Background:Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments.Objective:To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance.Methods:This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs.Results:The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy.Conclusions:The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

Purpose: Traditional value assessment frameworks are challenged in comprehensively assessing the societal value new therapies bring to individuals with rare, progressive, genetic, fatal, neuromuscular diseases such as Duchenne muscular dystrophy (DMD). The objective of this study was to identify how value assessment frameworks may need to be adapted to measure the value to society of DMD therapies. Patients and Methods: Three stakeholder groups (6 patient advocates, 4 clinicians, 3 health economists; N = 13) participated in semi-structured interviews around the International Society for Pharmacoeconomics and Outcomes Research's Value Flower, which includes elements to consider within value assessments of healthcare technologies. Results: All stakeholders agreed that traditional value assessment frameworks based on the quality-adjusted life year (QALY) are narrow and will undervalue new DMD therapies. All stakeholders expressed some level of concern that using the QALY as a key metric of value discriminates against patients with severe progressive diseases and disabilities. Some stakeholders saw value in using the QALY for cross-disease comparisons in resource-constrained environments if the methodology was appropriate. All stakeholders recommended considering additional elements of value in decision-making around new DMD therapies. These elements reflect: economic and humanistic costs incurred by patients, caregivers, and families with Duchenne, such as indirect out-of-pocket costs, lost productivity, and family spillovers; meaningful attributes for individuals with disabilities and high unmet need, such as severity of disease, value of hope, and real option value; and factors that contribute to improvements in population health, such as insurance value, equity, and scientific spillovers. Conclusion: These findings highlight the need to expand traditional value assessment frameworks and take a holistic approach that incorporates the perspectives of individuals with Duchenne, caregivers, clinicians, and health economists when assessing the societal value of new DMD therapies. Broadening value assessment will prevent restricted or delayed access to therapies for individuals with Duchenne.

Background: Duchenne muscular dystrophy (DMD) is a progressive, life-limiting, neuromuscular disorder. Clinicians play an important role in informing families about therapy options, including approved gene therapies and clinical trials of unapproved therapies. Objective: This study aimed to understand the perspectives of clinicians about gene therapy for DMD, which has not previously been studied. Methods: We conducted interviews with specialist clinicians treating patients with DMD in the United States (n = 8) and United Kingdom (n = 8). Interviews were completed in 2022, before any approved gene therapies, to gain insight into barriers and facilitators to implementing gene therapy and educational needs of clinicians. Results: Most respondents expressed cautious optimism about gene therapy. Responses varied regarding potential benefits with most expecting delayed progression and duration of benefit (1 year to lifelong). Concern about anticipated risks also varied; types of anticipated risks included immunological reactions, liver toxicity, and cardiac or renal dysfunction. Clinicians generally, but not uniformly, understood that gene therapy for DMD would not be curative. Most reported needing demonstrable clinical benefit to justify treatment-related risks. Conclusions: Our data demonstrate variability in knowledge and attitudes about gene therapy among clinicians who follow patients with DMD. As our knowledge base about DMD gene therapy grows, clinician education is vital to ensuring that accurate information is communicated to patients and families.

