured but flexible manner would accelerate consensus and improve regulatory acceptance, while aligning trial outcomes with what PLDM and caregivers identify as meaningful improvements in quality of life. 4.2.2 Create a Comprehensive, Coordinated Registry Clinical trial progress is slowed by fragmented data and limited sharing. Competition among companies has created barriers to collaboration, and access to natural history data is particularly challenging for smaller firms. A comprehensive data sharing platform would go beyond registry concepts and definitions. A comprehensive data sharing platform would include data from contact registries, natural history studies, completed clinical trials data, comprehensive clinical records, clinical trial data, patient reported outcomes and genetic testing data. Such longitudinal data structures would: Consolidate and represent data from existing registries and standardize practices globally. Support trial design, recruitment, and patient notification. Enable pre-screening for inclusion/exclusion criteria, reducing patient burden. Directly and indirectly capture meaningful patient impact. Allow sharing of placebo arm data to reduce participant exposure. Inform and guide the clinical care community. Such platforms could support the definition of inclusion criteria, enable more efficient trial designs, support post-market surveillance, and lay the foundation for newborn screening. PAGs can play a central role in fostering collaboration, establishing best practices, and advocating for scalable data-sharing models that balance industry needs with societal benefit. Integrated registries will be increasingly needed to support future clinical trials. Today, clinical trial recruitment in DM relies primarily on clinical care centers, with existing natural history studies serving largely as screening tools. However, this approach will not be sufficient for the next generation of therapeutic development [[ 19 ], [ 20 ]]. As in many other disease areas [ 21 ], advancing drug development in DM will likely require more refined inclusion criteria that integrate genetic information, emerging modifier loci, clinical data, and patient-reported outcomes. Evidence for genotype–phenotype correlations and genetic modifiers of repeat instability is steadily increasing, underscoring the likely need for robust, well-curated datasets to define clinically meaningful patient subgroups. Furthermore, experience from other rare diseases demonstrates that disease-modifying therapies are most effective when administered early, before irreversible manifestations occur [ 21 ]. As the field moves toward earlier intervention or relies on more comprehensive inclusion criteria, recruitment strategies based solely on local clinical networks will no longer suffice [ 22 ]. Comprehensive, longitudinal patient registries will be essential to identify appropriate cohorts rapidly and to enable timely therapeutic intervention. Projecting pre- and post-market approval needs, a culture of collaboration, and a comprehensive registry that benefits industry, researchers, and PLDM is paramount. PAGs, as trusted partners, are uniquely positioned to promote this collaboration and support the development of a registry or the integration of existing ones. 4.2.3 Improve Site Preparedness and Recruitment Recruitment is not currently viewed as a critical issue, but with multiple trials advancing for DM, along with trials for other diseases, demand might soon outpace current capacity. Many sites rely on existing patients for enrollment and face staffing shortages that could limit participant support. Furthermore, if current interventional trials prove inconclusive or require refined genetic inclusion criteria, current participant pools may prove insufficient. To prepare, trial sites and sponsors should coordinate to: Plan and invest in staffing and research coordinator support. Anticipate biomarker-based, targeted trials, which may reduce sample sizes but require broader registry data. Draw lessons from spinal muscular atrophy (SMA), where small, rigorously defined cohorts enabled efficient trial success. Early preparation is key to ensuring readiness as more DM trials move forward. 4.2.4 Develop Patient-Centered Trial Design PLDM and caregivers repeatedly underscored the heavy burden of trial participation, including financial, logistical, and physical demands. Unless trial design is more patient-centered, participation will skew toward wealthier or less burdened individuals, limiting inclusivity and potentially biasing results. Recommendations include: Covering travel, hotel, and childcare costs upfront. Offering flexible reimbursement methods (direct deposit, cash, check). Providing at-home visits for blood draws and basic testing. Training staff in DM-specific care needs. Expanding opportunities for patients to initiate contact with trial sites. As one PLDM explained, “Failure to address inequities may lead to skewed samples of healthier, wealthier participants.” Importantly, PAGs have a central role in this area. By elevating patient voices and working with sponsors, they can advocate for participant-friendly trial structures, ensure adequate financial and logistical support, and help design approaches that reduce barriers for PLDM and caregivers. They can also monitor whether trial practices align with patient priorities and push for changes when gaps remain. 4.3 Integrated Approach These recommendations are interdependent. Validated endpoints require robust data to establish, registries support both recruitment and trial design, and patient-centered approaches depend on site preparedness. PAGs are uniquely positioned to weave these efforts together, convening stakeholders, amplifying patient voices, and ensuring alignment across the ecosystem. Addressing barriers collectively will prepare the DM community for trials and accelerate treatments. Figure 4 provides a roadmap linking these solutions to the barriers they are designed to overcome. While these solutions offer a roadmap forward, several limitations of this study should be acknowledged. First, survey responses from research coordinators, PIs, and pharmaceutical partners were limited and may not represent the full global and international landscape, especially as current experiences with DM1 trials are limited. While outreach was conducted internationally, most respondents were U.S.-based. Second, PLDM and caregivers engaged through MDF may be more connected than those outside the advocacy network, potentially biasing perspectives toward more favorable views of MDF or greater awareness of clinical trial readiness. Third, reliance on self-reported data from surveys and interviews may introduce social desirability bias. Fourth, this study focuses primarily on DM1. As current pharmaceutical development efforts focus on DM1, the study included only few participants with DM2. For PLDM and caregivers, the majority of respondents either have DM1, care for someone with DM1, or are working towards a DM1 clinical trial. This limits the generalizability of information from this study for patients with DM2. In conclusion, this study demonstrates an urgent and actionable need for the myotonic dystrophy community to coalesce around the development of comprehensive, standardized, and validated clinical endpoints that fully capture the multisystemic complexity of DM. Equally essential are robust frameworks for data and resource sharing and the systematic inclusion of patient and caregiver perspectives to overcome substantial barriers to clinical trial participation as a result of disease burden and symptom variability. We advocate for immediate, coordinated action: establishment of a dedicated working group on endpoints, a scientific session with the U.S. Food and Drug Administration (FDA), development of a comprehensive and accessible registry, strengthened trial site readiness, and the adoption of patient-centered trial designs that minimize participation burden. With numerous therapeutic candidates approaching or entering clinical development, the window of opportunity is now. Building the necessary infrastructure, aligning stakeholders, and embedding patient priorities at the core of trial design are critical to accelerating the path to effective therapies and transforming outcomes for individuals with DM. Declarations Ethics Approval and Consent to Participate This study was determined to be exempt by the Advarra Institutional Review Board (IRB) as Pro00081721. All participants were informed of the potential risks and benefits of their participation through verbal or written informed consent processes (or a combination of the two). Consent for Publication All participants consented to use of the data collected for this research for publication. Additionally, all data has been de-identified. Availability of Data and Materials The datasets generated and/or analyzed during the current study are not publicly available due to confidentiality of the participants but are available from the corresponding author on reasonable request. Competing Interests The authors declare no competing interests. Funding Funding for this study was provided by the Myotonic Dystrophy Foundation as part of its role as a patient advocacy organization, and Third Plateau, a consulting firm, was hired by MDF to conduct this study. Third Plateau and Myotonic Dystrophy Foundation together conceptualized the study, reviewed and analyzed the data, and prepared the manuscript collaboratively. Authors’ Contributions JSW and AR designed the phased, mixed-method study methodology and served as co-principal investigators. JSW, ARM, and JW developed the data collection tools (e.g., interview guides, survey) with input from AR and TS. JSW, ARM, and JW collected all qualitative and quantitative data and completed the analysis of the data. JSW led the qualitative data analysis while ARM led the quantitative data analysis. JSW, ARM, EH, and JW created the data visualizations. JSW, ARM, JW, and EH drafted the original draft of the manuscript. TS and AR edited the manuscript. All authors read and approved the final manuscript. Acknowledgements We would like to acknowledge and thank the participants in this study, particularly those with lived experiences dealing with DM, as a patient or a caregiver. We appreciate your expertise and your time participating in this study to hopefully improve the clinical trial process for the future. We would also like to thank Drs. Nadine Skinner, Jane Larkindale, and Jacinda Sampson for critical review and feedback. References Johnson NE, Butterfield RJ, Maybe K, Newcomb T, Imburgia C, Dunne D et al. Population-based prevalence of myotonic dystrophy type 1 using genetic analysis of statewide blood screening program. Neurology. 2021;96(7):1045-53. Available from: https://pubmed.ncbi.nlm.nih.gov/33472919/ National Organization for Rare Disorders. Myotonic dystrophy [Internet]. 2017 [cited 2025 Jun 30]. Available from: https://rarediseases.org/rare-diseases/dystrophy-myotonic/ Harper PS. Myotonic dystrophy. Oxford: Oxford University Press; 2009. Smith GK, Jie J, Fox GE, Gao X. DNA CTG triplet repeats involved in dynamic mutations of neurologically related gene sequences form stable duplexes. Nucleic Acids Res. 1995;23(21):4303–11. 