Capturing the True Impact of Duchenne Muscular Dystrophy: How Clinical Evidence and Societal Value Should Evolve for Better Healthcare Decisions

Valeria A Sansone, MD, PhD, University of Milan, the NeMO Clinical Center in Milan, Italy; Conny Pelicaen, MSc, Duchenne Parent Project Belgium,  Leuven, Belgium; Paolo Bettica, MD, PhD, Italfarmaco SpA, Milan, Italy; Fleur Chandler, MSc, Patient Access Specialist, London, England, UK; Erik Landfeldt, PhD, IQVIA and Sage Publishing, Stockholm, Sweden; Meindert Boysen, PharmD, MSc, Independent HTA Expert, Arnhem, The Netherlands

Duchenne muscular dystrophy (DMD) is a rare, lethal genetic progressive neuromuscular disease characterized by progressive muscle degeneration, loss of ambulation, and multisystem complications. Beyond the detrimental impact on patients, DMD imposes substantial burden on caregivers, families, and society.

While clinical measures capture disease progression, they often miss the lived experience. This article highlights why health technology assessment (HTA) frameworks must evolve to reflect both measurable outcomes and what matters most to patients and families.

DMD is typically diagnosed in early childhood, with signs of muscle weakness. Patients progressively lose lower limb function, resulting in loss of ambulation (LoA), followed by loss of upper limb function, cardiorespiratory deterioration, and eventually premature death. Measuring this trajectory is fundamental in managing care and evaluating treatment effectiveness.

Validated clinical endpoints are used in both trials and practice to monitor disease status and treatment response. One of the most common endpoints is the 4-stair climb (4SC). A slower 4SC correlates with a reduced participation in physical and social activities of daily living¹ and is predictive of an LoA.²

North Star Ambulatory Assessment (NSAA), time to rise (TTR), and 6-minute walk test (6MWT) each reflect different aspects of disease progression. NSAA directly correlates with increased risk of LoA,³ TTR as an early prognostic factor of disease progression,⁴ and 6MWT as a predictor of disease progression.⁵

As well as predicting clinical value, these endpoints carry practical significance. NSAA reflects tasks related to dressing, bathing, and general mobility. The 4SC indicates when a child can no longer safely climb stairs. These clinical tests, while quantitative, reflect patients’ daily functioning and quality of life (QoL).

As patients progress through different stages of DMD, the relevance of each functional domain shifts. During early stages, walking ability may dominate concerns. Later, the ability to sit upright or maintain minimal arm function becomes essential for communication, independence, and self-care. Delaying early milestones has been associated with the postponement of later milestones.

Slowing down disease progression maintains independence and protects critical developmental periods in childhood. This is important when assessing treatment benefits.

When designing successful clinical trials, the primary endpoint, patient population definition, and duration are key factors. DMD trial design must consider how to align endpoints with both the investigational treatment’s mechanism of action and the specific patient population. If outcomes are selected without regard for baseline function, age, or disease trajectory, results risk missing a treatment difference when one exists.

Furthermore, following patients’ long-term outcomes takes longer than most trials, with evidence gaps necessitating reliance on well-curated, controlled, and high-quality natural history data (NHD).

The United States Food and Drug Administration (FDA) has accepted matched NHD as confirmatory evidence of clinical findings in DMD,⁶ marking a shift toward more pragmatic approaches for assessing long-term outcomes in rare diseases. HTA bodies are beginning to follow, although broader adoption and harmonization are still needed.

Families value stability and preserving function, giving patients and caregivers time to adapt. Delaying the need for hoists or ventilation, preserving the ability to weight-bear, feed oneself, or be able to turn in bed or remain upright can have disproportionate value to patients and their caregivers that traditional quality-adjusted life year (QALY) measures often miss. Failure to consider the patient’s lived experience risks undervaluing therapies slowing disease progression.

Slowing down disease progression maintains independence and protects critical developmental periods in childhood. This is important when assessing treatment benefits.

The cost and complexity of caring for patients increase as the patients’ disease progresses, for both the families and society.

The economic and societal burden of DMD is substantial. Caregivers face income loss (current, future, and pension), home adaptation costs, and considerable emotional, physical, and psychological strain, which increases as the child ages. Caregivers’ mental health and QoL are too often overlooked.⁷ Family relationships are often impacted (eg, with UK divorce rates at 87% for parents of children with physical disabilities⁸), and siblings grow up in the shadow of the condition. As the disease progresses, care complexity increases for both families and systems.