OBJECTIVES/GOALS: This study surveyed parents and/or caregivers of children with Duchenne and Becker muscular dystrophy (DBMD) to obtain their perspectives on experiences during multidisciplinary team (MDT) clinic visits. The goal was to improve DBMD care by identifying positive and negative aspects of the visits. METHODS/STUDY POPULATION: Multidisciplinary care models have been widely used in many disciplines, as they provide excellent opportunities for patient-centered care (PCC). Survival of patients with Duchenne muscular dystrophy (DMD) has improved with multidisciplinary care. As the model continues to evolve, additional services and disciplines are added, and exploring parents’ and caregivers’ perspectives on multidisciplinary care for patients with DBMD must be assessed. A survey, via a non-identifiable Redcap link, was emailed to registered parents/caregivers through The Duchenne Registry provided by Parent Project Muscular Dystrophy (PPMD). The survey contained questions concerning the children’s demographics, medical information, knowledge, and perspectives on MDT visits. RESULTS/ANTICIPATED RESULTS: A total of 186 parents/caregivers of DMBD patients responded to the survey. Respondents were white (83.1%), bi/multi-racial (9.3%), African American (1.6%), and other (2.7%). The average travel distance to the care site was 228.37 miles. Most respondents (75%) had their visits within one day, but 25% had visits over ≥2 days. 89.0% of respondents preferred a single MDT meeting with their child’s care providers; 89.4% indicated they had enough time with each provider, 86.1% were satisfied with the MDT care, and 81% said they received enough information prior to the visit. Scheduling difficulties were rare for MDT visits, but common when arranging care with providers not included in the MDTs. DISCUSSION/SIGNIFICANCE: MDT clinic visits enable patients to see multiple caregivers in a single visit. Our study suggests that parents and caregivers of DBMD patients prefer to have MDT visits and are satisfied with the care. This information will support the DBMD community as they continue to advocate for MDT visits.

Background: Corticosteroids are recommended to all people with Duchenne as standard of care; patient experience data is important to guide corticosteroid decision making and as a comparator for new treatment options. Objective: This study assesses patient and caregiver-reported benefits and side effects from corticosteroids to treat Duchenne muscular dystrophy, their importance, and satisfaction. Methods: Using one-on-one interviews (n = 28) and an online survey (n = 236), parents and adults with Duchenne reported corticosteroid benefits and side effects rated as both experienced and important. Results: Benefits to breathing, heart function, arm strength, slowing progression of weakness, and getting around were rated as particularly important, regardless of ambulatory status. Important side effects included increased fracture risk, unwanted weight gain, and diabetes/prediabetes. Parents rated behavior issues and adults rated delayed puberty as having high importance. Being ambulatory was independently associated with reporting more net benefit (p = 0.02). For side effects, parent scores were significantly higher than adult score (p = 0.02). Corticosteroid type was not significant. Participants were, overall, satisfied with corticosteroids (means ranging from 6.2 to 7.7 on a scale of 0-10), with no significant differences based on corticosteroid type. Conclusions: Overall, most participants were satisfied with the use of corticosteroids. While a range of side effects were rated as important and relatively common, individuals using corticosteroids and their caregivers indicate that benefits outweigh the side effects. Qualitative data indicate that high acceptability is influenced by lack of treatment alternatives. Patient experience data on use of corticosteroids in Duchenne may be relevant to drug development, regulatory assessment of new treatments, and to families making decisions about corticosteroid use.

Caregivers routinely inform medical and regulatory decision making in rare pediatric diseases. While differences in treatment preferences across caregivers and patients have been observed for Duchenne muscular dystrophy, this evidence was limited by small samples of patients and results were confounded by patient age and disease progression. We tested caregiver and patient preference concordance for treating Duchenne. Preferences and demographic/clinical information from 115 caregivers and 107 patients were collected in an international study (response = 80%) using a previously developed discrete-choice experiment consisting of 12 experimentally controlled choice tasks. Each task presented two profiles that varied across four attributes: disease progression, drug failure probability, kidney damage risk, and fracture risk. Caregivers and patients were matched 1:1 based on patient age. We tested for concordance across each task and by comparing caregivers’ and patients’ maximum acceptable risk of drug failure, kidney damage, and fracture for a slowing of disease progression. The final analysis included 77 caregivers and 77 patients. No differences were observed in nationality (p = 0.969), disease stage (p = 0.180), or demographic/clinical factors (p = 0.093–0.857); however, patients were more optimistic (p = 0.030). Caregivers and patients chose similarly across tasks (p = 0.101–0.993). To slow disease progression by 1 year, caregivers and patients would tolerate a 9% and 11% increase in drug failure probability, respectively (p = 0.267). Alternatively, they would accept a 3% and 4% increase in the risk of kidney damage (p = 0.719) or a 15% and 20% increase in the risk of fracture (p = 0.534). Caregivers and patients had concordant preferences for treating Duchenne. Providers and regulators can trust both caregiver and patient report of preferences to inform medical decision making.