10.1093/nar/23.21.4303 . PMID: 7501450; PMCID: PMC307384. Udd B, Krahe R. The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol. 2012;11(10):891–905. Meola G. Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies. Acta Myol. 2013;32(3):154–65. PMID: 24803843; PMCID: PMC4006279. Gourdon G, Radvanyi F, Lia AS, Duros C, Blanche M, Abitbol M, et al. Moderate intergenerational and somatic instability of a 55-CTG repeat in transgenic mice. Nat Genet. 1997;15:190–2. 10.1038/ng0297-190 . Ho G, Cardamone M, Farrar M. Congenital and childhood myotonic dystrophy: current aspects of disease and future directions. World J Clin Pediatr. 2015;4(4):66–80. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4637811/ Cho DH, Tapscott SJ. Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Biochim Biophys Acta. 2007;1772(2):195–204. 10.1016/j.bbadis.2006.05.013 . PMID: 16876389. National Organization for Rare Disorders. Myotonic dystrophy – symptoms, causes, treatment [Internet]. 2017 [cited 2025 Jul 7]. Available from: https://rarediseases.org/rare-diseases/dystrophy-myotonic/ Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W et al. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003;60(4):657 – 64. 10.1212/01.wnl.0000054481.84978.f9 . PMID: 12601109. Antonini G, Soscia F, Giubilei F, De Carolis A, Gragnani F, Morino S, et al. Health-related quality of life in myotonic dystrophy type 1 and its relationship with cognitive and emotional functioning. J Rehabil Med. 2006;38(3):181–5. 10.1080/16501970500477967 . Pascual-Gilabert M, Artero R, López-Castel A. The myotonic dystrophy type 1 drug development pipeline: 2022 edition. Drug Discov Today. 2023;28(3):103489. 10.1016/j.drudis.2023.103489 . PMID: 36634841. Lumsden JM, Urv TK. The Rare Diseases Clinical Research Network: a model for clinical trial readiness. Ther Adv Rare Dis. 2023;4. 10.1177/26330040231219272 . Huml R, Dawson J, Bailey M, Nakas N, Williams J, Kolochavina M, et al. Accelerating rare disease drug development: lessons learned from muscular dystrophy patient advocacy groups. Ther Innov Regul Sci. 2020;55:370. Furlong P, Dugar A, White M. Patient engagement in clinical trial design for rare neuromuscular disorders: impact on the DELIVER and ACHIEVE clinical trials. Res Involv Engagem. 2024;10:1. 10.1186/s40900-023-00535-1 . Crossnohere NL, Fischer R, Crossley E, Vroom E, Bridges JF. The evolution of patient-focused drug development and Duchenne muscular dystrophy. Expert Rev Pharmacoecon Outcomes Res. 2020;20(1):57–68. 10.1080/14737167.2020.1734454 . Myotonic Dystrophy Foundation. 2023 Myotonic dystrophy research landscape assessment [Internet]. 2023 Dec 22 [cited 2025 Oct 1]. Available from: https://www.myotonic.org/2023-myotonic-dystrophy-research-landscape-assessment University of Utah. More examples of precision medicine in action [Internet]. Learn.Genetics; n.d. [cited 2025 Oct 8]. Available from: https://learn.genetics.utah.edu/content/precision/action/ Balch B. Making medicine personal: moving away from a one-size-fits-all approach to health care [Internet]. AAMC; 2024 Feb 22 [cited 2025 Oct 8]. Available from: https://www.aamc.org/news/making-medicine-personal-moving-away-one-size-fits-all-approach-health-care Gatto F, Benemei S, Piluso G. The complex landscape of DMD mutations: moving towards personalized medicine. Front Genet. 2024;15. 10.3389/fgene.2024.1360224 . Al-Jedai A, Al-Mudaiheem H, AlSakran A, Bashiri FA, Ghamdi F, Almuhaizea MA, et al. Pioneering SMA therapies for all types: survival gains, cost dynamics, and performance-based agreements. Cost Eff Resour Alloc. 2025;23(1). 10.1186/s12962-025-00647-3 . Martiniano SL, Sagel SD, Zemanick ET. Cystic fibrosis: a model system for precision medicine. Curr Opin Pediatr. 2016;28(3):312–7. 10.1097/MOP.0000000000000351 . 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8961613","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":601686646,"identity":"ab0d7fdc-9ed4-48ad-aa24-41e7eb3d5673","order_by":0,"name":"Julia Stellmann Wrenn","email":"","orcid":"","institution":"Third Plateau","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"Stellmann","lastName":"Wrenn","suffix":""},{"id":601686647,"identity":"76338e16-8322-457e-b56b-bcbe76d3c849","order_by":1,"name":"Ali Ryan-Mosley","email":"","orcid":"","institution":"Third 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23:46:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8961613/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8961613/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104545494,"identity":"7279bf53-1c8b-47e4-ae5c-7a6d76e581ae","added_by":"auto","created_at":"2026-03-13 07:13:43","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37847,"visible":true,"origin":"","legend":"\u003cp\u003ePhases of data collection for this mixed-methods study.\u003c/p\u003e","description":"","filename":"groupimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8961613/v1/3cdc28887a794902906b01a9.jpeg"},{"id":104545495,"identity":"4373ecda-a4f3-462d-9063-ff76dccd9e78","added_by":"auto","created_at":"2026-03-13 07:13:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":166426,"visible":true,"origin":"","legend":"\u003cp\u003eRoadmap of barriers to successful clinical trials for DM.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8961613/v1/56165756cfc810792fd02ab6.png"},{"id":104781746,"identity":"4439f400-f29b-4531-95ff-1e842c0899be","added_by":"auto","created_at":"2026-03-17 07:56:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":127734,"visible":true,"origin":"","legend":"\u003cp\u003ePrimary areas of concern for each group of participants.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8961613/v1/4badf06e9811d6b7e6f245fd.png"},{"id":104545497,"identity":"5452a31c-3dac-4695-aa66-6d2f4fb8e18e","added_by":"auto","created_at":"2026-03-13 07:13:43","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":446431,"visible":true,"origin":"","legend":"\u003cp\u003ePotential solutions to identified barriers\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8961613/v1/8f7031422f83ff4684b76901.jpeg"},{"id":104784739,"identity":"20e2548f-1155-4a3d-8ee4-b72b9374ff1d","added_by":"auto","created_at":"2026-03-17 08:08:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1917423,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8961613/v1/48ef00ed-1dd2-44b6-879e-f01607b47f1d.pdf"}],"financialInterests":"","formattedTitle":"Exploring Barriers to Clinical Trial Readiness Among the Myotonic Dystrophy Community: A Mixed-Methods Study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eMyotonic dystrophy (DM) is a rare, autosomal-dominant, multisystemic, and progressive disease affecting up to 1 in 2,100 people [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is the most common form of muscular dystrophy in adults, and given its wide spectrum of severity, symptoms, and age of onset, is considered one of the most variable diseases in medicine [[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]]. Disease manifestations include myotonia, muscle weakness, fatigue, excessive daytime sleepiness, apathy, and cognitive difficulties. DM also frequently causes cardiac, gastrointestinal, vision, and endocrine complications [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. As a repeat expansion disorder, DM demonstrates genetic anticipation, with disease severity worsening across successive generations [[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]].\u003c/p\u003e \u003cp\u003eDM occurs in two distinct genetic forms: (1) Myotonic dystrophy type 1 or DM1, caused by a repeat expansion in the \u003cem\u003eDMPK\u003c/em\u003e gene. DM1 is the more common type and can affect individuals of all ages. Subtypes include congenital DM (CDM), where symptoms present at birth and are linked to longer repeat lengths, and childhood/juvenile-onset DM, typically presenting before age 18 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. (2) Myotonic Dystrophy Type 2 or DM2 is caused by a repeat expansion in the \u003cem\u003eCNBP\u003c/em\u003e gene, and it generally presents in adulthood [[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]].\u003c/p\u003e \u003cp\u003eThe variability and multisystemic nature of DM present major challenges. For patients and caregivers, symptoms generate physical, cognitive, emotional, and logistical burdens [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Many caregivers are themselves affected, further complicating care dynamics. For clinicians, variability hinders timely recognition and diagnosis of the disease, and for those planning, designing and running clinical trials, it complicates guidance on meaningful selection of clinical trial endpoints. For the industry, it creates obstacles in trial design, patient stratification, and endpoint selection. For regulatory agencies, matching clinical trial endpoints with true and meaningful patient impact is a logical concern.\u003c/p\u003e \u003cp\u003eCurrently, no disease-modifying therapies exist, and treatment remains limited to symptom management. Nonetheless, drug development efforts are progressing, indicated by a robust and expanding development pipeline, with more than 12 therapies in preclinical stages and over 10 in clinical trials [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Still, substantial barriers remain. Ensuring clinical trial readiness or the community overall being best prepared to conduct, engage, and succeed with clinical trials operations and outcomes requires coordinated action to address challenges faced by industry sponsors, trial sites, clinicians, patients, and families, while also anticipating barriers to treatment access once therapies become available.\u003c/p\u003e \u003cp\u003ePatient advocacy groups (PAGs) are central to this process. PAGs often serve as the first point of contact for disease-specific information and are recognized advocates for rare disease drug development. Yet DM\u0026rsquo;s rarity and variability complicate progress in drug development and clinical trials. Key challenges include small patient populations, insufficient natural history data, evolving regulatory frameworks, and difficulty defining consistent endpoints and biomarkers [[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]]. Prior research has shown how muscular dystrophy PAGs have mitigated these hurdles. Huml et al. (2020) identified five effective strategies: establishing national registries, reducing barriers to patient participation, partnering with biopharmaceutical companies, collaborating with regulators on disease-specific guidance, and integrating market access considerations early in development. Humel et al. also emphasized the importance of direct patient engagement to identify needs, evaluate registries, and strengthen collaboration across stakeholders.\u003c/p\u003e \u003cp\u003eTo accelerate progress toward effective therapies, continuous information exchange among patients, caregivers, clinicians, regulators, and industry is critical. People living with DM, as the true experts of their condition, must play a central role in shaping trial design and research priorities [[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]].