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Purpose Fabry disease is a rare multisystemic disorder caused by functional deficiency of the lysosomal enzyme alpha-galactosidase A. Gastrointestinal (GI) signs and symptoms are among the earliest clinical manifestations in patients with Fabry disease but are often nonspecific, misdiagnosed, and untreated. No instruments have been developed specifically to assess GI signs and symptoms in Fabry disease. The FAB ry disease P atient- R eported O utcome- G astro I ntestinal (FABPRO-GI) was developed to address this unmet need and is intended for use in clinical trials (24-h FABPRO-GI) and real-world settings (7-day FABPRO-GI). Methods Findings from a literature review, expert advisory meetings, and patient concept elicitation interviews (CEIs) were summarized into conceptual models. These conceptual models were used to develop preliminary versions of the 24-h and 7-day FABPRO-GI. Cognitive debriefing interviews (CDIs) were conducted with additional patients to assess content validity, including understandability, relevance, and comprehensiveness of the preliminary versions of the 24-h and 7-day FABPRO-GI. Results Literature review ( n  = 17 articles), expert advisory meetings ( n  = 5), and patient CEIs ( n  = 17) identified mostly overlapping Fabry disease-related GI signs and symptoms, including abdominal cramps, bloating, and diarrhea, and informed development of the preliminary 24-h and 7-day FABPRO-GI. CDIs ( n  = 15) provided evidence of content validity and informed revisions of the 24-h and 7-day FABPRO-GI. Conclusion With evidence of content validity, the 24-h and 7-day FABPRO-GI are the first Fabry disease-specific patient-reported outcomes to assess GI signs and symptoms in patients with Fabry disease with potential for use in clinical trials and real-world settings, respectively.

Background Advanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations. To fill that gap, this study documents the development and content validity of instruments evaluating signs and symptoms of systemic mastocytosis. Methods A review of peer-reviewed literature, advice meetings with clinical therapeutic area experts, patient concept elicitation interviews, concept selection and questionnaire construction meetings, and patient cognitive debriefing interviews were conducted, and regulatory feedback was incorporated. Results For AdvSM, 26 sign- and symptom-level concepts were identified in literature, 39 by clinicians, and 33 by patients. For ISM/SSM, 38 sign- and symptom-level concepts were identified in the literature, 39 by clinicians, and 57 by patients. Two patient-reported instruments, the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) and Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF)(©Blueprint Medicines Corporation), were developed based on consolidated findings. Cognitive debriefing interviews with AdvSM and ISM patients showed the AdvSM-SAF and ISM-SAF were understood and interpreted as intended by the majority of patients. Conclusion The AdvSM-SAF and ISM-SAF are content-valid tools measuring symptoms from AdvSM and ISM patients’ perspective.

Background The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (©Blueprint Medicines Corporation), a 12-item daily diary that assesses 11 signs and symptoms of indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), was psychometrically evaluated among patients with ISM. Additionally, thresholds of the ISM-SAF total symptom score (TSS) to distinguish patients with moderate to severe symptoms from those with mild symptoms were evaluated. Methods The ISM-SAF was completed daily as an electronic diary in a prospective, observational study utilizing an online survey of patients with ISM in the United States. Descriptive statistics, psychometric analyses, and analyses to estimate ISM-SAF TSS clinical cutoff values were conducted. Results A total of 103 patients (81.6% female; mean age = 50.2 [± 12.6]) with a self-reported diagnosis of ISM or SSM (58 of whom also had a medically documented diagnosis) contributed to the analyses. Psychometric analysis supported the trustworthiness of the biweekly TSS, which was reliable ( α  > 0.8, ICC > 0.9), construct-valid, and able to distinguish among clinically distinct groups as specified by the Patient Global Impression of Severity, 12-item Short-Form Health Survey, and Mastocytosis Quality of Life Questionnaire ( p  < 0.01). A biweekly ISM-SAF TSS from 21 to 28 begins to distinguish the moderately to severely symptomatic ISM/SSM patients from mildly symptomatic patients. Conclusion The biweekly TSS of ISM-SAF was reliable, construct-valid, and able to distinguish among clinically distinct groups. A cut-off value of 28 is a conservative threshold that can be used for screening purposes in future clinical studies to identify patients with at least a moderate severity of ISM symptoms.

