Long-term durability between parent and child patient-reported outcomes in eosinophilic esophagitis.

BACKGROUND: Because young children cannot self-report symptoms, there is a need for parent surrogate reports. Although early work suggested parent-child alignment for eosinophil esophagitis (EoE) patient-reported outcomes (PROs), the longitudinal alignment is unclear. OBJECTIVE: We sought to assess the agreement and longitudinal stability of PROs between children with EoE and their parents. METHODS: A total of 292 parent-child respondents completed 723 questionnaires over 5 years in an observational trial in the Consortium of Eosinophilic Gastrointestinal Disease Researchers. The change in and agreement between parent and child Pediatric Eosinophilic Esophagitis Symptom Score version 2 (PEESSv2.0) and Pediatric Quality of Life Eosinophilic Esophagitis Module (PedsQL-EoE) PROs over time were assessed using Pearson correlation and Bland-Altman analyses. Clinical factors influencing PROs and their agreement were evaluated using linear mixed models. RESULTS: The cohort had a median disease duration equaling 3.7 years and was predominantly male (73.6%) and White (85.3%). Child and parent PEESSv2.0 response groups were identified and were stable over time. There was strong correlation between child and parent reports (PEESSv2.0, 0.83;PedsQL-EoE, 0.74), with minimal pairwise differences for symptoms. Longitudinally, parent-reported PedsQL-EoE scores were stable (P ≥ .32), whereas child-reported PedsQL-EoE scores improved (P = .026). A larger difference in parent and child PedsQL-EoE reports was associated with younger age (P < .001), and differences were driven by psychosocial PRO domains. CONCLUSIONS: There is strong longitudinal alignment between child and parent reports using EoE PROs. These data provide evidence that parent report is a stable proxy for objective EoE symptoms in their children.

Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.

Parent-reported outcome measures evaluating communication in individuals with rare neurodevelopmental disorders: A systematic review.

BACKGROUND: Communication impairments are a leading concern for parent caregivers of individuals with rare neurodevelopmental disorders (RNDDs). Clinical trials of disease modifying therapies require valid and responsive outcome measures that are relevant to individuals with RNDDs. Identifying and evaluating current psychometric properties for communication measures is a critical step towards the selection and use of appropriate instruments. AIMS: This systematic review offers (1) a description of parent-reported communication measures and (2) evidence for their psychometric properties, in RNDDs. METHODS: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022334649). MEDLINE (Ovid), Embase, PsychINFO, Web of Science, CINAHL Plus, Cochrane Library, ClinicalTrials.gov, the Australian New Zealand Clinical Trials Registry were searched from inception to August 2023. Methodological assessment of quality was completed using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist. Parent-reported measures used in observational studies and clinical trials were identified. Data on utility, reliability and validity for RNDDs were extracted. MAIN CONTRIBUTION: Sixteen parent-reported communication measures were used in RNDD research, the Vineland Adaptive Behavior Scales being most commonly used. Validation data in RNDDs were identified for six of these measures. Limitations related to sample size or the scope of psychometric testing. CONCLUSIONS: Many communication measures have been used for RNDDs but there are few data validating their use. Valid and reliable methods of measuring communication in persons with RNDDs is a priority for future high-quality clinical trials. WHAT THIS PAPER ADDS: What is already known on the subject Communication is a critical domain for families with a child with a rare neurodevelopmental disorder (RNDD). Validated outcome measures are essential for accurate evaluation and interpretation of responses to treatments in clinical trials. What this paper adds to existing knowledge We identified 16 parent-reported communication measures that have been used with RNDDs, but only six measures had validation data for at least one RNDD. High quality evidence is accumulating, with all validation studies in this review published between 2020 to 2023. Modifications of existing measures may be required to assess communication for RNDDs. What are the clinical implications of this work? This systematic review catalogues the available psychometric data for communication measures and indicates an ongoing need for new validation studies to ensure they are fit-for-purpose for upcoming clinical trials in RNDDs. This review will inform the selection of communication measures for clinical trials and research studies.

Measuring the inch stones for progress: Gross motor function in the developmental and epileptic encephalopathies.