\u003c/p\u003e \u003cp\u003eThis study builds on previous work by systematically assessing barriers to clinical trial readiness. The first phase captured challenges reported by industry partners, patients, and caregivers. These findings then informed further assessments with clinical and non-clinical trial site leaders. Together, results highlighted both organizational and systemic gaps, underscoring the need for targeted solutions and coordinated, ecosystem-wide action.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eTo understand the gaps, barriers, and needs of myotonic dystrophy (DM) community members and industry partners as they relate to clinical trial readiness, the following thematic questions were explored:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;What are the current challenges and barriers to clinical trial readiness among industry partners, patients, the DM community, and the clinical trial sites?\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;What potential solutions to the challenges and barriers exist?\u003c/p\u003e\n\u003cp\u003ea. \u0026nbsp; How do potential solutions align or not within and across these groups?\u003c/p\u003e\n\u003cp\u003eb. \u0026nbsp; Which potential solutions are acceptable to the three groups?\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe employed a mixed-methods approach by gathering, analyzing, and reporting findings that included both qualitative and quantitative data. The qualitative data informed the quantitative survey method.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEach form of data collection included a consent process outlining confidentiality, data privacy, and potential harms of participation. This study was determined to be exempt by the Advarra Institutional Review Board (IRB) as Pro00081721.\u003c/p\u003e\n\u003ch3\u003e2.1 Qualitative Data Collection\u003c/h3\u003e\n\u003cp\u003eWe directly engaged 75 individuals through interviews and focus groups, contacted through the Myotonic Dystrophy Foundation\u0026rsquo;s extensive network. This process included:\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;11 focus groups with different pharmaceutical companies (40 participants);\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;11 individual interviews with people living with DM (PLDM);\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;4 caregiver focus groups (24 participants).\u003c/p\u003e\n\u003cp\u003eWritten and verbal consent were obtained for PLDM and caregivers, while verbal consent only was obtained for pharmaceutical partners due to privacy concerns. The pharmaceutical companies involved in this research all have active drug development programs for DM, but they are in various stages, including discovery, preclinical, and clinical trial phases. PLDM and caregivers also represented people at various stages of disease and with a range of symptoms and experiences with prior interventional and/or natural history trials.\u003c/p\u003e\n\u003ch3\u003e2.2 Quantitative Data Collection\u003c/h3\u003e\n\u003cp\u003eIn the second phase, we distributed two confidential surveys, one to pharmaceutical industry partners and another to representatives at current and potential interventional and/or natural history study sites. For simplicity, these sites are collectively referred to as Clinical Trial Sites, although they might not be currently running interventional drug trials. Written consent was included in the survey prior to any questions.\u003c/p\u003e\n\u003cp\u003eThe Pharmaceutical Partners Questionnaire was distributed to each focus group participant, and 27 complete responses were received. Because participants were able to share the survey with other colleagues outside of the focus group and the survey was not required, we cannot calculate the response rate because we do not know the total distribution volume. Participants were not asked to report their names or the names of their companies.\u003c/p\u003e\n\u003cp\u003eThe Clinical Trial \u0026amp; Study Site Survey consisted of two versions, one tailored to the clinical trial principal investigators (PIs) and another tailored to trial site research coordinators. Participants were invited to participate in the survey via email based on their role at current DM clinical trial sites and DM clinics, which may be selected as future clinical trial sites. All known sites were included in the sampling pool. The Clinical Trial Site Survey received 24 complete responses, including 12 from clinical research coordinators at the clinical trial sites and 12 from principal investigators (PIs) who are running DM studies and trials. This represents response rates of 16% and 41%, respectively. These responses represent many different sites, though not all unique.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e2.3 Qualitative Analysis\u003c/h3\u003e\n\u003cp\u003eThe data was analyzed in phases, as insights from certain data informed the design of other parts of the study. During the preliminary analysis process, we conducted a rapid qualitative data analysis process that elevated the key themes and findings across interviews and focus groups. Once key themes were identified, the preliminary findings were used to conduct an in-depth analysis, coding each transcript using a mix of deductive and inductive codes. This process was conducted in NVivo (Lumivero, Denver, CO), a qualitative coding software. From this, a qualitative coding matrix was created to explore patterns within and among key themes and various participant groups. These findings, in addition to analysis of the Pharmaceutical Partners Questionnaire, guided and informed the design of the Clinical Trial Site Survey.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e2.4 Quantitative Analysis\u003c/h3\u003e\n\u003cp\u003eThe survey was distributed through Qualtrics (Qualtrics, Provo, UT), a survey distribution software. To analyze the quantitative survey data, both Qualtrics and Excel\u0026rsquo;s descriptive statistics tools were used. The key themes and patterns from the qualitative data were triangulated with data from the two surveys. Data from the surveys was given more depth and nuance by pairing it with individual perspectives from the focus groups and interviews. Additional context and information were provided. The mixed-methods process is outlined in Figure 1.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eTables 1\u0026ndash;3 summarize participant characteristics. The study engaged four primary groups: pharmaceutical partners, people living with DM (PLDM), caregivers, and clinical trial site principal investigators (PIs) and research coordinators.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1: Number of Participants in Interviews and Focus Groups by Type of DM\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConversations with Patient and Caregiver Community\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of DM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eForm of Involvement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 156px;\"\u003e\n \u003cp\u003eDM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 133px;\"\u003e\n \u003cp\u003eDM1 Adults\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 124px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eCaregiver focus group (n=7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eInterviews with PLDM (n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eJuvenile-onset DM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eCaregiver focus group (n=8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eCongenital DM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eCaregiver focus group (n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 289px;\"\u003e\n \u003cp\u003eDM2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 124px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eCaregiver focus groups (n=5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eInterview with PLDM (n=1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u0026nbsp;\u003cp\u003eTable 2: Breakdown of Engagements with Pharmaceutical Partners\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEngagement with Pharmaceutical Partners\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eForm of Involvement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eFocus group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e11 focus groups with 11 different companies\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePharmaceutical Partners Questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e25 questionnaire responses from focus group participants\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u0026nbsp;\u003cp\u003eTable 3: Clinical Trial Site Survey Participants by Role\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Trial Site Survey Participants\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 327px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurvey Type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 297px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Responses\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 327px;\"\u003e\n \u003cp\u003eClinical Trial Site Research Coordinator Survey\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 297px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 327px;\"\u003e\n \u003cp\u003eClinical Trial Site Principal Investigator Survey\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 297px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u0026nbsp;\u003cp\u003eFrom these data, three major categories of barriers to trial readiness emerged:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Lack of Comprehensive and Meaningful Endpoints\u003cbr\u003e\u0026nbsp;a. Current Endpoints Do Not Reflect the Multi-system Nature of the Disease\u003cbr\u003e\u0026nbsp;b. Importance of Patient Input for Endpoints\u003cbr\u003e\u0026nbsp;c. Need for Further Research on Endpoints\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; Industry Need for Data Sharing and Coordination\u003cbr\u003e\u0026nbsp;a. Importance and Cost of Natural History Study Data\u003cbr\u003e\u0026nbsp;b. Competition Instead of Collaboration\u003cbr\u003e\u0026nbsp;c. Potential Solution of a Centralized Registry\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; Challenges with Trial Design and Participation\u003cbr\u003e\u0026nbsp;a. Prioritization of Known Participants in Recruitment while avoiding selection bias\u003cbr\u003e\u0026nbsp;b. Issues with Finding and Enrolling in Trials\u003cbr\u003e\u0026nbsp;c. Trial Accessibility and Burden of Participation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEach theme is examined in detail below, with triangulation from the Clinical Trial Site Survey and Pharmaceutical Partners Questionnaire. Figure 2 maps and summarizes barriers along the trajectory of interventional trial design and execution.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e3.1 Lack of Comprehensive and Meaningful Endpoints\u003c/h3\u003e\n\u003ch4\u003e3.1.1 Current Endpoints Do Not Reflect the Multi-system Nature of the Disease\u003c/h4\u003e\n\u003cp\u003eAcross groups, participants emphasized the absence of standardized, validated, and patient-centered trial endpoints. DM\u0026rsquo;s hallmark symptom is myotonia, but the disorder affects multiple organ systems and varies widely, even within families. In most cases, PLDM and caregivers described years-long diagnostic delays due to heterogeneous symptoms and limited clinical awareness. