INCLUDING PATIENT RELEVANT ENDPOINTS (QUALITY OF LIFE) IN MULTICOMPONENT ENDPOINTS WITH GENERALIZED PAIRWISE COMPARISONS

Abstract

resulting in pediatric self-report and observer-reported versions. Exploratory analyses of initial data from adolescent trial participants were used to evaluate the performance of the self-report version and to confirm a single-factor structure. Results: 15 children and adolescents aged 8-17 years and 11 parents of children aged 4-7 years took part in concept elicitation and cognitive debriefing interviews using the draft pediatric withdrawal questionnaires. After iterative rounds of edits and review, self-report and pediatric observer versions of an 11-item measure were finalized for use in a clinical trial. Data from 108 trial participants provided support for an 11-item self-report version of the measure completed by children and adolescents with ADHD aged 8-17 years with internally reliability (Cronbach's alpha 0.74) and clear regression results of binary item endorsement predicting the total frequency score (adj r 2 0.87). Conclusions: The adapted SMWQ for pediatric and adolescent populations with ADHD is a new measure with appropriate content validity for assessing study medication withdrawal in pediatric ADHD trials. Initial evaluation of the self-report version shows appropriate measurement properties. Evaluation of the measurement properties for the parent-report version is pending and subject to data availability from the ongoing trial. Belgium Objectives: When assessing the efficacy of a treatment in any clinical trial, in addition to hard clinical endpoints, patient relevant outcomes such as quality of life, are also valuable to several stakeholders. However, combining outcomes in a multi-component endpoint is limited in several ways, not the least in the number and type of endpoints that can be combined. Recently, a class of non-parametric generalized pairwise comparisons (GPC) tests haven been proposed that allow for any number and type of outcomes, including patient relevant outcomes, and has good small sample properties. Our objective is to use the GPC methodology to integrate patient-reported outcomes in a multicomponent analysis. Methods: Epidermolysis bullosa simplex (EBS) is a rare genetic disease, characterized by the formation of blisters on the skin under low mechanical stress, and impacting importantly the quality of life in daily activities. A clinical trial with 16 paediatric patients is re-analysed with GPC using a multicomponent endpoint containing the reduction in blister count and change in quality of life. Additionally, the type I error and power of GPC is evaluated in a simulation study based on permuting data from an actual EBS trial. Results: While there is insufficient data to show a treatment effect on the blister endpoint alone, adding quality of life in a multicomponent GPC analysis shows evidence for a positive treatment effect (p = 0.0051). The Net Treatment Benefit, or the difference in probability of a better outcome, is high at 59% (95% CI: 18-100%). Moreover, the power to detect a treatment effect increases from less than 60% to above 90%, when adding the QoL outcome to the blister outcome, while adequately controlling the Type I error. Conclusions: GPC is a flexible statistical methodology that combines any number and type of outcomes, including patient relevant outcomes , and has good small sample properties. Objectives: Conventional value assessment based on regulatory anchored data often fall short when capturing the patient experience. It is often not clearly defined what additional patient centric value elements (PEx) should be collected that are specifically relevant to a disease. This research aims to compare the importance of PEx vs. conventional value elements from patients' perspective and reveal which are the most important PEx to be considered in value assessment. Methods: During a 2-day workshop, a combined quantitative (coin allocation) and qualitative (moderated group discussion) method was used in Spinal Muscular Atrophy (SMA), as a case study. Participants were asked to prioritize between clinical trial endpoints (e.g. standardized motor scale outcomes) utilized in the approval of SMA treatments (referred to as traditional value elements) and additional PEx; and secondly, to prioritize among PEx to be considered when selecting a disease-modifying treatment for SMA, by allocating 10 coins. Finally, their experience was qualitatively analyzed according to coin-allocation exercises based on the workshop transcript. Results: 9 participants allotted 41.25% of their coins for traditional endpoints and 58.75% for PEx. However, patients acknowledged that "today's revolutionary disease-modifying treatments couldn't have been developed without old endpoints". Their most highly ranked PEx were 1) Ability to reach personal milestones ("Allowing myself to think about the future"), 46.25% of overall