FDA Patient-Focused Drug Development Guidances: Considerations for Trial Readiness in Rare Developmental and Epileptic Encephalopathies

Developmental and epileptic encephalopathies (DEE) are rare, often monogenic neurodevelopmental conditions. Most affected individuals have refractory seizures. All have multiple severe impairments which can be as life-limiting as or more limiting than the seizures themselves. Mechanism- and gene-targeted therapies for these individually rare, genetic conditions hold hope for treatment, amelioration of disease expression, and even cure. The near absence of fit-for-purpose (FFP) clinical outcome assessments (COA) to establish the benefits for nonseizure outcomes of these new therapies in clinical trials poses significant challenges to drug development. The Food and Drug Administration Patient-Focused Drug Development guidance series provides direction for how to overcome these challenges and to ensure FFP measures are available for trials. The goal is to have measures that address outcomes of importance to patients and caregivers, reliably and accurately measure the outcome in the spectrum of abilities for the target disease, and are sensitive to meaningful change over time. The guidances identify 3 primary strategies: (1) directly adopting and implementing available outcome measures; (2) creating measures de novo; and (3) a middle path of adapting or modifying existing measures. Emphasized throughout the guidances is the indispensable and extensive role of the patient or caregiver to assuring the goal of having fit measures is achieved. This review specifically considers the difficulties of adopting available COAs in severely impaired patient groups and ways to adapt or modify existing COAs to be FFP as encouraged in the guidances. Adaptations include alternative scoring, use of assessments in out-of-intended age ranges, and modifications for individuals with sensory or motor impairments. Some additional considerations that may facilitate achieving adequate clinical outcome measures, especially for rare diseases, include use of personalized endpoints, merging of existing COAs, and developing a consortium of rare DEE advocates and researchers to ensure fitness of adapted COAs across multiple rare disease groups. The FDA guidances help ensure that clinical trials targeting nonseizure outcomes, especially in severely impaired populations, will have adequately valid and sensitive outcome measures. This in turn will strengthen the ability of trials to provide informative tests of whether treatments provide meaningful therapeutic efficacy.

What does better look like in individuals with severe neurodevelopmental impairments? A qualitative descriptive study on SCN2A-related developmental and epileptic encephalopathy.

PURPOSE: There are limited psychometric data on outcome measures for children with Developmental Epileptic Encephalopathies (DEEs), beyond measuring seizures, and no data to describe meaningful change. This study aimed to explore parent perceptions of important differences in functional abilities that would guide their participation in clinical trials. METHODS: This was a descriptive qualitative study. Semi-structured one-on-one interviews were conducted with 10 families (15 parent participants) with a child with a SCN2A-DEE [8 male, median (range) age 7.5 (4.5-21)] years. Questions and probes sought to understand the child's functioning across four domains: gross motor, fine motor, communication, and activities of daily living. Additional probing questions sought to identify the smallest differences in the child's functioning for each domain that would be important to achieve, if enrolling in a traditional therapy clinical trial or in a gene therapy trial. Data were analyzed with directed content analysis. RESULTS: Expressed meaningful differences appeared to describe smaller developmental steps for children with more limited developmental skills and more complex developmental steps for children with less limited skills and were different for different clinical trial scenarios. Individual meaningful changes were described as important for the child's quality of life and to facilitate day-to-day caring. CONCLUSION: Meaningful change thresholds have not been evaluated in the DEE literature. This study was a preliminary qualitative approach to inform future studies that will aim to determine quantitative values of change, applicable to groups and within-person, to inform interpretation of specific clinical outcome assessments in individuals with a DEE.

Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Preoperative evaluation and surgical management of infants and toddlers with drug-resistant epilepsy.

OBJECTIVE Despite perioperative risks, epilepsy surgery represents a legitimate curative or palliative treatment approach for children with drug-resistant epilepsy (DRE). Several factors characterizing infants and toddlers with DRE create unique challenges regarding optimal evaluation and management. Epilepsy surgery within children < 3 years of age has received moderate attention in the literature, including mainly case series and retrospective studies. This article presents a systematic literature review and explores multidisciplinary considerations for the preoperative evaluation and surgical management of infants and toddlers with DRE. METHODS The study team conducted a systematic literature review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, targeting studies that investigated children < 3 years of age undergoing surgical treatment of DRE. Using the PubMed database, investigators selected peer-reviewed articles that reported seizure outcomes with or without developmental outcomes and/or perioperative complications. Studies were eliminated based on the following exclusion criteria: sample size < 5 patients; and inclusion of patients > 3 years of age, when demographic and outcomes data could not be separated from the cohort of patients < 3 years of age. RESULTS The study team identified 20 studies published between January 1990 and May 2017 that satisfied eligibility criteria. All selected studies represented retrospective reviews, observational studies, and uncontrolled case series. The compiled group of studies incorporated 465 patients who underwent resective or disconnective surgery (18 studies, 444 patients) or vagus nerve stimulator insertion (2 studies, 21 patients). Patient age at surgery ranged between 28 days and 36 months, with a mean of 16.8 months (1.4 years). DISCUSSION The study team provided a detailed summary of the literature review, focusing on the etiologies, preoperative evaluation, surgical treatments, seizure and developmental outcomes, and potential for functional recovery of infants and toddlers with DRE. Additionally, the authors discussed special considerations in this vulnerable age group from the perspective of multiple disciplines. CONCLUSIONS While presenting notable challenges, pediatric epilepsy surgery within infants and toddlers (children < 3 years of age) offers significant opportunities for improved seizure frequency, neuro-cognitive development, and quality of life. Successful evaluation and treatment of young children with DRE requires special consideration of multiple aspects related to neurological and physiological immaturity and surgical morbidity.

The use of the coping power program to treat a 10-year-old girl with disruptive behaviors.

This article describes the successful application of the Coping Power program by school-based clinicians to address a 10-year-old girl's disruptive behavior symptoms. Coping Power is an empirically supported cognitive-behavioral program for children at risk for serious conduct problems and their parents. The following case study illustrates the core features of the Coping Power child and parent components while describing the use of assessment data and clinical decision making during the implementation of a manualized intervention.