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePIs and pharmaceutical partners acknowledged the challenge of controlling for disease variability in trial design, underscoring the need for endpoints that capture DM\u0026rsquo;s multisystemic presentation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMost pharmaceutical partners reported incorporating Video Hand Opening Time (vHOT) in their designs, but noted high variability in both vHOT and other outcome measures. Several cited disagreements with regulators, particularly the FDA, regarding acceptable endpoints and what constitutes and defines meaningful change for patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;I don\u0026apos;t think we\u0026apos;re so interested in producing a statistically significant improvement in the relaxation in the muscle on the index finger on one hand, and saying we\u0026apos;ve got a successful drug. We\u0026apos;re trying to find methodologies to assess the whole of the phenotype, and we invested a massive amount to try and develop an outcome measure that didn\u0026apos;t work, to do that.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- Pharmaceutical Partner\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;We\u0026apos;ve had long debates with the [regulatory agency] about composite outcome measures that allow you to have a measure of brain function, a measure of muscle function and then collapse them into one measure, and the [regulatory agency] won\u0026apos;t agree to that. So it\u0026apos;s difficult when you\u0026apos;ve got a population where almost any organ system of the body can be compromised, but isn\u0026apos;t necessarily compromised in any one patient, how do you come up with an outcome measure?\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- Pharmaceutical Partner\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants noted that these regulatory uncertainties make it difficult to identify which outcomes are meaningful, what endpoints might demonstrate improvement across DM\u0026rsquo;s diverse spectrum of symptoms, and whether an identified trial endpoint is truly a proxy for patients\u0026rsquo; experiences and ultimately an indicator of meaningful change or improvement. This uncertainty reflects the fundamental issue of how to define \u0026ldquo;meaningful change\u0026rdquo; in clinical trial settings that also translates into real improvements in patients\u0026rsquo; quality of life. Not surprisingly, this issue also transcends and manifests in the lack of regulatory clarity.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003e3.1.2 Importance of Patient Input for Endpoints\u003c/h4\u003e\n\u003cp\u003ePLDM and caregivers valued vHOT but stressed the need for broader endpoints, including measures of GI function, cardiac function, cognitive decline, daytime sleepiness, and apathy. These symptoms profoundly affect daily life but are rarely assessed beyond questionnaires. Concerns extended to other muscles, such as cardiac and pharyngeal.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;There\u0026apos;s no biomarkers for speech or for swallowing. Swallowing is a big deal. I\u0026rsquo;ve choked four times. I needed the Heimlich three times, the fourth I did to myself.\u0026rdquo; - PLDM\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;You know, there are muscle treatments, studies are going on, but the key is going to be getting a brain treatment. The executive function loss of kids needs to be reversed. Too many of them are robbed of their futures and their dreams because they just don\u0026apos;t have the executive functions.\u0026rdquo; - PLDM\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eParticipants criticized patient-reported surveys as inconsistent, yet noted their regulatory endorsement.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;The [regulatory agency] has pointed us to certain patient reported outcomes, like the DM1-Activ. And then when you take that to adult onset patients, they hate it, and it\u0026apos;s a standard \u0026hellip; You can see that the [regulatory agency] has been giving the same advice to all of the pharma companies in the space. And it\u0026apos;s now a running joke of the \u0026lsquo;soup questionnaire,\u0026rsquo; because the first question is, can you eat soup?\u0026rdquo; - Pharmaceutical Partner\u003c/em\u003e\u003cem\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003ch4\u003e3.1.3 Need for Further Research on Endpoints\u003c/h4\u003e\n\u003cp\u003eLess than half of pharmaceutical partners (45%) felt moderately ready to assess non-muscular endpoints; 20% reported being not very ready. Thirty-five percent judged the broader field as not very or not at all ready, with cost and regulatory hurdles cited as key barriers. Survey data corroborated and confirmed these concerns: 90% of PIs agreed that more research is needed on endpoints, and 90% supported a structured forum to advance consensus.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;So this is where there is still a lot of discussion and also no agreement between the community and the [regulatory agency]\u0026hellip;. We were quite convinced with our study design \u0026hellip; yet we\u0026apos;ve confronted some, I don\u0026apos;t want to call it criticism, but further clarifications needed for what is clinically meaningful for these patients. If myotonia gets improved \u0026hellip; What does it mean in terms of the disease progression? What does it mean in terms of patients\u0026rsquo; perception of improved quality of life, and how should we measure it? So, there is a battery of validated tools as of today, and yet we hear different opinions of acceptance by the regulators, by [regulatory agency] \u0026hellip; there is no consensus on that. So it makes it really difficult to talk about the study designs that would kind of accommodate all these different needs.\u0026rdquo; - Pharmaceutical Partner\u003c/em\u003e\u003cstrong\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ch3\u003e3.2 Industry Need for Data Sharing and Coordination\u003c/h3\u003e\n\u003cp\u003eNatural history data, patient experience data, as well as\u0026ndash;when available\u0026ndash;genetic diagnostic data are considered foundational for the drug development process. In DM, the identification of comprehensive and meaningful endpoints is still limited and hindered by the fact that DM natural history and clinical trial data are not yet freely accessible. In general, participants identified the siloed and competitive culture among trial sponsors and research organizations as a deterrent to data sharing, trial design, and collaboration, and criticized the lack of a central, free database containing natural history data, disease progression data, and genetic information.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003e3.2.1 Importance and Cost of Natural History Study Data\u003c/h4\u003e\n\u003cp\u003eParticipants identified siloed data and a lack of coordination as barriers. Natural history data, while critical, is largely restricted to a \u0026ldquo;pay-to-play\u0026rdquo; model. The Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1(END-DM1) study by the DMCRN is the most comprehensive resource, but sponsorship is costly.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhile the END-DM1 study has been enabled and its expansion funded by early entrants in the DM drug development space, these early funders receive regular \u0026ldquo;data-cuts\u0026rdquo; serving as reference points for general disease progression, prior to clearly outlined publication plans and milestones of the entire study. This arrangement acts as a perceived major barrier for smaller pharmaceutical companies with limited budgets who are trying to enter the space.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;\u0026hellip; I\u0026apos;ve never worked [on a disease] where you\u0026apos;ve had to pay. \u0026hellip; I\u0026apos;ve worked in places where you have to pay, but it\u0026apos;s just to cover costs, it\u0026apos;s not to make money \u0026hellip; I think other advocacy groups for rare diseases, they also charge based on the company\u0026apos;s size and revenue. There\u0026apos;s another way of doing it. And I think the DMCRN actually do not bother if you\u0026apos;re like a top 10 pharma or a small, tiny biotech, they charge you the same flat rate, which is kind of really, really uneven playing ground here.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- Pharmaceutical Partner\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants criticized the lack of public dissemination despite FDA and advocacy group funding for the study. Many acknowledged willingness to share data but cited competitive barriers. Suggestions included advocacy groups convening sponsors to coordinate. Industry representatives pointed to opportunities for sharing placebo or failed trial data, noting success in ALS. Yet most stressed the need for collective agreements to reduce individual risk.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;[Placebo data] is of great use to patient groups who are setting up a database establishing a natural history where you have such a frequent collection of data in a very systemic fashion \u0026hellip; I would not want to give [data] to a patient group upfront unless I am pushed. And I\u0026apos;m not only me. If other sponsors are pushed too, I would say, \u0026lsquo;well, I\u0026apos;m happy to do it, would [company name] do it? Would [company name] do it, would [company name] do it? Would [company name] do it?\u0026rsquo; And MDF tells them \u0026lsquo;look guys we want to set this consortium. This will be an anonymized data set but will support your \u0026hellip; efforts if you commit to submission of this data.\u0026rsquo;\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- Pharmaceutical Partner\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSome large pharma partners expressed less concern, viewing DM as relatively advanced in terms of available data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;I think myotonic dystrophy is actually ahead, and that through the DMCRN, most companies do have access to that data. Do we pay for it? Of course we pay for it. But most of us do have access to a good chunk of reasonably well-collected natural history data.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- Pharmaceutical Partner\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003ch4\u003e3.2.2 Competition Instead of Collaboration\u003c/h4\u003e\n\u003cp\u003eDespite shared concerns, many companies reported siloed approaches. The lack of a standardized assay for \u003cem\u003eDMPK\u003c/em\u003e gene repeat lengths was particularly noted, with larger firms developing in-house tools without wider dissemination.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;This is a disease caused by the presence of CUG repeat RNA, right? There is no assay for CUG repeat RNA, so \u0026hellip; there is no way of measuring whether you\u0026apos;re treating the disease. That\u0026apos;s like trying to do HIV research without a way of measuring HIV virus or anti-infective research, without a way of measuring whether you can remove infections. And we\u0026apos;re having to build our own assay. And when I\u0026apos;ve asked all of the academics that we speak to, why is there no assay, I get no good answer.