OBJECTIVE: Developmental and epileptic encephalopathies (DEE) entail moderate to profound impairments in gross motor skills and mobility, which are poorly quantified with clinical outcomes assessments (COA) used in neuro-typical populations. We studied the motor domain of the Adaptive Behavior Assessment System-3 for ages 0-5 years (ABAS) used outside of its intended age range with a focus on raw scores. METHODS: In a cross-sectional survey, 117 parents of children with a variety of DEEs (ages 1-35 years, median = 9) completed the motor domain section of the ABAS. Floor and ceiling effects and associations with epilepsy-related factors were assessed with appropriate parametric and nonparametric statistical techniques. The sensitivity of the ABAS and additional measures of mobility borrowed from the cerebral palsy literature (Functional Activities Questionnaire (FAQ-22) walking level (FAQ-WL)) to different levels of the Functional Mobility Scale was determined. RESULTS: ABAS motor scores corresponded to a median age equivalent of 20.5 months (Inter-Quartile Range (IQR) 8-34). Most raw scores corresponded to standardized scores > 2 standard deviations below the ABAS standardization sample mean. ABAS raw scores demonstrated minimal floor and ceiling effects (<5%). In linear regression models, scores increased with age under 6 years (p < 0.0001) but flattened out thereafter. Scores varied substantially by DEE group (p < 0.001) and decreased with higher convulsive seizure frequency (<0.0001) and number of seizure medications (p < 0.001). ABAS and other motor scores were sensitive to important differences in mobility as represented by the FMS at 5 yards. Further, they correlated with declines in mobility function from 5 to 500 yards. SIGNIFICANCE: An out-of-range COA with raw scores may provide a measure of motor ability and mobility sensitive within the range of moderate to profound impairment seen in patients with DEE. This approach could shorten the time to appropriate COA development and ensure timely clinical trial readiness for novel therapies for rare DEEs.

Rare diseases - rare outcomes: Assessing communication abilities for the developmental and epileptic encephalopathies.

OBJECTIVE: Developmental and epileptic encephalopathies (DEE) entail moderate to profound communication and other impairments that are poorly measured by typical clinical outcomes assessments (COA). We examined the potential of alternative approaches, specifically, the use of raw scores and COAs outside of their intended age ranges. METHODS: In a cross-sectional survey, 120 parents of children with Dravet Syndrome, Lennox-Gastaut syndrome, KCNQ2-DEE, KCNB1-DEE, and SCN2A-DEE (ages 1-35 years) completed the Adaptive Behavior Assessment System-3 for ages 0-5 years, modified checklist for autism (mCHAT), communication and social behavior scales (CSBS), communication matrix (CM), and several parent-reported classifiers of communication. Adaptive Behavior Assessment System communication and social raw scores were the primary and adjunctive outcomes. Floor and ceiling effects, dispersion and convergence with related measures were assessed with appropriate parametric and nonparametric statistical techniques. RESULTS: Median chronological age (CA) was 8.7 years (Interquartile range (IQR): 5.3-13.5). Adaptive Behavior Assessment Systemcommunication and social age equivalents were 12.5 months (IQR 7.5-28) and 16.5 months (IQR 9-31). Most raw scores corresponded to standardized scores indicating performance <3 standard deviations below the general population mean. Adaptive Behavior Assessment System raw scores demonstrated minimal floor and ceiling effects (<1-2.5%). In linear regression models, scores correlated with age under 6 years (communication, p = 0.001; social, p = 0.003) but significantly flattened out thereafter. Scores varied substantially by DEE group (both p < 0.001) and decreased with higher convulsive seizure frequency (communication, p = 0.01, social, p = 0.02). There was good convergence with mCHAT, CSBS, and CM scores (all r > 0.8). SIGNIFICANCE: Raw scores and out-of-range COAs may provide measures that are sensitive at the very limited levels of functioning typical of profoundly impaired, older patients with DEEs. To ensure that targeted trial outcomes are responsive to meaningful change, development of these approaches will be essential to clinical trial readiness for novel therapies for rare DEEs.

Pediatric Outcomes Data Collection Instrument is a Useful Patient-Reported Outcome Measure for Physical Function in Children with Osteogenesis Imperfecta.

PURPOSE: Patient-reported outcome measures (PROMs) are increasingly recognized as valuable endpoints in clinical trials. The Pediatric Outcomes Data Collection Instrument (PODCI) is a PROM utilized in children with musculoskeletal disorders. We evaluated the validity and reliability of PODCI in children with osteogenesis imperfecta (OI). METHODS: Physical functioning and psychological well-being were assessed using PODCI in a large cohort of children enrolled in a multicenter study conducted by the Brittle Bone Disorders Consortium. Physical function scores were correlated with a validated, observer-rated scale, Brief Assessment of Motor Function (BAMF), and with psychological well-being scores. We calculated sample sizes required to detect clinically meaningful differences in physical function. RESULTS: Four hundred seventeen children with OI types I, III, and IV were enrolled. Physical function scores in OI type III were significantly lower than those in OI types I and IV. There were no significant differences in psychological well-being. PODCI physical function scores showed moderate-to-strong correlation with BAMF. The Global Functioning Scale, a composite of physical function, did not consistently correlate with psychological well-being. CONCLUSION: PODCI can be a reliable measure of physical functioning in children with OI and offers valuable information about patient-reported health status and new ways to examine the utility of interventions in this population.