The cost and complexity of caring for patients increase as the patients’ disease progresses, for both the families and society.⁷

The true cost of DMD extends beyond direct healthcare costs, impacting education, social care, and government budget. Yet HTA frameworks rarely incorporate these broader value elements in reimbursement decisions.⁹ Recognizing these gaps, methodological evolution of evidence generation is underway in DMD, including quantifying informal care costs, work absenteeism and presenteeism (valued through human-capital approach), and loss of leisure time (eg, informal care costs estimated using proxy good or opportunity costs methods). Some HTA agencies now recommend including these costs; however, more guidance is needed.

Paradoxically, DMD cost-effectiveness models including caregiver health spillovers may show reduced cost-effectiveness for life-extending therapies. Prolonging survival with high care demands increases caregiver disutility, potentially offsetting QALY gains for patients by losses to caregivers. This trade-off of extending life versus increasing caregiver burden is known as the “caregiver QALY trap.”¹⁰

Several methodological innovations begin to address this: time-dependent bereavement effects, treatment-specific caregiver utilities, and one-off QALY losses associated with major transitions.

Methodologies must evolve to reflect the true burden of DMD and the value of innovation. NHD play a central role. When properly designed and matched for baseline characteristics, NHD offer a powerful alternative to life-long placebo follow-up, especially in rare diseases where such designs may be ethically or practically impossible. In DMD, NHD are increasingly used as comparators to assess long-term outcomes like LoA, loss of upper limb function, or ventilation dependency. These approaches are gaining recognition among regulatory and HTA bodies, but more consistency is needed.

Preference-based measures, such as DMD-QoL-8D and those developed by Project HERCULES, aim to capture dimensions that matter to patients and caregivers: autonomy, social participation, and psychological well-being. These are often missed by generic QoL instruments. Without such measures systematically captured and incorporated into economic models, HTA will continue to undervalue treatments that deliver stability, delay loss, or reduce caregiver stress.

Evolving HTA frameworks should explicitly incorporate caregiver burden and utility, societal costs, bereavement disutility, and supported use of high-quality NHD to inform long-term outcomes in rare diseases such as DMD.

Broader, preference-based tools are essential to capture what truly matters to patients and families.

Ultimately, the value of DMD treatments must be valued based on their real-world impact on both patients and their families. The physical, emotional, and economic toll on caregivers demands formal recognition in HTA cost and QoL dimensions. The growing acceptance of reliable NHD as a comparator reflects a pragmatic evolution to rare diseases’ evidence challenges. Properly matched NHD enable evaluation of long-term treatment effects not captured in clinical trials. Embracing both methodological evolution and real-world relevance will inform and empower decision makers to recognize the full impact of DMD and support innovation where it matters most to society.

References

1. Bendixen RM, Lott DJ, Senesac C, Mathur S, Vandenborne K. Participation in daily life activities and its relationship to strength and functional measures in boys with Duchenne muscular dystrophy. Disabil Rehabil. 2014;36(22):1918-1923.
2. McDonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve. 2013;48(3):343-356.
3. Zambon AA, Gupta VA, Ridout D, et al. Peak functional ability and age at loss of ambulation in Duchenne muscular dystrophy. Dev Med Child Neurol. 2022;64(8):979-988.
4. Mazzone ES, Coratti G, Sormani MP, et al. Timed rise from floor as a predictor of disease progression in Duchenne muscular dystrophy: an observational study. PLoS One. 2016;11(3):e0151445.
5. Mercuri E, Signorovitch JE, Swallow E, et al. Categorizing natural history trajectories of ambulatory function measured by the 6-minute walk distance in patients with Duchenne muscular dystrophy. Neuromuscul Disord. 2016;26(9):576-583.
6. Jahanshahi M, Gregg K, Davis G, et al. The use of external controls in FDA regulatory decision making. Ther Innov Regul Sci. 2021 Sep;55(5):1019-1035.
7. Landfeldt E, Edström J, Buccella F, Kirschner J, Lochmüller H. Duchenne muscular dystrophy and caregiver burden: a systematic review. Dev Med Child Neurol. 2018;60(10):987-996.
8. Wilson M. Raising Children with Additional Needs and Divorce. Ellisons Solicitors. https://ellisons.com/news/raising-children-with-additional-needs-and-divorce/. Published December 21, 2023. Accessed June 26, 2025.
9. Pennington BM. Inclusion of carer health-related quality of life in National Institute for Health and Care Excellence appraisals. Value Health. 2020;23(10):1349-1357.
10. Mott DJ, Schirrmacher H, Al-Janabi H, et al. Modelling spillover effects on informal carers: the carer QALY trap. Pharmacoeconomics. 2023;41(12):1557-1561.