\u0026rdquo; - Pharmaceutical Partner\u0026nbsp;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePharmaceutical partners and PIs also expressed growing interest in genetic modifiers and CTG repeat length, though few current trials incorporate them. Eighty percent of PIs judged repeat composition and modifier loci as likely to influence disease severity. While promising, this could complicate recruitment if\u0026nbsp;the infrastructure for genetic stratification is lacking.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ch4\u003e3.2.3 Potential Solution of a Centralized Registry\u003c/h4\u003e\n\u003cp\u003eWhen asked about registries, participants generally supported the idea of a centralized natural history registry, either through the coordination of existing registries or the development of a new resource. No such registry currently exists for DM, although there are several registries currently operating. Desired data include demographics, natural history data, natural history study data (e.g. END-DM1), comprehensive and inclusive clinical data from the patient\u0026rsquo;s electronic health record (EHR), genetic testing data, all clinical visit data, reference to available biospecimens, and consent for trial eligibility testing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;\u0026hellip; Collecting [data on symptoms] and then constantly kind of looking in [the registry] and saying like, \u0026lsquo;what are the key symptoms\u0026rsquo; so that you could eventually go to a physician and say \u0026lsquo;you see people with diarrhea, you see people with exhaustion, you see people with hand cramping. But if you see all three of those things together \u0026hellip; you should thank DM1.\u0026rsquo;\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- Pharmaceutical Partner\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegistries were also viewed as tools for patient education and awareness.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;Not every patient out there knows everything about their disease \u0026hellip; so having the resources available to them is fantastic because that allows them to understand more about themselves, more about the opportunities that are open to them and their family. And that is where I think a patient registry becomes very helpful. So it\u0026apos;s not necessarily a recruitment tool \u0026hellip; [but] the patients become more educated as well because they have outreach from other patient advocacy groups.\u0026rdquo; - Pharmaceutical Partner\u003c/em\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSixty percent of PIs (6 out of 10 participants) judged a comprehensive registry as helpful for trial planning, though fewer currently use registries for recruitment. This is likely due to the fact that most centers draw on their own pools of patients for study recruitment. Some participants cautioned against duplicative registries, stressing consolidation and core data sharing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;There already are other registries that are bigger, and what I don\u0026apos;t like to see \u0026hellip; is all these little registries, and I think it\u0026apos;s better to have one central registry \u0026hellip;. I don\u0026rsquo;t like rival registries. \u0026hellip; It\u0026rsquo;s almost better if a lot of these organizations came together and just decided, \u0026lsquo;okay, well, we\u0026apos;re going to have one registry. We\u0026apos;re going to share core data.\u0026rsquo; And then, yes, each [registry] will have the flexibility \u0026hellip; [to] add other things depending on what they think they need. But it would be nice to have one core registry, or at least not the 100 that we have.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- Pharmaceutical Partner\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOthers expressed skepticism about the feasibility, citing reluctance to share and potential sensitivities around global access. Still, PLDM and caregivers were generally eager to contribute, though some raised concerns about privacy and insurance.\u003c/p\u003e\n\u003ch3\u003e3.3 Challenges with Trial Design and Participation\u003c/h3\u003e\n\u003cp\u003eFor PLDM and caregivers, a major barrier to clinical trial readiness in the DM community is the actual design of trials and their ability to participate. Despite a willingness to volunteer for clinical trials, many participants discussed how the process of screening and being selected for trials requires much more than offering to be part of the study.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003e3.3.1 Prioritization of Known Participants in Recruitment\u003c/h4\u003e\n\u003cp\u003eRecruitment was perceived by PLDM and caregivers as heavily dependent on clinic affiliation. Many felt proximity to selected sites increased access, prompting some to travel interstate for care. Survey data confirmed that recruitment is largely through prior clinic or study connections rather than patient-initiated contact, with almost all PIs and research coordinators (90%, n=10, of PIs and 89%, n=9, of research coordinators) indicating that the participants are known from the clinic.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, the majority responded that potential interventional trial participants are known from being registered in a \u0026ldquo;registry\u0026rdquo; (50% of PIs and 56% of research coordinators) or from a natural history study (50% of PIs and 44% of research coordinators, Table 4). The term registry here also implies \u0026ldquo;study record structures\u0026rdquo;. Patient-initiated contact in the clinical trial enrollment process played only a very minor role, cited by only 10% (n=10) of responding PIs and less than a quarter of responding research coordinators (22%, n=9).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4: PI and Research Coordinator Responses by Answer Choice. This data originates from the Clinical Trial \u0026amp; Study Site Survey.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnswer Choice (Participants Could Select Multiple Options)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePIs (n=10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoordinators (n=9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cem\u003eParticipant is known from clinic\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e88.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cem\u003eParticipant is registered in a registry\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e55.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cem\u003eParticipant is known from other natural history study\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e44.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cem\u003eParticipant is known from END-DM1 natural history study\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e33.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cem\u003eParticipant initiated contact\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e22.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cem\u003eOther (please describe)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e11.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cem\u003eNone\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u0026nbsp;\u003ch4\u003e3.3.2 Issues with Finding and Enrolling in Trials\u003c/h4\u003e\n\u003cp\u003eParticipants frequently noted difficulty identifying trial opportunities. PLDM described reliance on clinicaltrials.gov, which they found challenging to navigate. Consistent with a lack of interventional trials for juvenile and pediatric-onset disease forms as well as DM2, caregivers emphasized limited opportunities for DM2 and adults with juvenile-onset DM. Many PLDM reported educating their own physicians about DM, raising concerns about clinicians\u0026apos; capacity to inform patients of trial options.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026quot;It\u0026apos;s not a disease that \u0026hellip; I would say a lot of doctors are familiar with. And so there\u0026apos;s a lot of misinformation or just no information. Like my dad, when he first was diagnosed, his doctor was like \u0026lsquo;oh well, you\u0026apos;re like his repeats are low, so you\u0026apos;re not really going to have any other symptoms.\u0026rsquo; And then he had to have an emergency pacemaker placed in. And he would have died. \u0026hellip; I\u0026apos;m very confident in the team of doctors I have, but I also have a wealth of medical knowledge to fall back on, whereas I think a lot of people don\u0026apos;t. And so, you know \u0026hellip; You try to trust your doctor, but if your doctor isn\u0026apos;t putting in any effort to understand your disease then \u0026hellip; They\u0026rsquo;re not really doing their job.\u0026quot; - PLDM\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBoth PLDM and caregivers requested more proactive dissemination of trial opportunities from advocacy groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;I think just helping to \u0026hellip; make us more aware of what\u0026apos;s out there, at least until we get to a point where maybe we\u0026apos;re stable enough that we can take the time to do that. I don\u0026apos;t know if and when that\u0026apos;ll happen. But it would be nice to know, to be alerted of those types of things. And if there\u0026apos;s something that we\u0026apos;re interested in, we can research it more. But, you know, something that\u0026apos;s just say, \u0026lsquo;hey, you know, this is what\u0026apos;s out there.\u0026rsquo;\u0026rdquo; - Caregiver\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants also highlighted frustrations with trial pacing and regulatory delays. Pharmaceutical partners expressed interest in discussing accelerated approval pathways with regulatory agencies, like the FDA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;So from a regulatory policy standpoint, I think the [regulatory agency] has been very open to defining and discussing, I guess, accelerated approval pathways for other neuromuscular disorders. So I think it\u0026apos;s important to have a discussion with them around, what is the path to accelerated approval for myotonic dystrophy and that it should be a priority for them, you know? And how do we get to a place where the [regulatory agency] is having a discussion with companies right in terms of, are they willing to think about this as a regulatory pathway for myotonic dystrophy drugs?\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- Pharmaceutical Partner\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eExclusion criteria were another major concern. PLDM reported being excluded for DM-related comorbidities, age, or concomitant medications, which they perceived as contradictory. While such perception indicates a lack of understanding of the trial process per se, it also highlights education opportunities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;When they\u0026apos;re looking for individuals with certain symptoms, finding the individuals within DM that don\u0026apos;t have other symptoms that are very characteristic of the disease. That\u0026apos;s very hard. So it really limits that pool of individuals that they have to draw from.