The Rare Diseases Clinical Research Network: a model for clinical trial readiness.

Background: The current road to developing treatments for rare diseases is often slow, expensive, and riddled with risk. Change is needed to improve the process, both in how we think about rare disease treatment development and the infrastructure we build to support ongoing science. The National Institutes of Health (NIH)-supported Rare Diseases Clinical Research Network (RDCRN) was established to advance the diagnosis, management, and treatment of rare diseases and to promote highly collaborative, multi-site, patient-centric, translational, and clinical research. The current iteration of the RDCRN intends to build upon and enhance successful approaches within the network while identifying innovative methods to fill gaps and address needs in the approach to the rare disease treatment development process through innovation, collaboration, and clinical trial readiness. Objective: The objective of this paper is to provide an overview of the productivity and influence of the RDCRN since it was first established 20 years ago. Design and methods: Using a suite of tools available to NIH staff that provides access to a comprehensive, curated, extensively linked data set of global grants, patents, publications, clinical trials, and FDA-approved drugs, a series of queries were executed that conducted bibliometric, co-author, and co-occurrence analysis. Results: The results demonstrate that the entire RDCRN consortia and network has been highly productive since its inception. They have produced 2763 high-quality publications that have been cited more than 100,000 times, expanded international networks, and contributed scientifically to eight FDA-approved treatments for rare diseases. Conclusion: The RDCRN program has successfully addressed some significant challenges while developing treatments for rare diseases. However, looking to the future and being agile in facing new challenges that arise as science progresses is important.

A National Institute of Health-funded research network working toward better treatments for people with rare diseases The Rare Diseases Clinical Research Network (RDCRN) is a Federally directed research network that targets research to help investigators move closer to treatments for rare diseases. The network supports 20 different groups that study rare diseases. Each group focuses on three or more rare diseases and the research is conducted at multiple sites. Each group works closely with both the National Institutes of Health (NIH) and patient advocacy groups. The primary focus of the network is clinical trials readiness, which simply means knowing who to treat, when to treat, and how to treat, thus taking some of the risk out of clinical trials. This knowledge is gained through natural history studies. The network, supported by grants, holds a competition every five years to select groups to participate in the network. The RDCRN is supported by ten different institutes at the NIH. To date the RDCRN has published numerous manuscripts in topics ranging from findings from natural history studies and case reports to practice guidelines and clinical trials. To date the RDCRN has been involved in work that has led to eight treatments being approved by the Food and Drug Administration (FDA).

Clinical Trial Readiness for Spinal Muscular Atrophy: Experience of an International Educational-Training Initiative.

Several successful clinical trials have been conducted in spinal muscular atrophy (SMA) over recent years which have led to the approval of splicing modifiers and gene transfer therapies. With an increasing number of other agents progressing through pre-clinical and clinical development, increasing worldwide clinical trial readiness is becoming essential.SMA Europe initiated a clinical trial readiness project, which included the development of a pilot face-to-face educational-training initiative for clinical specialists and physiotherapists involved in SMA, with an emphasis on the patient perspective. Participants were selected through two surveys and, ahead of the meeting, a mock protocol with specific questions was provided. The initiative involved a series of presentations, role-play and interactive exercises. We describe here our experience and evaluation of this educational-training initiative, emphasising scientific aspects, psychosocial implications and level of satisfaction.From a participant, patient and industry perspective, such training was considered successful and met the objective, which was to improve clinical trial readiness in emerging sites. Resource planning, ethical considerations and communication with patients were identified as three important topics for future training. This initiative highlights the need to develop a training programme to achieve clinical trial readiness across Europe and showcases a collaborative effort with different stakeholders, clinicians, patient advocacy groups and sponsors to address an important issue.

Clinical and Research Readiness for Spinal Muscular Atrophy: The Time Is Now for Knowledge Translation.