coins; 2) patient's financial burden ("Without insurance none of this becomes possible at all"); and 3) Value of Hope /Balance timing of risks and benefits ("Hope and the bouncing of that risk is a big mental gain"), 12.5% of coins, respectively. Conclusions: Our holistic approach highlighted differences in prioritizing traditional value elements vs. PEX, from perspective of SMA patients'. Our findings may contribute to improved disease outcomes by emphasizing the importance of including PEx not only in value assessment but already at the regulatory phase. Objectives: Measuring health-related quality of life (HRQoL) is key to patient-centered value assessment of genomic medicine interventions, including genomic sequencing and gene-based therapies. Our objective is to describe the empirical literature on HRQoL of pediatric patients with genetic conditions, as well as HRQoL and well-being of their family members. Methods: We conducted a scoping review following published methodological guidelines (PRISMA-ScR). We systematically searched PubMed, EMBASE, and grey literature for original research articles published since January 1, 2010 that reported primary data on: 1) pediatric HRQoL for patients with genetic conditions; 2) HRQoL in family members and caregivers of pediatric patients with genetic conditions; 3) family well-being in families affected by pediatric genetic conditions. This review is registered on OSF (https://osf.io/sxk8 u/). Results: Our PubMed search yielded 7,576 records, and our Embase search yielded 13,061 of which 8,299 remained after PubMed duplicates were removed. After title and abstract review, 1,460 records were retained for full-text review. With 67% of full-text screening complete, 689 articles were included for analysis. Articles reported data on pediatric HRQoL (68%), family HRQoL and well-being (20%), or both (12%). Most research was led in the US (34%) or the United Kingdom (7%). The most frequently studied conditions include: sickle cell anemia (13%), cystic fibrosis (13%), hemophilia (9%), Duchenne muscular dystrophy (8%), thalas-semia (6%), and Down syndrome (6%). The majority of pediatric HRQoL studies (63%) employed a cross-sectional survey study design, whereas 15% reported data from interventional trials. The Pediatric Quality of Life Inventory (PedsQL) was the most frequently used instrument (24%) to assess pediatric HRQoL. Conclusions:-While the heterogeneity of conditions and approaches to HRQoL assessment pose challenges for comprehensive evaluations of genomic medicine interventions, there is a growing body of empirical HRQoL literature across a wide range of pe-diatric genetic conditions. Objectives: To develop a conceptual model and clinical outcome assessment (COA) measurement strategy in propionic acidemia (PA) and methylmalonic acidemia (MMA). Methods: Concept elicitation interviews were conducted with patients with PA/MMA and their caregivers, supplemented by discussions with clinical experts/ patient advocates. Thematic analysis identified important concepts, including signs/ symptoms and health-related quality-of-life (HRQoL) impacts, for patients/care-givers. Concepts in the PA/MMA conceptual model were mapped to the PedsQL TM Generic Core Scales (GCS) [covering ages 13 months to 18 years] and Family Impact Module, on a per-item basis. Gap analysis assessed potential COAs measuring relevant concepts to PA/MMA. Results: Twenty-six interviews were conducted in total (caregivers: n=14 PA, n=7 MMA; patients: n=3 PA, n=2 MMA), representing 22 patients ages 0.5-34 years. Key sign/symptom domains included metabolic crises, developmental delays (communication, motor functioning), and diet/feeding. HRQoL impacts included negative emotional impact, sleep difficulties, decreased endurance, limits on activities/sports, impacts on peer relationships, and missing school; care-giver/family impacts were also identified. The PedsQL TM GCS mapped closely to HRQoL impacts in the PA/MMA conceptual model, with the exception of additional physical symptom and cognitive functioning items in the infant version. The PedsQL TM Family Impact module also showed good overlap with the PA/MMA conceptual model. The Cogstate computerized battery, NIH Toolbox Motor Battery, and Bayley Scales of Infant and Toddler Development (Bayley TM-4) were determined to be fit-for-purpose for measuring cognitive and/or motor function (depending on age of patient). Conclusions: This is the first conceptual model for PA/MMA identifying core concepts of patient/caregiver importance. Symptoms and impacts were broad-ranging and the PedsQL TM GCS and Family Impact modules map appropriately to assess HRQoL in the PA/MMA patients and caregivers, respectively. The Cogstate, NIH Toolbox Motor Battery, and Bayley TM-4 appropriately measure cognitive and/or motor function impacts. Future research should aim to develop a measure of core signs/symptoms in PA/MMA. VALUE IN HEALTH-JUNE 2023 S335