\u0026quot; - PLDM\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026ldquo;Some of [the trials] you have to be off your meds. And if I didn\u0026apos;t take my Ritalin and my Nuvigil this morning, I wouldn\u0026apos;t be sitting up here talking to you. I\u0026apos;d be a dish rag. I was in one [study] where I had to be off them for I think it was two weeks. And I was still working full time. And it was hard. I had a lot of caffeine to get me through the day \u0026hellip; So a lot of people have to be off certain meds they can\u0026apos;t really function without. So that\u0026apos;s a big issue I have.\u0026rdquo; - PLDM\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePLDM participants also expressed disappointment with the screening process for trial participation. Disappointed when finding out they are excluded, PLDM felt the inclusion/exclusion criteria were at times conservative, and the screening process unclear and burdensome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026quot;So far, I haven\u0026apos;t [participated in a trial]. I did screen for one clinical trial. But \u0026hellip; I didn\u0026apos;t fit the criteria because one of my blood works was off. So I did spend a whole day at [site] screening for the [company] clinical trial. It\u0026apos;s a phase three clinical trial. I would have loved to take part, but I didn\u0026apos;t qualify.\u0026rdquo; - PLDM\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003e3.3.3 Trial Accessibility and Burden of Participation\u003c/h4\u003e\n\u003cp\u003eFor clinical trial sites, staffing emerged as the top barrier (Table 5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 5: Top 1-3 challenges in getting clinical trials for myotonic dystrophy up and running, according to PIs and Research Coordinators. This data originates from the Clinical Trial \u0026amp; Study Site Survey.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnswer Option\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePIs (n=10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoordinators (n=9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eStaffing (number of staff)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e70.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e44.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eExtensiveness of the assessment protocols\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e30.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e33.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eNavigating regulations/requirements\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e30.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e44.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eFinances\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e30.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e11.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eOther (please describe)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e30.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e11.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eCompeting with other neuromuscular disease clinical trials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e20.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e22.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eCommunication with sponsors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e10.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e11.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eEquipment (e.g., purchasing, set up, function)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e10.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eParticipant retention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e10.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eParticipant enrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e10.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eParticipant recruitment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e10.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e11.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eStaffing (staff expertise)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e10.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e11.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eParticipant education\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eBelief in the success of the intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 400px;\"\u003e\n \u003cp\u003eUnsure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e33.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u0026nbsp;\u003cp\u003eInterestingly and in contrast, 50% (5 of 10 respondents) of PIs also indicated that their site was prepared to start three or more trials in the next year, and 40% (4 of 10 respondents) indicated that they were prepared for 1-2 trials to start in the next year. With surveying sites that were and were not currently conducting interventional trials, staffing shortages point towards a potential bottleneck in trial execution, especially at a time when we expect more trials for DM to begin.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePLDM participants highlighted perceived variable site readiness.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;What we\u0026apos;ve learned from all this is all centers aren\u0026apos;t created equal. Some have great infrastructure. Some have great admin, some have great coordinators. And others are missing that piece or that center doesn\u0026apos;t have the support of their own faculty to cheer you on and say, okay, let\u0026apos;s go.\u0026rdquo; -Caregiver\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe logistical burden of remembering appointments and appointment details is high and particularly challenging for PLDM who experience brain fog, anosognosia, apathy, and fatigue. Clinical trial site research coordinators flagged this issue, some even naming it as the greatest challenge for participants in an interventional trial. Site research coordinators unanimously (100%, n=9) indicated that they currently send multiple follow-ups and reminders about appointments. The symptoms of DM uniquely require this type of extra attention and follow-up for retention, even though PLDM are willing to participate in trials. \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, caregivers and PLDM alike noted that most of the logistical burden still falls on the caregiver, who might be taking care of multiple family members with DM and some of whom might also have DM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePLDM and caregivers frequently described burdens of travel, site accessibility, and cognitive/financial stress.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;One of the things that gets talked about in our group a lot is just the actual physical hands-on challenges of flying. Getting on and off of a plane, the amount of equipment that it takes just to go to a hotel for a night because you have to have a certain level of surface to get off of for the bed, for the toilet, for all those things.\u0026rdquo; - Caregiver\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe travel burden is high for many clinical trials, which might require multiple days of travel for relatively simple and quick but frequently occurring procedures, like a blood sample collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;We\u0026apos;re currently traveling \u0026hellip; to be in a study. And it is really tiring when you go for a five-minute blood draw. And then you go home. You know, because [closer study site] wasn\u0026apos;t up and running yet. And it just was months and months and months of waiting.\u0026rdquo; - Caregiver\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinancial barriers include upfront costs and delayed reimbursement, as well as reimbursements in less usable formats, like a prepaid debit card.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;DM1 is associated with difficulty keeping a job. There\u0026apos;s a lot of poverty there. So if you\u0026apos;re on your own, it would be impossible to participate. Really, if you barely have enough money for food and rent, you can\u0026apos;t necessarily pay for something and wait a month to get it back. If you\u0026apos;re even going to get it back because maybe the systems are just too complicated to follow \u0026hellip; And you can\u0026apos;t pay rent with a charge card \u0026hellip; So there\u0026apos;s probably a lot of people who just can\u0026apos;t do it.\u0026rdquo;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e- PLDM\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCaregivers described the compounded burden of supporting multiple affected relatives. The logistical burden of being in a study also emerged as a barrier to participation. Frequently, the time commitment to participate is not limited to the person participating but extends to caregivers or even whole families, as they may have to travel together. Some caregivers also discussed the burden placed on them due to the cognitive impairment of the people they care for.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;The obstacle to getting any of [my family members] into clinical trials is that I would be the one doing it because they don\u0026apos;t have the executive function to follow through and be looking to think to themselves, \u0026lsquo;oh, let me initiate this task, oh, let me maintain this task. Oh, let me finish this task.\u0026rsquo; None of those skills exist for any of them. And so I would be the one doing it and I\u0026apos;m the one doing everything.\u0026rdquo; - Caregiver\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;And in my case, my wife is dealing with all of it, and the follow-up and everything. If I was single I would not be able to handle it. \u0026hellip;Because of the fatigue you get from DM1 and then you get a lot of cognitive issues, brain fog, inability to focus for long periods of time.\u0026rdquo; - PLDM\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite the concerns from the perspective of patients and caregivers, few pharmaceutical partners or PIs see participant recruitment as a current barrier to clinical trial success, with most indicating that study recruitment is going really well. According to the Clinical Trial Site Survey, 80% (n=10) of PIs agree or strongly agree with the statement, \u0026ldquo;patient recruitment for upcoming clinical drug trials is not a concern\u0026ndash;we have enough participants that meet eligibility criteria,\u0026rdquo; and the other two responded neutrally. However, when asked about future levels of recruitment, multiple pharmaceutical partners expressed concerns, particularly considering the number of upcoming trials.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;We have lots of interest and lots of potential patients, so I think we\u0026apos;re feeling as of now, generally pretty good about [patient recruitment]. That may, of course, change as more studies start in the area. But right now, finding participants has not been the problem. We will see as more and more studies get up and going, particularly larger ones.