Disease-modifying therapies for spinal muscular atrophy (SMA) are rapidly changing the outlook for many individuals by substantially altering the clinical course, phenotypic expression, and functional outcomes. Physical therapists have played critical roles in the effective conduct and execution of clinical trials leading to the approval of these therapies. Given the treatment landscape, educating practicing clinicians to understand best practice is of great importance, and a timely call to action to facilitate knowledge translation from SMA researchers to clinicians is necessary. The SMA Clinical Trial Readiness Program engaged clinical and research centers, identified physical therapy knowledge gaps related to evaluation and outcomes assessment, and provided educational resources, including the development of a SMA Best Practices Clinical Evaluator Toolkit. Toolkit content synthesizes evidence and covers a breadth of issues relevant to practice, including background on SMA and the drug pipeline; therapist roles and responsibilities related to research; clinical and research evaluation; and useful materials and resources for additional education, training, and professional development. Surveys and telephone interviews were conducted with physical therapists managing individuals with SMA to determine their SMA practice experience and educational needs. Their recommendations, along with synthesized SMA research evidence, provided input into toolkit content development and assisted in identifying gaps important to address. Impact was assessed over time via utilization feedback surveys downloaded by clinicians across various settings. Open-ended feedback supported beneficial use of the toolkit for clinicians and researchers working with individuals with SMA. Next steps should include timely dissemination to bring this resource and others into practice in a systematic, efficacious, and engaging manner. As the treatment landscape for SMA evolves, the therapist's role in multidisciplinary care and research is of great importance, and a call to action for the development, implementation, evaluation and reporting of informed knowledge using evidence-based knowledge translation strategies is critical. IMPACT: Partnership among patient advocacy groups, industry collaborators, and key opinion leaders/experts can optimize essential resource development to address the knowledge gap for best practices in physical therapy. This partnership model can be replicated for other diseases, providing an efficient way to support clinical trial readiness and target early development of evidence-based content and resources related to both research and best practice clinical evaluation for physical therapist researchers, clinicians, and patients. While identifying knowledge gaps and resource development are initial steps toward change in SMA practice, a rapidly changing rehabilitation outlook warrants a call to action for enhanced efforts aimed at improving rehabilitation evaluation, assessment, and care for this population. It is critical to forge a timely path forward for development, implementation, and sustainability of effective knowledge translation to practice for SMA.

Consensus Guidelines for Improving Quality of Assessment and Training for Neuromuscular Diseases.

Critical components of successful evaluation of clinical outcome assessments (COAs) in multisite clinical trials and clinical practice are standardized training, administration, and documented reliability of scoring. Experiences of evaluators, alongside patient differences from regional standards of care, may contribute to heterogeneity in clinical center's expertise. Achieving low variability and high reliability of COA is fundamental to clinical research and to give confidence in our ability to draw rational, interpretable conclusions from the data collected. The objective of this manuscript is to provide a framework to guide the learning process for COAs for use in clinics and clinical trials to maximize reliability and validity of COAs in neuromuscular disease (NMD). This is a consensus-based guideline with contributions from fourteen leading experts in clinical outcomes and the field of clinical outcome training in NMD. This framework should guide reliable and valid assessments in NMD specialty clinics and clinical trials. This consensus aims to expedite study start up with a progressive training pathway ranging from research naïve to highly experienced clinical evaluators. This document includes recommendations for education guidelines and roles and responsibilities of key stakeholders in COA assessment and implementation to ensure quality and consistency of outcome administration across different settings.

Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials.

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson's disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.

The SMA Clinical Trial Readiness Program: creation and evaluation of a program to enhance SMA trial readiness in the United States.

Spinal muscular atrophy (SMA) is a rare neuromuscular disease with a rapidly evolving treatment landscape. To better meet the needs of trial sponsors and the patient community in the United States (US) in this evolving context, Cure SMA established a clinical trial readiness program for new and prospective SMA clinical trial sites. Program development was informed by a review of the SMA clinical trial landscape, successful NMD trial and care networks, and factors important to effective trial conduct in SMA. The program was piloted in 2018 with a virtual site readiness evaluation, a trial readiness toolkit, and a readiness program for physical therapists and clinical evaluators. Nine US research hospitals participated in the pilot. Cure SMA evaluated the pilot program and resources through feedback surveys, which supported the program's relevance and value. Since 2018, the program has been expanded with additional sites, new best practices toolkits, and workshops. In partnership with Cure SMA, SMA Europe is also extending programming to European countries. The program is significant as an example of a patient advocacy group working successfully with pharmaceutical companies, other patient advocacy organizations, and research hospitals to promote trial readiness, and may serve as a model for organizations in other regions and diseases.