Duchenne muscular dystrophy (DMD) is a progressive, fatal neuromuscular disorder typically diagnosed between 4 and 5 years of age. DMD currently has five FDA approved therapies, which has led to increased interest in newborn screening (NBS) for DMD. Our objective was to explore the perspectives and predicted practices of physicians (primarily neurologists) who will likely be responsible for the follow-up of infants identified with DMD through NBS. A short survey was developed and distributed to physicians who are responsible for providing care for patients with Duchenne at Certified Duchenne Care Centers across the USA. Twenty-seven physicians responded to statements about benefit and readiness for dystrophinopathy NBS, which care recommendations they would make at initial infant visits, and when they would recommend initiating approved therapies. Most DMD physicians indicated they see benefit in NBS (82%) and believe the DMD care community is ready for NBS in dystrophinopathies (74%). The majority of physicians would recommend multiple interventions, including genetic counseling, maternal carrier testing, referral to early intervention services, screening siblings, discussion of clinical trials, exon skipping therapies, and assessment of social and language development at initial visits. The majority of physicians also indicated they would recommend initiating approved therapies much earlier than the typical age of diagnosis.

Duchenne muscular dystrophy has been a launching pad for patient-focused drug development (PFDD). Yet, PFDD efforts have largely neglected non-ambulatory patients. To support PFDD efforts in this population, we primarily sought to understand the needs of non-ambulatory Duchenne patients and, secondarily, to examine these needs in the context of the PUL-PROM—a validated patient-reported outcome measure of upper limb functioning. Non-ambulatory Duchenne patients or their caregivers from eight countries answered open-ended survey questions about patients’ needs related to their most significant symptoms and important benefits of new treatments. The PUL-PROM was used to evaluate patients’ upper limb functioning and was compared to data collected on non-ambulatory stage and quality of life. We thematically analyzed open-ended data, descriptively analyzed close-ended data, and compared themes by non-ambulatory stage. The study included 275 participants. Mean patient age was 24. Most patients were early-stage non-ambulatory (67%). Thematic analysis identified three congruent themes between significant symptoms and important benefits of new treatments: muscle functioning, especially upper limb function; body system functioning; and quality of life. Muscle functioning and body system functioning were endorsed more frequently in responses from early- and late-stage patients, respectively. Mean PUL-PROM total score was 22 with higher scores in early-stage patients (p ≤ 0.001). Upper limb function positively correlated with quality of life (r = 0.42, p ≤ 0.001). Non-ambulatory Duchenne patients want new treatments that improve upper limb functioning and body system functioning, and not exclusively regaining ambulation. The PUL-PROM can be used as a patient-centric measure that accounts for the needs of later-stage Duchenne patients.

Duchenne muscular dystrophy is the most common form of muscular dystrophy diagnosed in childhood but is not routinely screened for prenatally or at birth in the United States. We sought to characterize the diagnostic experiences of families and describe their preferences for newborn screening (NBS). We conducted a registry-based survey of families with Duchenne and Becker muscular dystrophy that included open- and closed-ended questions regarding the journey to a diagnosis, preferences for when to learn of a diagnosis, and how knowledge of a diagnosis would impact life decisions. Open-ended responses were analyzed thematically, and closed-ended responses were analyzed descriptively. Sixty-five families completed the survey. The average ages of first concern and diagnosis were 2 and 4 years, respectively. One-third of families (30%) indicated that they would prefer to receive a diagnosis in the newborn period irrespective of treatment options available, and nearly all of the remaining families (93%) indicated that they would want to learn about a diagnosis if there were treatments that worked well during the newborn period. All families (100%) indicated that a diagnosis in the newborn period would impact life decisions. We identified three overarching themes, which described the stages of the diagnostic journey, including having concerns about the child, seeking answers, and receiving the diagnosis. NBS can facilitate improved health outcomes through early access to care, and inform families on major health and nonhealth decisions. The preferences and experiences of families and other stakeholders should be considered when determining the potential value and benefit of expanding NBS programs.