\u0026rdquo; - Pharmaceutical Partner\u003c/em\u003e\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Barriers and Potential Solutions\u003c/h2\u003e \u003cp\u003eThis study identified three major barriers to clinical trial readiness in DM, reported consistently by pharmaceutical partners, people living with DM (PLDM), caregivers, and clinical trial site staff:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLack of comprehensive and meaningful endpoints;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eInsufficient data sharing and coordination across the industry; and\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eChallenges in trial design, recruitment, and site and participant burden.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e provides a visual summary of the primary concerns identified by each participant group. Although all groups discussed every barrier, the figure highlights only the most frequent concerns. Primary concerns were determined based on data richness, frequency with which participants raised them, and the level of consensus across groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e[Figure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThese findings align with prior landscape assessment research by the Myotonic Dystrophy Foundation (MDF) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and build on it by incorporating PLDM and caregiver perspectives. Our findings also echo other research exploring the role of patient advocacy groups for rare disease research [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe study also highlights potential solutions to address these barriers and move the DM community closer to effective treatments. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e illustrates these solutions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e[Figure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Exploring Solutions\u003c/h2\u003e \u003cdiv id=\"Sec24\" class=\"Section3\"\u003e \u003ch2\u003e4.2.1 A Process To Investigate, Explore, and Establish Endpoints; Hosting a Scientific Session\u003c/h2\u003e \u003cp\u003eDeveloping treatments is impossible without standardized, validated endpoints that reflect outcomes meaningful to patients. Current measures like vHOT capture hand myotonia but fail to represent the full DM experience. To establish a broader spectrum of informative endpoints that capture the patient experience within the relatively short duration of interventional studies, stakeholders emphasized the need for a scientific session with the FDA and a dedicated working group to establish multiple clinically relevant, patient-centered endpoints.\u003c/p\u003e \u003cp\u003eAction steps include:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eHosting a multi-stakeholder session with the FDA (i.e., patients, caregivers, pharma, researchers).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eExpanding research into outcomes meaningful to patients (e.g., GI, cognition, fatigue).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eExploring accelerated approval pathways.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePromoting industry collaboration and open data sharing.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA strong alliance across all stakeholders, including regulatory agencies, would create continuous processes to find consensus, integrate advances in knowledge, and support targeted efforts to overcome delays. Most importantly, such concerted efforts could also positively influence reimbursement decisions for DM at large or for defined subgroups. PAGs, as trusted conveners, can ensure patient perspectives remain central in convening such forums and defining endpoints.\u003c/p\u003e \u003cp\u003eA central barrier remains the lack of knowledge and consensus regarding how to assess, measure and prioritize the full spectrum of DM manifestations. PLDM and caregivers stressed that outcomes most relevant to daily functioning\u0026mdash;such as swallowing safety, fatigue, and executive function\u0026mdash;are rarely prioritized. Pharmaceutical partners also reported persistent uncertainty regarding regulatory acceptance of limited (e.g. myotonia specific) but quantifiable endpoints and their generalizability capturing or reflecting broad disease impact and improvement thereof. As one partner noted,\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eWe invested a massive amount to try and develop an outcome measure that didn\u0026rsquo;t work, and we are still struggling with how to demonstrate what matters to patients in a way that regulators will accept.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eEndpoint development must be dynamic, not static. Iterative processes that incorporate emerging evidence, patient-reported outcomes, biomarker discovery, and lessons from ongoing trials are needed. Standing multi-stakeholder groups with regulators, advocacy organizations, and experts would enable continuous refinement of endpoints in real time. Such dynamic processes are essential to move beyond reliance on limited measures like vHOT and toward tools that reflect the heterogeneity of DM. They would also facilitate the adoption of innovative digital endpoints, wearable technologies, and advanced imaging modalities. Expanding knowledge in a structured but flexible manner would accelerate consensus and improve regulatory acceptance, while aligning trial outcomes with what PLDM and caregivers identify as meaningful improvements in quality of life.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003e4.2.2 Create a Comprehensive, Coordinated Registry\u003c/h2\u003e \u003cp\u003eClinical trial progress is slowed by fragmented data and limited sharing. Competition among companies has created barriers to collaboration, and access to natural history data is particularly challenging for smaller firms.\u003c/p\u003e \u003cp\u003eA comprehensive data sharing platform would go beyond registry concepts and definitions. A comprehensive data sharing platform would include data from contact registries, natural history studies, completed clinical trials data, comprehensive clinical records, clinical trial data, patient reported outcomes and genetic testing data. Such longitudinal data structures would:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eConsolidate and represent data from existing registries and standardize practices globally.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSupport trial design, recruitment, and patient notification.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEnable pre-screening for inclusion/exclusion criteria, reducing patient burden.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDirectly and indirectly capture meaningful patient impact.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAllow sharing of placebo arm data to reduce participant exposure.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eInform and guide the clinical care community.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eSuch platforms could support the definition of inclusion criteria, enable more efficient trial designs, support post-market surveillance, and lay the foundation for newborn screening. PAGs can play a central role in fostering collaboration, establishing best practices, and advocating for scalable data-sharing models that balance industry needs with societal benefit.\u003c/p\u003e \u003cp\u003eIntegrated registries will be increasingly needed to support future clinical trials. Today, clinical trial recruitment in DM relies primarily on clinical care centers, with existing natural history studies serving largely as screening tools. However, this approach will not be sufficient for the next generation of therapeutic development [[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]]. As in many other disease areas [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], advancing drug development in DM will likely require more refined inclusion criteria that integrate genetic information, emerging modifier loci, clinical data, and patient-reported outcomes. Evidence for genotype\u0026ndash;phenotype correlations and genetic modifiers of repeat instability is steadily increasing, underscoring the likely need for robust, well-curated datasets to define clinically meaningful patient subgroups. Furthermore, experience from other rare diseases demonstrates that disease-modifying therapies are most effective when administered early, before irreversible manifestations occur [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. As the field moves toward earlier intervention or relies on more comprehensive inclusion criteria, recruitment strategies based solely on local clinical networks will no longer suffice [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Comprehensive, longitudinal patient registries will be essential to identify appropriate cohorts rapidly and to enable timely therapeutic intervention.\u003c/p\u003e \u003cp\u003eProjecting pre- and post-market approval needs, a culture of collaboration, and a comprehensive registry that benefits industry, researchers, and PLDM is paramount. PAGs, as trusted partners, are uniquely positioned to promote this collaboration and support the development of a registry or the integration of existing ones.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003e4.2.3 Improve Site Preparedness and Recruitment\u003c/h2\u003e \u003cp\u003eRecruitment is not currently viewed as a critical issue, but with multiple trials advancing for DM, along with trials for other diseases, demand might soon outpace current capacity. Many sites rely on existing patients for enrollment and face staffing shortages that could limit participant support. Furthermore, if current interventional trials prove inconclusive or require refined genetic inclusion criteria, current participant pools may prove insufficient.\u003c/p\u003e \u003cp\u003eTo prepare, trial sites and sponsors should coordinate to:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePlan and invest in staffing and research coordinator support.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAnticipate biomarker-based, targeted trials, which may reduce sample sizes but require broader registry data.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDraw lessons from spinal muscular atrophy (SMA), where small, rigorously defined cohorts enabled efficient trial success.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eEarly preparation is key to ensuring readiness as more DM trials move forward.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003e4.2.4 Develop Patient-Centered Trial Design\u003c/h2\u003e \u003cp\u003ePLDM and caregivers repeatedly underscored the heavy burden of trial participation, including financial, logistical, and physical demands. Unless trial design is more patient-centered, participation will skew toward wealthier or less burdened individuals, limiting inclusivity and potentially biasing results.\u003c/p\u003e \u003cp\u003eRecommendations include:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eCovering travel, hotel, and childcare costs upfront.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eOffering flexible reimbursement methods (direct deposit, cash, check).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eProviding at-home visits for blood draws and basic testing.