Background Indolent systemic mastocytosis (ISM) is a rare, clonal mast cell neoplasm characterized by severe, unpredictable symptoms. The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) items compose a Total Symptom Score (TSS), Gastrointestinal Symptom Score (GSS), and Skin Symptom Score (SSS) to assess symptom severity. This study evaluated the psychometric performance of ISM-SAF among ISM patients. Methods In PIONEER, a Phase 2 trial evaluating safety and efficacy of selective kinase inhibitor avapritinib in patients with ISM, the 12-item ISM-SAF was administered daily. Psychometric evaluation of score reliability, validity, and clinical interpretation was conducted using the trial data. Results Thirty-eight patients contributed to analyses (78.9% female; mean age = 49). Baseline internal consistency reliability (α) for bi-weekly TSS, GSS, and SSS was 0.86, 0.83, and 0.82, respectively. Test–retest reliability among patients exhibiting no change in Patient Global Impression of Symptom Severity (PGIS) between Baseline and Day 15 exceeded 0.74 universally. Construct validity and known-groups analysis showed moderate to strong ISM-SAF score correlation (r = 0.382–0.881) to supportive patient-reported questionnaires (e.g., PGIS and Mastocytosis Quality of Life Questionnaire) symptom and skin scores, and ability to distinguish among clinically unique groups. Correlations of ISM-SAF and other assessment change scores reflect evidence of score sensitivity. Clinically important difference and response estimates were 7–10 and 19, respectively. Discussion ISM-SAF produced reliable, construct-valid, sensitive scores when administered in PIONEER to patients in the target population. Results of this study support the use of the ISM-SAF as a reliable and valid measure to evaluate disease symptomology in ISM patients. Trial registration ClinicalTrials.gov, NCT03731260. Registered 10 October 2018, https://clinicaltrials.gov/ct2/show/study/NCT03731260 .

Background Barth syndrome (BTHS, OMIM 302060) is a rare, life-threatening, x-linked genetic disorder that occurs almost exclusively in males and is characterized by cardiomyopathy, neutropenia, skeletal muscle myopathy primarily affecting larger muscles, and shorter stature in youth. A greater number of individuals with BTHS are now surviving into adulthood due to advancements in diagnosis and disease management. Given these improvements in life expectancy, understanding the disease experience over time has become increasingly important to individuals with the condition, treatment developers, and regulatory agencies. A study was conducted to explore the experience of BTHS from the perspective of adult males at least 35 years of age with the condition via in-depth qualitative interviews. Results Findings showed that adults with BTHS experienced a variety of signs/symptoms with variable onset and severity throughout their lives, the most frequently reported being the symptoms of tiredness, muscle weakness, and a fast and/or irregular heart rate, and the sign of short stature in youth. These signs/symptoms negatively impacted individuals’ emotional, physical, social, and role functioning. Tiredness and weakness impacted some individuals’ physical functioning from an early age and into adulthood. These symptoms generally worsened over time, increasingly interfering with individuals’ ability to fully participate in paid and unpaid labor and to partake in family and leisure activities. Conclusions This research complements recent studies characterizing the potentially degenerative and progressive nature of BTHS and can encourage future research into the natural history and progression of BTHS in untreated individuals. Participants’ interview responses revealed a range of symptoms and the potential for multiple impacts on individuals’ physical, social, emotional, and role functioning as a result of BTHS symptoms, yet also revealed variability in severity of experience as well as the possibility of resilience and adaptation to the condition.

ObjectivesTo estimate thresholds for defining meaningful within-patient improvement from baseline to weeks 13–24 and interpreting meaningfulness of between-group difference for the non-transfusion-dependent beta-thalassaemia patient-reported outcome (NTDT-PRO) tiredness/weakness (T/W) and shortness of breath (SoB) scores. A secondary objective was to determine the symptom severity threshold for the NTDT-PRO T/W domain to identify patients with symptomatic T/W.DesignPooled blinded data from the phase 2, double-blind, placebo-controlled, randomised BEYOND trial in NTDT (NCT03342404) were used. Anchor-based analyses supplemented with distribution-based analyses and empirical cumulative distribution function (eCDF) curves were applied. Distribution-based analyses and receiver operating characteristic curves were used to estimate between-group difference and symptomatic thresholds, respectively.SettingGreece, Italy, Lebanon, Thailand, the UK and the USA.ParticipantsAdults (N=145; mean age 39.9 years) with NTDT who were transfusion-free ≥8 weeks before randomisation.MeasuresScore changes from baseline to weeks 13–24 in PROs used as anchors (correlation coefficient ≥0.3): NTDT-PRO T/W and SoB scores, Patient Global Impression of Severity, Functional Assessment of Chronic Illness Therapy–Fatigue (Fatigue Subscale, item HI12 and item An2) and Short Form Health Survey version 2.ResultsThe eCDF curves support the use of estimates from the improvement by one level group for all anchors to determine the threshold(s) for meaningful within-patient improvement. Mean (median) changes from these groups and estimates from distribution-based analyses suggest that a ≥1-point reduction in the NTDT-PRO T/W or SoB domains represents a clinically meaningful improvement. Meaningful between-group difference threshold ranges were 0.53–1.10 for the T/W domain and 0.65–1.15 for the SoB domain. The optimal symptomatic threshold for the T/W domain (by maximum Youden’s index) was ≥3 points.ConclusionsThe thresholds proposed may support the use of NTDT-PRO in assessing and interpreting treatment effects in clinical studies and identifying patients with NTDT in need of symptom relief.

