Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

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.

Across-site patterns of modulation detection in listeners with cochlear implants.

In modern cochlear implants, much of the information required for recognition of important sounds is conveyed by temporal modulation of the charge per phase in interleaved trains of electrical pulses. In this study, modulation detection thresholds (MDTs) were used to assess listeners' abilities to detect sinusoidal modulation of charge per phase at each available stimulation site in their 22-electrode implants. Fourteen subjects were tested. MDTs were found to be highly variable across stimulation sites in most listeners. The across-site patterns of MDTs differed considerably from subject to subject. The subject-specific patterns of across-site variability of MDTs suggest that peripheral site-specific characteristics, such as electrode placement and the number and condition of surviving neurons, play a primary role in determining modulation sensitivity. Across-site patterns of detection thresholds (T levels), maximum comfortable loudness levels (C levels) and dynamic ranges (DRs) were not consistently correlated with across-site patterns of MDTs within subjects, indicating that the mechanisms underlying across-site variation in these measures differed from those underlying across-site variation in MDTs. MDTs sampled from multiple sites in a listener's electrode array might be useful for diagnosing across-subject differences in speech recognition with cochlear implants and for guiding strategies to improve the individual's perception.

Psychophysical assessment of stimulation sites in auditory prosthesis electrode arrays.

Auditory prostheses use implanted electrode arrays that permit stimulation at many sites along the tonotopic axis of auditory neurons. Psychophysical studies demonstrate that measures of implant function, such as detection and discrimination thresholds, vary considerably across these sites, that the across-site patterns of these measures differ across subjects, and that the likely mechanisms underlying this variability differ across measures. Psychophysical and speech recognition studies suggest that not all stimulation sites contribute equally to perception with the prosthesis and that some sites might have negative effects on perception. Studies that reduce the number of active stimulation sites indicate that most cochlear implant users can effectively utilize a maximum of only about seven sites in their processors. These findings support a strategy for improving implant performance by selecting only the best stimulation sites for the processor map. Another approach is to revise stimulation parameters for ineffective sites in an effort to improve acuity at those sites. In this paper, we discuss data supporting these approaches and some potential pitfalls.

Nonword repetition with spectrally reduced speech: some developmental and clinical findings from pediatric cochlear implantation.

Nonword repetition skills were examined in 24 pediatric cochlear implant (CI) users and 18 normal-hearing (NH) adult listeners listening through a CI simulator. Two separate groups of NH adult listeners assigned accuracy ratings to the nonword responses of the pediatric CI users and the NH adult speakers. Overall, the nonword repetitions of children using CIs were rated as more accurate than the nonword repetitions of the adults. The nonword repetition accuracy ratings from both groups of subjects were correlated with open- and closed-set word recognition scores and forward digit spans. Only the perceptual accuracy scores from pediatric CI users were correlated with measures of speech production accuracy. These results suggest that although the pediatric CI users had more experience and success in perceiving speech under degraded auditory conditions, developmental differences in their memory skills prevent them from performing as well on working memory tasks as mature listeners.