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Gonzalez Castillo et al. J Transl Genet Genom. 2025;9:338-51 https://dx.doi.org/10.20517/jtgg.2025.57 Page 346

Regulatory divergence in treatment approvals
The FDA and the EMA have high concordance in decisions on marketing approvals. However, there are
also divergent authorization decisions based on clinical data, efficacy, safety conclusions and regulatory
authority differences .
[70]
Both the FDA and EMA have expedited approval pathways for therapies intended for serious, life
threatening and rare diseases. In the United States, the AA program allows authorization based on a
surrogate endpoint that is likely to predict a clinical benefit. By contrast, the conditional marketing
authorization (CMA) pathway in the European Union requires a higher level of clinical evidence and does
not rely on surrogate endpoints. These distinctions are illustrated by the FDA’s approval of exon skipping
therapy based on surrogate endpoint and the EMA’s initial approval of Ataluren based on preliminary
efficacy evidence and the benefit-risk balance .
[71]

MEASURES OF MOTOR FUNCTION IN CLINICAL TRIALS AND CLINICAL PRACTICE
Determination of treatment efficacy based on motor function changes must consider many factors.
Understanding the natural history and progressive nature of the disease, the effects of standardized
administration, and patient behavior or cognition on effort-based motor performance, as well as perception
of change and impact on quality of life, are all important when interpreting changes in motor function
measures. Clinical outcome assessments (COAs) have been validated to quantitatively measure clinically
meaningful functional changes in boys with DMD [72-74] . To better understand true change in response to
intervention and interpret clinical trial outcomes, estimates of minimal detectible change (MDC) and
anchored minimal clinically important differences (MCIDs) highlighting the relevance of function to
patient perception have been established for multiple COAs [73,75-77] . The North Star Ambulatory Assessment
(NSAA) incorporates items that may be gained in boys with DMD treated with disease modifying therapies
(DMTs) that would typically be lost with typical disease progression. Based on MDC and MCID estimates,
score thresholds may be applied to define clinical progression of disease and may aid in distinguishing non-
transient functional change using the NSAA. Additionally, timed function tests such as time to climb 4
stairs (4SC) and the Six Minute Walk Distance (6MWD) utilizing continuous data can be sensitive to
change. These may be used to convert data to calculate movement velocity and can be interpreted in the
context of maturation, using percent-predicted results relative to normative values . The Performance of
[78]
Upper Limb 2.0 (PUL 2.0) was designed to measure upper extremity function across the range of severity in
patients with DMD including those who are nonambulatory [79,80] . The scale measures gross and fine motor
function with items that relate to daily function utilizing upper limbs. Results of COAs administered to
assess changes in function must incorporate clinical reasoning, knowledge gained from scale validation, and
lessons learned from previous clinical trials and clinical care to set realistic expectations for functional
prognosis, which may influence clinical decision-making and the recommendations provided to patients
and their caregivers.

FROM CLINICAL TRIALS TO REAL-WORLD: LESSONS LEARNED
Extrapolating clinical trial findings to real-world patients is challenging due to multiple influencing factors.
The perception of gene therapy benefits can differ among patients, caregivers, and providers. Therefore, it is
essential to establish clear definitions and set realistic expectations.

Increases in dystrophin levels after treatment occur gradually over time, and clinical effects might not be
apparent until the first year post-treatment. High-dose steroids used in gene therapy can affect short-term
functional outcomes. This may create inaccurate perceptions of improvement among patients and families.
Discouragement may arise if progress appears to stall during steroid tapering.