BACKGROUND:Duchenne muscular dystrophy is a rare degenerative neuromuscular disorder with pediatric onset. Recent approvals in Duchenne have placed attention on the economic evaluation in pricing and reimbursement decisions across a range of rare conditions. We sought to assess the appropriateness of the EQ-5D, a common measure of generic health state utility, for use among patients and caregivers affected by Duchenne.METHODS:An international, cross-sectional sample of adults with Duchenne and caregivers reported patient health status using self- or proxy-reported EQ-5D-3L. Appropriateness was assessed across 6 domains of concern raised by stakeholders in Duchenne. These concerns were that the EQ-5D/EQ-VAS would not capture meaningful differences in health status, correlate with disease-specific measures, reflect real health status, exhibit face validity, be accurately interpreted, and be low burden. We evaluated these concerns by comparing EQ-5D index score and EQ-VAS scores to other condition-specific functional measures and open- and closed-ended questions.RESULTS:In total, 263 participants (74% response) completed the survey, 24% of whom were adult patients. Most participants lived in the United States or United Kingdom (58%). Patient age ranged from 1 to 48 y. EQ-5D index was higher in ambulatory than nonambulatory patients (0.60 v. 0.30, P < 0.001) and was negatively correlated with upper limb impairment (r = 0.61, P < 0.001). Three-quarters of respondents agreed that EQ-5D measured real health status (74%). Most respondents interpreted EQ-VAS anchors of best and worst imaginable health as full health (61%) and death/near death (58%). Respondents indicated the EQ-5D was easy to understand (86%) and answer (71%).CONCLUSIONS:Contrary to anecdotal concerns, we found support for the appropriateness of EQ-5D to assess health status in Duchenne. While other measures may be more sensitive to specific outcomes in Duchenne, there may be some value in results using the EQ-5D measure.

To the Editor: We read with interest the comment in response to our recent publication, ‘‘Assessing the Appropriateness of the EQ-5D for Duchenne Muscular Dystrophy: A Patient-Centered Study.’’ This comment provides some perspectives with which we would naturally agree, such as the importance of patient centeredness in medical decision making. There are several other points that highlight areas in which there is ambiguity with regard to the similarities and differences between patient-reported outcome measures (PROMs) and preference-based utilities measures such as the EQ-5D and particularly the evaluation of such measures to inform medical decision making based on economic evaluation. At the outset, it is important to note that our initial intent was to document the limitations of using the EQ-5D in Duchenne. As the EQ5D is a short and generic measure of health status, it was expected that it would not comprehensively capture all important aspects of any condition. However, an empirical assessment of the data seemed to indicate that there may be fewer barriers to using this measure than one would think a priori. As the comment points out, our work does not provide strong evidence of the content validity of the EQ5D measure in Duchenne. This is in part because demonstrating content validity was not an objective of our study, nor did we claim that the measure demonstrates content validity. Rather, we sought to address the ‘‘real needs and controversies in the Duchenne community regarding the use of the EQ-5D to inform the costeffectiveness of emerging therapies,’’ as well as to explore ‘‘broader questions regarding the use of preference-based measures and QALYs in rare and pediatric diseases.’’ Although we did not primarily focus on content validity, that most respondents indicated that the instrument was easy to answer and that it was consistent with the health state does indicate that the EQ-5D instrument may have some content validity in the context of Duchenne. While there is a growing focus on patient centeredness throughout economic evaluation and the medical product life cycle, current decision making regarding resource allocation is still largely determined by generic measurements of health status, which allow for comparisons to be made across all conditions (e.g., Duchenne, cancer, asthma, etc.). The notion that one need first establish that the measure captures the correct content is not consistent with the predominant paradigm of bodies such as National Institute for Health and Care Excellence (NICE) in the United Kingdom or the Institute for

