Mindy Leffler, who developed the Duchenne Video Assessment used in Capricor’s Phase 3 study and consults on its data, writes from personal experience. Her son has Duchenne muscular dystrophy and has been receiving Capricor’s deramiocel for five years. She recounts how he remains independent and is preparing for another academic year while on treatment, setting a personal tone for the subsequent discussion about trial design and regulatory decisions.
Capricor’s deramiocel was the subject of an FDA advisory committee review that returned a negative vote on a secondary outcome related to the drug’s definitiveness in stabilizing heart function. The advisory committee found the cardiac data for the overall study population to be noisier than the signal observed in a subpopulation of participants who already had signs of heart dysfunction. That contrast between the full cohort and the subpopulation shaped the committee’s view of the strength of the evidence for cardiac stabilization.
Leffler emphasizes that designing trials for rare diseases involves hundreds of small, consequential choices. Sponsors must decide inclusion and exclusion criteria, outcome measures and their definitions, which domains to emphasize, and how to analyze heterogeneous data. Each choice is made with the best available knowledge but without certainty about its downstream impact. Yet these decisions directly affect patients’ access to therapies and the interpretation of whether a treatment is effective.
A concrete example from the Phase 3 trial is the handling of the upper limb primary outcome, which is divided into shoulder, arm, and hand function tasks. Using a total upper-limb measure increases the number of tasks that could capture meaningful change across participants who differ in strengths and weaknesses. However, aggregating domains can introduce noise when many participants have already lost function in certain domains (for example, shoulder tasks) while retaining others (for example, hand tasks).
Focusing on an individual domain, such as arm tasks, can improve the likelihood of detecting statistically significant effects because it reduces heterogeneity, but doing so risks overlooking clinically meaningful changes that occur in weaker or stronger participants outside that chosen domain. The author frames this as a persistent tension: broader measures can be more inclusive and clinically relevant, while narrower measures can be more statistically powerful.
The Duchenne field has now been conducting clinical trials for more than a decade, yet collective experience still leaves many of these trial-design trade-offs unresolved. There is not yet sufficient data to provide definitive guidance on many small decisions, and the field must continue to learn as studies accumulate. Leffler notes that other rare diseases face the same problem: limited historical data make it difficult to select the optimal balance of inclusivity and statistical power in advance.
Leffler poses a central question for regulators: what is the appropriate balance between strict pre-specification of analyses — a foundational principle of rigorous scientific experimentation — and the flexibility to learn and adapt when evidence is sparse? Both sides of this debate have valid arguments. Advocates for flexibility cite urgent unmet patient needs, while proponents of strict pre-specification underscore the importance of avoiding biased, post hoc decisions.
In the case of Capricor, the FDA allowed the company to submit additional upper-limb data and analyses rather than requiring a complete new biologics licensing application. The agency explicitly weighed the time required to generate a new BLA against the potential loss of life and function for patients during that delay, and chose to permit resubmission of analyses. Leffler describes this as a form of regulatory flexibility that can be exercised in rare-disease settings without necessarily sacrificing scientific rigor.
She expresses gratitude for that decision while also urging that the agency use appropriate and rigorous methods when reviewing the new analyses. The goal, she says, should be to accurately understand what is happening to young men on treatment like her son.
The essay concludes by underscoring how the collective outcome of countless small decisions in trial design determines regulatory outcomes and, ultimately, patients’ fates. Leffler’s perspective — informed both by her professional involvement in assay development and by her family’s lived experience — calls for regulators and sponsors to carefully weigh trade-offs, to apply rigorous methods when adapting analyses, and to remember the human consequences of these technical choices.
Mindy Leffler’s disclosure appears in the piece: she developed the Duchenne Video Assessment used in the trial and consults on its data. The article frames the FDA’s allowance for additional analyses as a pragmatic decision aimed at balancing scientific standards with urgent patient needs, while urging rigorous review of those analyses to reach a clear understanding of treatment effects.