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTraining staff in DM-specific care needs.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eExpanding opportunities for patients to initiate contact with trial sites.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAs one PLDM explained, \u003cem\u003e\u0026ldquo;Failure to address inequities may lead to skewed samples of healthier, wealthier participants.\u0026rdquo;\u003c/em\u003e\u003c/p\u003e \u003cp\u003eImportantly, PAGs have a central role in this area. By elevating patient voices and working with sponsors, they can advocate for participant-friendly trial structures, ensure adequate financial and logistical support, and help design approaches that reduce barriers for PLDM and caregivers. They can also monitor whether trial practices align with patient priorities and push for changes when gaps remain.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Integrated Approach\u003c/h2\u003e \u003cp\u003eThese recommendations are interdependent. Validated endpoints require robust data to establish, registries support both recruitment and trial design, and patient-centered approaches depend on site preparedness. PAGs are uniquely positioned to weave these efforts together, convening stakeholders, amplifying patient voices, and ensuring alignment across the ecosystem. Addressing barriers collectively will prepare the DM community for trials and accelerate treatments. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e provides a roadmap linking these solutions to the barriers they are designed to overcome.\u003c/p\u003e \u003cp\u003eWhile these solutions offer a roadmap forward, several limitations of this study should be acknowledged. First, survey responses from research coordinators, PIs, and pharmaceutical partners were limited and may not represent the full global and international landscape, especially as current experiences with DM1 trials are limited. While outreach was conducted internationally, most respondents were U.S.-based. Second, PLDM and caregivers engaged through MDF may be more connected than those outside the advocacy network, potentially biasing perspectives toward more favorable views of MDF or greater awareness of clinical trial readiness. Third, reliance on self-reported data from surveys and interviews may introduce social desirability bias. Fourth, this study focuses primarily on DM1. As current pharmaceutical development efforts focus on DM1, the study included only few participants with DM2. For PLDM and caregivers, the majority of respondents either have DM1, care for someone with DM1, or are working towards a DM1 clinical trial. This limits the generalizability of information from this study for patients with DM2.\u003c/p\u003e \u003cp\u003eIn conclusion, this study demonstrates an urgent and actionable need for the myotonic dystrophy community to coalesce around the development of comprehensive, standardized, and validated clinical endpoints that fully capture the multisystemic complexity of DM. Equally essential are robust frameworks for data and resource sharing and the systematic inclusion of patient and caregiver perspectives to overcome substantial barriers to clinical trial participation as a result of disease burden and symptom variability.\u003c/p\u003e \u003cp\u003eWe advocate for immediate, coordinated action: establishment of a dedicated working group on endpoints, a scientific session with the U.S. Food and Drug Administration (FDA), development of a comprehensive and accessible registry, strengthened trial site readiness, and the adoption of patient-centered trial designs that minimize participation burden.\u003c/p\u003e \u003cp\u003eWith numerous therapeutic candidates approaching or entering clinical development, the window of opportunity is now. Building the necessary infrastructure, aligning stakeholders, and embedding patient priorities at the core of trial design are critical to accelerating the path to effective therapies and transforming outcomes for individuals with DM.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics Approval and Consent to Participate\u003c/h3\u003e\n\u003cp\u003eThis study was determined to be exempt by the Advarra Institutional Review Board (IRB) as Pro00081721. All participants were informed of the potential risks and benefits of their participation through verbal or written informed consent processes (or a combination of the two).\u003c/p\u003e\n\u003ch3\u003eConsent for Publication\u003c/h3\u003e\n\u003cp\u003eAll participants consented to use of the data collected for this research for publication. Additionally, all data has been de-identified.\u003c/p\u003e\n\u003ch3\u003eAvailability of Data and Materials\u003c/h3\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to confidentiality of the participants but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch3\u003eCompeting Interests\u003c/h3\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eFunding for this study was provided by the Myotonic Dystrophy Foundation as part of its role as a patient advocacy organization, and Third Plateau, a consulting firm, was hired by MDF to conduct this study. Third Plateau and Myotonic Dystrophy Foundation together conceptualized the study, reviewed and analyzed the data, and prepared the manuscript collaboratively.\u003c/p\u003e\n\u003ch3\u003eAuthors\u0026rsquo; Contributions\u003c/h3\u003e\n\u003cp\u003eJSW and AR designed the phased, mixed-method study methodology and served as co-principal investigators. JSW, ARM, and JW developed the data collection tools (e.g., interview guides, survey) with input from AR and TS. JSW, ARM, and JW collected all qualitative and quantitative data and completed the analysis of the data. JSW led the qualitative data analysis while ARM led the quantitative data analysis. JSW, ARM, EH, and JW created the data visualizations. JSW, ARM, JW, and EH drafted the original draft of the manuscript. TS and AR edited the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch3\u003eAcknowledgements\u003c/h3\u003e\n\u003cp\u003eWe would like to acknowledge and thank the participants in this study, particularly those with lived experiences dealing with DM, as a patient or a caregiver. We appreciate your expertise and your time participating in this study to hopefully improve the clinical trial process for the future. We would also like to thank Drs.\u0026nbsp;Nadine Skinner, Jane Larkindale, and Jacinda Sampson for critical review and feedback.\u003cstrong\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJohnson NE, Butterfield RJ, Maybe K, Newcomb T, Imburgia C, Dunne D et al. Population-based prevalence of myotonic dystrophy type 1 using genetic analysis of statewide blood screening program. Neurology. 2021;96(7):1045-53. 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Curr Opin Pediatr. 2016;28(3):312\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MOP.0000000000000351\u003c/span\u003e\u003cspan address=\"10.1097/MOP.0000000000000351\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Myotonic Dystrophy, clinical trial barriers, mixed-methods, patient advocacy groups, registry, rare disease","lastPublishedDoi":"10.21203/rs.3.rs-8961613/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8961613/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMyotonic dystrophy (DM) is a multisystemic disorder characterized by significant heterogeneity in symptom manifestation, progression, and severity. This variability complicates clinical trial design and implementation, thereby affecting therapeutic development. This study aimed to identify barriers to clinical trial readiness in DM and explore actionable solutions by incorporating perspectives from pharmaceutical partners, clinical trial site staff, people living with DM (PLDM), and caregivers. Focus groups, surveys, and interviews were conducted with pharmaceutical partners (n\u0026thinsp;=\u0026thinsp;65), PLDM and caregivers (n\u0026thinsp;=\u0026thinsp;35), principal investigators (n\u0026thinsp;=\u0026thinsp;12), and clinical research coordinators (n\u0026thinsp;=\u0026thinsp;12). Qualitative findings were thematically analyzed and triangulated with survey data to enhance validity. Three major barriers consistently emerged: (1) a lack of comprehensive, validated endpoints that capture outcomes meaningful to patients; (2) insufficient data sharing and coordination across industry; and (3) challenges in trial design, recruitment, and participant burden. PLDM emphasized under-studied but debilitating symptoms\u0026mdash;such as dysphagia, fatigue, and cognitive impairment\u0026mdash;that are rarely prioritized in clinical trials. Pharmaceutical partners cited regulatory uncertainty surrounding composite outcome measures as well as the value of quantitative myotonia indicators as informative holistic disease indicators. Limited access to natural history data, often prohibitively costly for smaller companies, reinforces competitive rather than collaborative dynamics. PLDM and caregivers also highlighted substantial financial, logistical, and accessibility challenges associated with trial participation. Participants favored several strategies to address these barriers: (1) convening a multi-stakeholder scientific session with the U.S. Food and Drug Administration (FDA) and establishing a working group to define and standardize patient-centered, clinically relevant endpoints; (2) developing a comprehensive, coordinated registry that integrates existing data sources, longitudinal health and study data, genetic diagnostic data, supports recruitment and refinement of study inclusion criteria, and enables post-market surveillance; (3) strengthening trial site preparedness and anticipating recruitment needs, including biomarker-driven cohorts; and (4) adopting patient-centered trial designs that minimize burden, with patient advocacy groups (PAGs) serving a central convening and advocacy role by bringing various groups together to discuss these topics. While barriers to DM clinical trial readiness are significant, they are addressable. Coordinated action among industry, regulators, clinicians, and advocacy groups\u0026mdash;guided by patient priorities\u0026mdash;will be essential. Implementing these strategies could accelerate therapeutic development, improve trial inclusivity, and ultimately enhance quality of life for individuals living with DM.\u003c/p\u003e","manuscriptTitle":"Exploring Barriers to Clinical Trial Readiness Among the Myotonic Dystrophy Community: A Mixed-Methods Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-13 07:13:34","doi":"10.21203/rs.3.rs-8961613/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-03-06T12:17:37+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-06T07:14:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-03T12:48:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2026-03-02T10:04:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4649ed05-0fae-444c-a8d4-6efcc874c6fd","owner":[],"postedDate":"March 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T13:44:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-13 07:13:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8961613","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8961613","identity":"rs-8961613","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}