Background In clinical trials for rare diseases, such as Duchenne muscular dystrophy, clinical outcome assessments (COA) used to assess treatment benefit are often generic and may not be sensitive enough to detect change in specific patient populations. Thus, there is a need for disease specific COAs that track meaningful change among individuals. When developing such measures, input from clinicians, caregivers and patients is critical for assessing clinically relevant concepts and ensuring validity of the measure. Method The aim of this study was to develop two Duchenne-specific global impression items for use in clinical trials. The development of the Duchenne Clinical Global Impression of Change (CGI-C) and Caregiver Global Impression of Change (CaGI-C) was informed by findings from concept elicitation (CE) interviews with clinicians, caregivers and individuals with Duchenne. Through cognitive debriefing (CD) interviews, clinicians and caregivers evaluated draft CGI-C and CaGI-C items to ensure relevance and understanding of the items and instructions. Suggestions made during the CD interviews were incorporated into the finalized CGI-C and CaGI-C measures. Results The symptoms most frequently reported by clinicians, caregivers and individuals with Duchenne were muscle weakness, fatigue, cardiac difficulties and pain. Regarding physical functioning, all three populations noted that small changes in functional ability were meaningful, particularly when independence was impacted. Caregivers and clinicians reported that changes in speed, endurance and quality of movement were important, as was improvement in the ability of individuals to keep up with their peers. A change in the ability to complete everyday activities was also significant to families. These results were used to create two global impression of change items and instruction documents for use by clinicians (CGI-C) and caregivers (CaGI-C). Overall, both items were well understood by participants. The descriptions and examples developed from the CE interviews were reported to be relevant and appropriate for illustrating different levels of meaningful change in patients with Duchenne. Modifications were made based on caregiver and clinician CD feedback . Conclusions As part of a holistic measurement strategy, such COA can be incorporated into the clinical trial setting to assess global changes in relevant symptoms and functional impacts associated with Duchenne.

Abstract Background Gene therapy offers an etiologically targeted treatment for genetic disorders. Little is known about the acceptance of mortality risk among patients with progressive, fatal conditions. We assessed patients’ and caregivers’ maximum acceptable risk (MAR) of mortality for gene therapy when used to treat Duchenne muscular dystrophy (DMD). Methods The threshold technique was used to assess tolerance for mortality risks using a hypothetical vignette. Gene therapy was described as non‐curative and resulting in a slowing of progression and with a 10‐year benefit duration. MAR was analyzed using interval regression for gene therapy initiated “now”; in the last year of walking well; in the last year of being able to bring arms to mouth; and in newborns (for caregivers only). Results Two hundred eighty‐five caregivers and 35 patients reported the greatest MAR for gene therapy initiated in last year of being able to lift arms (mean MAR 6.3%), followed by last year of walking well (mean MAR 4.4%), when used “now” (mean MAR 3.5%), and when used in the newborn period (mean MAR 2.1%, caregivers only). About 35% would accept ≥200/2000 risk in the last year of being able to lift arms. Non‐ambulatory status predicted accepting 1.8 additional points in MAR “now” compared with ambulatory status (p = 0.010). Respondent type (caregiver or patient) did not predict MAR. Conclusion In this first quantitative study to assess MAR associated with first‐generation DMD gene therapy, we find relatively high tolerance for mortality risk in response to a non‐curative treatment scenario. Risk tolerance increased with disease progression. Patients and caregivers did not have significantly different MAR. These results have implications for protocol development and shared decision making.

