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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.

Purpose of Review Based on shared decision-making (SDM) principles, a decision aid was previously developed to help patients, their caregivers, and physicians decide which peanut allergy management approach best suits them. This study refined the decision aid’s content to better reflect patients’ and caregivers’ lived experience. Recent Findings Current standard of care for peanut allergy is avoidance, although peanut oral immunotherapy has been approved by the Food and Drug Administration for use in patients 4–17 years old. Summary An advisory board of allergy therapy experts ( n  = 3) and patient advocates ( n  = 3) informed modifications to the decision aid. The revised tool underwent cognitive debriefing interviews (CDIs) among adolescents (12–17 years old) with peanut allergy and caregivers of patients 4–17 years old with peanut allergy to evaluate its relevance, understandability, and usefulness. The 20 CDI participants understood the information presented in the SDM tool and reported it was important and relevant. Some revisions were made based on participant feedback. Results support content validity of the Peanut Allergy Treatment SDM Tool.

Patient-reported outcome (PRO) questionnaires considered in this paper contain multiple subscales, although not all subscales are equally relevant for administration in all target patient populations. A group of measurement experts, developers, license holders, and other scientific-, regulatory-, payer-, and patient-focused stakeholders participated in a panel to discuss the benefits and challenges of a modular approach, defined here as administering a subset of subscales out of a multi-scaled PRO measure. This paper supports the position that it is acceptable, and sometimes preferable, to take a modular approach when administering PRO questionnaires, provided that certain conditions have been met and a rigorous selection process performed. Based on the experiences and perspectives of all stakeholders, using a modular approach can reduce patient burden and increase the relevancy of the items administered, and thereby improve measurement precision and eliminate wasted data without sacrificing the scientific validity and utility of the instrument. The panelists agreed that implementing a modular approach is not expected to have a meaningful impact on item responses, subscale scores, variability, reliability, validity, and effect size estimates; however, collecting additional evidence for the impact of context may be desirable. It is also important to recognize that adequate rationale and evidence (e.g., of fit-for-purpose status and relevance to patients) and a robust consensus process that includes patient perspectives are required to inform selection of subscales, as in any other measurement circumstance, is expected. We believe that the considerations discussed within (content validity, administration context, and psychometric factors) are relevant across multiple therapeutic areas.

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.

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 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.

Background Barth syndrome (BTHS) is a rare, X-linked disorder that stems from mutations in the TAFAZZIN (TAZ) gene with varying disease severity among patients. The Barth Syndrome Symptom Assessment (BTHS-SA) is a patient-reported outcome questionnaire developed to assess BTHS symptom severity. The current study reflects the first exploration of the assessment’s psychometric performance. Methods The BTHS-SA was administered in TAZPOWER, a phase 2, randomized, double-blind, placebo-controlled crossover study to evaluate daily subcutaneous injections of elamipretide in subjects with genetically confirmed BTHS. Descriptive and correlational analyses were used to assess the score distributions, reliability, and construct-related validity of BTHS-SA items and domains including a two-item (2 FS), three-item (3 FS), and four-item (4 FS) fatigue score, and a five-item myopathy score (5MS). Results Among the N = 12 white males (M age = 19.5, SD = 7.7) participating in the TAZPOWER trial, overall symptoms were rated as mild (n = 5, 41.7%), moderate (n = 5, 41.7%), severe (n = 1, 8.3%), or very severe (n = 1, 8.3%). Descriptive statistics for the BTHS-SA scores indicate variability of symptom severity both within symptom cluster and across patients. Promising results were found for both internal consistency (α = 0.67, 0.72, and 0.66 for the 3 FS, 4 FS, and 5MS, respectively) and test–retest reliability (ICC values ranging from 0.79 to 0.94 across two test–retest intervals). Correlational analyses showing moderate to strong relationships to other patient reports of fatigue (e.g., r = 0.59, 0.76, 0.68, and 0.61 between the PROMIS Fatigue SF and the 2 FS, 3 FS, 4 FS, and 5MS, respectively) and symptom severity (e.g., r = 0.60, 0.62, 0.56, 0.53 between a patient global rating and the 2 FS, 3 FS, 4 FS, and 5MS, respectively) support the measure’s convergent validity. A similar pattern of relationships was observed when correlating changes in BTHS-SA scores to reference measures, including moderate to strong relationships between the BTHS-SA and direct patient reports of change (r = 0.81, 0.79, 0.82, and 0.80 between a global impression of change score and the 2 FS, 3 FS, 4 FS, and 5MS, respectively). Conclusion Though the small sample size limits strong conclusions, this analysis suggests the BTHS-SA can produce reliable scores upon which valid inferences may be drawn. The BTHS-SA may be a useful tool to evaluate treatment benefits in this underserved population. Trial registration ClinicalTrials.gov identifier, NCT03098797. Registered 05 May 2017, https://www.clinicaltrials.gov/study/NCT03098797 .

Background Barth Syndrome (BTHS) is a rare genetic disorder that presents as a complex of debilitating symptoms and reduced life expectancy. Well-developed, BTHS-specific assessments measuring primary signs and symptoms of BTHS are not currently available, making it difficult to evaluate treatment effects in BTHS clinical studies. The objective of this research was to develop symptom-focused patient-reported outcome (PRO) measures for use in clinical studies with adolescents and adults with BTHS. Methods Concept elicitation interviews (CEIs) with pediatric (n = 18, age < 16 years) and adult (n = 15, age ≥ 16 years) individuals with BTHS and/or their caregivers were conducted to identify signs and symptoms relevant to BTHS and important to individuals with the condition. Based on CEI results, questionnaire construction activities were conducted to create unique adolescent and adult versions of the Barth Syndrome-Symptom Assessment (BTHS-SA). The questionnaires were evaluated in cognitive debriefing interviews (CDIs) with adolescents (n = 12; age 12- < 16 years) and adults (n = 12; age ≥ 16 years) with BTHS to assess relevance and readability of the tools. Results During the CEIs, a total of 48 and 40 signs and symptoms were reported by the pediatric and adult groups, respectively; 31 were reported by both age groups. Fatigue/tiredness and muscle weakness were the symptoms most frequently reported by both pediatric and adult patients with BTHS as important to improve with an effective treatment. The CEI results informed construction of a nine-item version of the BTHS-SA for adolescents and an eight-item version for adults. Developed for daily administration, each version asks respondents to rate symptom severity “at its worst” over the 24 h prior to administration. CDIs with both adolescents and adults with BTHS demonstrated that each BTHS-SA version was reflective of the disease experience and that respondents could interpret the questionnaire as intended and provide responses that accurately reflected their symptom experience. Conclusions The BTHS-SA adolescent and adult versions are content-valid PRO measures that can be used to evaluate severity of disease-specific symptoms in future clinical trials. Given the lack of available and well-developed assessments in this underserved therapeutic area, these tools fulfill a need for clinical researchers developing treatments for individuals with BTHS.