Patient-reported outcome (PRO) data are increasingly being implemented in oncology clinical trial research to evaluate treatment benefit, such as disease-related symptoms, treatment-related adverse events, and health-related quality of life impacts. However, only a small amount of PRO data collected is used to support labeling claims, leaving a substantial amount of data that could be shared by sponsors to further convey treatment benefit from the patient perspective. This paper describes how pharmaceutical sponsors can realize the value of PRO data derived from oncology trials with regard to the following stakeholders: payers, health care providers (HCPs), and patient advocacy groups. Further, ideas are presented for integrating PRO data and implementing PRO assessments within oncology, by stakeholder type. Finally, a summary is provided to describe how PRO data can benefit the patient by facilitating better, more symptom-focused care and enhancing treatment decisions. With the goal of motivating further use of PRO assessments in oncology, we present examples of how payers utilize PRO data to inform reimbursement decisions (eg, PRO data inform decisions made by Germany׳s Institute for Quality and Efficiency in Health Care and the United Kingdom׳s National Institute for Health and Care Excellence); how communication of results with patient advocacy groups can lead to a better understanding of what is important to patients; and how HCPs can use PRO instruments to inform patient treatment decisions through real-world application. Integrating PRO data can enhance health care by allowing the patient’s voice to carry beyond regulatory decisions and into those made by payers and HCPs, which are crucial to quality care and assessing the value of care. Utilizing PRO assessments and communicating results to key stakeholders in the oncology space can allow sponsors to report treatment benefit and, more importantly, can provide valuable insight into the patient treatment experience.

Background Chronic rhinosinusitis (inclusive of subtypes with nasal polyps [CRSwNP], without nasal polyps [CRSsNP], and allergic fungal rhinosinusitis [AFRS]) causes inflammation of the nose mucosa and paranasal sinuses. Unfortunately, evidence supporting use of clinical outcome assessments (COAs) in regulated clinical trials to assess key measurement concepts of these conditions is limited. Objective To identify key disease-related symptoms and impacts, potential outcomes of interest for new treatments, and COAs available to measure those outcomes among adult and adolescent individuals living with CRSwNP, CRSsNP, and AFRS. Methods Literature, clinical trial, and product label reviews were conducted to identify symptoms, impacts, and COAs used to assess CRSwNP, CRSsNP, and AFRS patient experiences in clinical trials. The disease related concepts identified in the literature were mapped to selected COAs to determine conceptual coverage of each COA. Results Twenty-five articles, twenty-five clinical trial records, and four product labels were included in the review. Across conditions, nasal obstruction, nasal discharge, and altered smell were the most frequently identified symptoms. The most frequently identified impacts of CRSwNP and CRSsNP were on emotional functioning and sleep, and adopting new behaviors for AFRS. Findings for key symptoms and impacts in adolescents were limited. More than 20 COAs used in these conditions were identified, and 14 COAs (e.g., Sinonasal Outcome Test [SNOT-22]) were evaluated for conceptual coverage of the concepts identified in the literature. Conclusion Results specify several symptom and impact outcomes, that if improved, would reflect treatment benefit for patients living with CRSwNP, CRSsNP, and/or AFRS. Several COAs demonstrated coverage of key measurement concepts and warrant further evaluation for use in clinical trials.