Introduction: There is a groundswell of interest from patient, industry, and regulatory groups to rigorously and transparently integrate patient-voice into regulatory decision-making. Patient-focused drug development (PFDD) is an approach established by the US Food and Drug Administration to systematically incorporate patient experiences into drug development and evaluation. It has created a demand for scientific advancement to measure and integrate patient-voice into decision-making. Areas covered: This narrative review describes the evolving nature of advocacy-regulatory relations preceding PFDD, characterizes current PFDD and other patient-engagement activities, and explores future opportunities for patient participation along the drug development pipeline. We present Duchenne muscular dystrophy as a case study to illustrate how PFDD is being operationalized by patient groups and regulators using both verbal and written data sources. Expert opinion: PFDD represents the most widespread approach yet to integrate the patient voice as a source of evidence to inform regulatory decision-making. Regulatory approvals are just one frontier in drug development. On the horizon remain uncertainties in how patient experience can inform post-marketing surveillance, pricing, reimbursement, and health technology assessment. Patient-input may be particularly crucial to demonstrate the value of expensive first-generation rare disease treatments that confer meaningful benefits but do not meet traditional thresholds for cost-effectiveness.

Project HERCULES is an international patient led multi stakeholder collaboration developing tools and evidence supporting HTA for new treatments for Duchenne Muscular Dystrophy (DMD) including a bespoke Quality of Life metric, a natural history model, a burden of illness study and a core economic model. The evidence reflects patient experience and patients and patient organisations can shape the framework for HTA in DMD. This has led to a new paradigm for developing evidence for HTA and an improved understanding of DMD impacting on HTA decisions. Project HERCULES is led by Duchenne UK with a core team including two parents of boys with DMD, one of whom is also a health economist. This unique combination brings health economics and HTA expertise combined with the lived patient experience to deliver this ambitious health economics research programme. Patient organisation leadership enables access to data sources and expertise which may be inaccessible for individual researchers. An iterative approach to the individual workstreams ensures each workstream has high levels of patient involvement, shaping outcomes to embody actual patient and family experience. This patient led approach has led to each workstream of Project HERCULES better reflecting the true impact of DMD:•Identification of a previously undefined disease stage between the traditional stages of late ambulatory and early non ambulatory•Development of a bespoke Quality of Life metric•An economic model encompassing the actual experience of patients and families•A burden of illness study focussing on what is most impactful on patients and families.•Identification of future research priorities reflecting what is important to patients. Project HERCULES has demonstrated the potential impact of patient led evidence generation in a rare disease for use in HTA.

Objectives Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder that causes progressive weakness and early death. Gene therapy is an area of new therapeutic development. This qualitative study explored factors influencing parents' and adult patients' preferences about gene therapy. Methods We report qualitative data from 17 parents of children with DMD and 6 adult patients. Participants responded to a hypothetical gene therapy vignette with features including non-curative stabilizing benefits to muscle, cardiac and pulmonary function; a treatment-related risk of death; and one-time dosing with time-limited benefit of 8-10 years. We used NVivo 11 to code responses and conduct thematic analyses. Results All participants placed high value on benefits to skeletal muscle, cardiac, and pulmonary functioning, with the relative importance of cardiac and pulmonary function increasing with disease progression. More than half tolerated a hypothetical 1% risk of death when balanced against Duchenne progression and limited treatment options. Risk tolerance increased at later stages. Participants perceived a 'right time' to initiate gene therapy. Most preferred to wait until a highly-valued function was about to be lost. Conclusion Participants demonstrated a complex weighing of potential benefits against harms and the inevitable decline of untreated Duchenne. Disease progression increased risk tolerance as participants perceived fewer treatment options and placed greater value on maintaining remaining function. In the context of a one-time treatment like gene therapy, our finding that preferences about timing of initiation are influenced by disease state suggest the importance of assessing 'lifetime' preferences across the full spectrum of disease progression.