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.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are pressing public health problems occurring alongside the rising prevalence of obesity and diabetes. This feasibility study explored the use of a novel prescription digital therapeutic (PDT) in this patient population. METHODS: A prospective, open-label study was conducted at two hepatology clinics. Eligible patients had a baseline FibroScan controlled attenuation parameter >274 dB/m. Participants were given access to a PDT containing a novel form of cognitive behavioral therapy designed to treat cardiometabolic disease. Laboratory assessments, FibroScan, and magnetic resonance imaging proton density fat fraction (MRI-PDFF) imaging were conducted preintervention and postintervention. RESULTS: Twenty-two participants were enrolled. Mean baseline fat fraction on MRI-PDFF was 18.7%. After the 90-day intervention, the mean relative reduction in MRI-PDFF was -16.2% (P = .011) in those with baseline PDFF >= 10%. Mean alanine transaminase decreased by -17.1 IU/L (P = .002). Participants achieved an average total body weight loss of -2.9% (P = .008) and controlled attenuation parameter score was reduced by -18.8 dB/m (P = .021). No serious or device-related adverse events were reported. An average improvement in health-related quality of life of +2.2 Healthy Days per month (P = .500) and high treatment satisfaction (mean Net Promoter Score of +75) were reported. CONCLUSION: After 90 days of digitally delivered cognitive behavioral therapy, improvements were observed in multiple endpoints without any adverse device effects. The safety, efficacy, and usability data observed strengthen the hypothesis that PDTs provide a scalable tool to address unmet behavioral treatment needs in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (ClinicalTrials.gov number, NCT05357248).

The path to effective therapies across the landscape of the approximately 7,000 rare genetic diseases has been both tortuous and transformative. The Duchenne muscular dystrophy (DMD) experience represents the former and may be emblematic of the challenges faced when developing therapies for those genetic diseases with high unmet need but variable presentations that ultimately progress to disabling and fatal outcomes. To date, the FDA has approved four treatments in DMD, all through the mechanism of "accelerated approval" (AA).

Currently, pediatric research involving investigational gene therapies (GT, used without intending to imply a therapeutic effect) targets a broad range of indications (including rare and ultra-rare diseases) that vary in severity and availability of approved disease-modifying therapies. Because of this diversity of circumstances, there is no one-size-fits-all list of ethical concerns relevant to all uses of investigational GTs in children. Here, we review the main ethical issues, specifically those surrounding the current state of knowledge about GT product-related immunogenicity, toxicity, duration, irreversibility, informed consent/assent, trial design (including the question of who 'goes first'), participant and caregiver burdens, and equity in diagnosis and access to research opportunities. Ethical issues that can be anticipated to arise in pediatric GT clinical trials, e.g., the uncertainty and risk of this research, the resultant preclusion of GT trial participants from other research, the length of follow-up monitoring, and the urgency often felt by caregivers dealing with dire, rapidly progressive conditions, should be proactively identified, addressed in accordance with existing best practices, and transparently discussed among all stakeholders.

Advancements in fetal assessment and therapeutic intervention in medical practice and clinical research call for corresponding progress in regulatory and ethical guidance. In “A new ethical framework for assessing the unique challenges of fetal therapy trials,” Hendriks et al. (2022) propose a new way of thinking about the ethics of clinical research on fetal therapies, which necessarily involve both the pregnant woman and the fetus. They reject the current view that we should look only at the clinical risks and benefits. Instead, they argue that psychosocial factors are crucial and recommend that considering such factors is the only adequate way to address the asymmetrically distributed risks and benefits that accrue to the fetus and the pregnant woman. Current US Health and Human Service regulations limit research to studies where the risk to the fetus is minimal unless it holds out the prospect of a direct benefit to the fetus or the pregnant woman (45C.F.R. 46.204 (b)). Hendricks et al. (2022) argue for an alternative where individual risks for the pregnant woman and the fetus should be justified by both the benefits for each of them and also by the study’s social value, ultimately permitting research with a mildly unfavorable risk–benefit ratio for pregnant women and/or the fetus. Federal regulations guiding pediatric research, based on the Belmont Report and elaborated in the Common Rule Subpart D, offer an instructive perspective and rely heavily on two distinctions (21C.F.R. 50 (d)). The first is between research and clinical practice. To be considered research, there must be a formal protocol designed to produce generalizable knowledge. Innovative therapy is not necessarily research, and medical practice involves clinical recommendations made in the best interest of an individual patient (Earl 2019). In pediatric research, there is a further distinction between projects that have a prospect of direct benefit to the child and those that do not (Bhatnagar et al. 2021). With a prospect of direct benefit, protocols must consider whether potential benefits outweigh potential risks. In the absence of this prospect, protocols are only permissible if they involve minimal (or minor increase over minimal) risk. Additionally, many congenital and genetic diseases require intervention before certain stages of maturation or disease progression. The inability to study therapies in adults or even assenting adolescents means we must instead resolve which protocols are permissible for fetal research with no applicable adult model or limited preliminary data. Despite parallels between pediatric and fetal therapy, the pediatric framework is insufficient to guide the ethical conduct of fetal therapy protocols with pregnant participants. There are important ways in which fetal therapy and fetal therapy research differ from therapy and research involving children. First, almost all fetal research has a prospect of direct benefit which simplifies the analysis. As minimal risk becomes irrelevant, the risk-benefit ratios take priority. The second unique feature of fetal therapy is the more evident one: usually, there are risks to the pregnant woman with no balancing direct medical benefits to her. There are, however, significant indirect benefits. A pregnant woman who consents to a potentially risky antenatal intervention likely does so in the hope that her presumed baby will be better off, the prospect of which is beneficial to her. The medical risks of therapy are balanced by the psychological benefits to the pregnant woman. Outside the scope of traditional medical benefits are intangible aims such as identifying as a “good mother,” benefitting other family members, or the satisfaction that comes from advancing knowledge that may help others. The key threshold question, then, requires a balancing of potential clinical risks and benefits to both fetus and pregnant woman, as well as less tangible though compelling psychological benefits to the pregnant woman. As Hendriks et al. (2022) note, “there is a point at which highly unfavorable risk-benefits to the pregnant women make research unacceptable,” yet precisely how that threshold is established remains unclear. As members of the Pediatric Gene Therapy and Medical Ethics (PGTME) Working Group housed in NYU Grossman School of Medicine’s Division of Medical Ethics, we examine this issue from the