Background Patient-reported outcomes (PROs) are underutilized in medical device evaluations, including in ophthalmology and intraocular lens (IOL) replacements. This article summarizes research conducted to develop the Patient-Reported Intraocular Lens Questionnaire (PR-ILQ) and support its content validity and psychometric performance. Use of the PR-ILQ in a regulated clinical trial to support new product approval decisions, secondary effectiveness claims, and safety observations is also discussed. Results The PR-ILQ, developed with ophthalmology experts ( n  = 10) and use of qualitative data generated from patients during concept elicitation ( n  = 44) and cognitive debriefing ( n  = 32) interviews, includes the Vision Correction Scale (VCS, three items), Vision Disturbance Scale (VDS, eight items), and IOL Replacement Satisfaction Scale (IOL-RSS, five items). Each assessment is distinct, and items within each are scored independently to address treatment benefit hypotheses. With its content validity established, the PR-ILQ was administered to 271 subjects (mean age = 68.3 years) participating in a clinical trial to evaluate the safety and effectiveness of an asymmetric segmented multifocal IOL (SBL-INI-02–13). Descriptively, item scores behaved as expected, with clustering of VCS and VDS scores at more- and less-severe levels at study entry and exit, respectively, though scores were distributed across response options across timepoints. Test-retest reliability results mostly indicate “fair”/“good” (weighted Kappa [KW]/intraclass correlation coefficient [ICC] > 0.40 to 0.60) to “excellent” (KW/ICC > 0.75) reproducibility for VCS, VDS, and IOL-RSS items in two independent analyses. Construct validity hypotheses, including those associated with sensitivity to change, were supported via correlational analysis showing a pattern of expected relationships among PR-ILQ items and with other variables including ratings of visual acuity. For example, reduced use of vision correction at near ( r  = −0.28), intermediate ( r  = −0.42), and far ( r  = −0.57) distances were more strongly related to overall lens satisfaction at end of study than improved visual acuity at those same distances ( r  = −0.25. −0.26, and −0,14). Conclusions The PR-ILQ is content valid and early evidence suggests it is capable of producing reliable scores upon which valid conclusions may be drawn when administered among patients undergoing cataract lens replacement surgery. Acknowledging limitations and need for additional psychometric evaluation, the assessment recently supported a new product approval decision, secondary effectiveness claims, and safety observations. Together, this indicates that the PR-ILQ, along with the evidentiary basis and suggestions for use presented herein, will be of immediate value to IOL replacement outcomes researchers, regulators, and other stakeholders interested in generating evidence to inform health care decisions and improving cataracts patients’ lives. Trial registration Clinicaltrials.gov, NCT02487160. Registered 25 June 2015, https://clinicaltrials.gov/study/NCT02487160 .

ObjectivesThe non-transfusion-dependent beta-thalassaemia-patient-reported outcome (NTDT-PRO) questionnaire was developed for assessing anaemia-related tiredness/weakness (T/W) and shortness of breath (SoB) among patients with NTDT. Psychometric properties were evaluated using blinded data from the BEYOND trial (NCT03342404).DesignAnalysis of a phase 2, double-blind, randomised, placebo-controlled trial.SettingUSA, Greece, Italy, Lebanon, Thailand and the UK.ParticipantsAdults (≥18 years) (N=145) with NTDT who had not received a red blood cell transfusion within 8 weeks prior to randomisation, with mean baseline haemoglobin level ≤100 g/L.MeasuresNTDT-PRO daily scores from baseline until week 24, and scores at select time points for the 36-Item Short Form Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) and Patient Global Impression of Severity (PGI-S).ResultsCronbach’s alpha at weeks 13–24 was 0.95 and 0.84 for the T/W and SoB domains, respectively, indicating acceptable internal consistency reliability. Among participants self-reporting no change in thalassaemia symptoms via the PGI-S between baseline and week 1, intraclass correlation coefficients were 0.94 and 0.92 for the T/W and SoB domains, respectively, indicating excellent test–retest reliability. In a known-groups validity analysis, least-squares mean T/W and SoB scores at weeks 13–24 were worse in participants with worse scores for the FACIT-F Fatigue Subscale (FS), SF-36v2 vitality or PGI-S. Indicating responsiveness, changes in T/W and SoB domain scores were moderately correlated with changes in haemoglobin levels, and strongly correlated with changes in SF-36v2 vitality, FACIT-F FS, select FACIT-F items and the PGI-S. Improvements in least-squares mean T/W and SoB scores were higher in participants with greater improvements in scores on other PROs measuring similar constructs.ConclusionsThe NTDT-PRO demonstrated adequate psychometric properties to assess anaemia-related symptoms in adults with NTDT and can be used to evaluate treatment efficacy in clinical trials.