Evaluation and Modification of a Shared Decision-Making Tool for Peanut Allergy Management.

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. 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.

Administering selected subscales of patient-reported outcome questionnaires to reduce patient burden and increase relevance: a position statement on a modular approach.

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.

A Comparative Evaluation of the Measurement Properties of Three Histological Indices of Mucosal Healing in Ulcerative Colitis: Geboes Score, Robarts Histopathology Index and Nancy Index.

BACKGROUND AND AIMS: To inform their future use in regulated clinical trials to evaluate treatment efficacy hypotheses, the measurement properties of three histological indices, Geboes Score [GS], Robarts Histopathology Index [RHI] and Nancy Index [NI], were evaluated among patients with ulcerative colitis. METHODS: Analyses were conducted on data from a Phase 3 clinical trial of adalimumab [M14-033, n = 491] and focused on evaluating the measurement properties of the GS, RHI and NI. Specifically, internal consistency and inter-rater reliability, convergent, discriminant and known-group validity, and sensitivity to change were assessed at Baseline, and at Weeks 8 and 52. RESULTS: Internal consistency for the RHI showed lower alpha [α] values at Baseline [α = 0.62] relative to Weeks 8 [α = 0.82] and 52 [α = 0.81]. The inter-rater reliability values of RHI [0.91], NI [0.64] and GS [0.53] were excellent, good and fair, respectively. Regarding validity, Week 52 correlations were moderate to strong between full and partial Mayo scores and Mayo subscale scores and the RHI and GS, and were weak to moderate for the NI. Significant differences between mean scores of all three histological indices were observed across known-groups based on Mayo endoscopy subscores and full Mayo scores at Weeks 8 and 52 [p < 0.001]. CONCLUSIONS: The GS, RHI and NI are each capable of producing reliable and valid scores that are sensitive to changes in disease activity over time, in patients with moderately to severely active ulcerative colitis. While all three indices demonstrated relatively acceptable measurement properties, the GS and RHI performed better than the NI.

Psychometric evaluation of the NTDT-PRO questionnaire for assessing symptoms in patients with non-transfusion-dependent beta-thalassaemia.

OBJECTIVES: The 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). DESIGN: Analysis of a phase 2, double-blind, randomised, placebo-controlled trial. SETTING: USA, Greece, Italy, Lebanon, Thailand and the UK. PARTICIPANTS: Adults (≥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. MEASURES: NTDT-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). RESULTS: Cronbach'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. CONCLUSIONS: The 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.

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF©) and determination of a threshold score for moderate symptoms.

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.

Psychometric performance of the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) in a randomized, double-blind, placebo-controlled crossover study in subjects with mitochondrial disease.

BACKGROUND: The Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) is a 10-item patient-reported outcome (PRO) measure designed to assess the severity of mitochondrial disease symptoms. Analyses of data from a clinical trial with PMM patients were conducted to evaluate the psychometric properties of the PMMSA and to provide score interpretation guidelines for the measure. METHODS: The PMMSA was completed as a daily diary for approximately 14 weeks by individuals in a Phase 2 randomized, placebo-controlled crossover trial evaluating the safety, tolerability, and efficacy of subcutaneous injections of elamipretide in patents with mitochondrial disease. In addition to the PMMSA, performance-based assessments, clinician ratings, and other PRO measures were also completed. Descriptive statistics, psychometric analyses, and score interpretation guidelines were evaluated for the PMMSA. RESULTS: Participants (N = 30) had a mean age of 45.3 years, with the majority of the sample being female (n = 25, 83.3%) and non-Hispanic white (n = 29, 96.6%). The 10 PMMSA items assessing a diverse symptomology were not found to form a single underlying construct. However, four items assessing tiredness and muscle weakness were grouped into a "general fatigue" domain score. The PMMSA Fatigue 4 summary score (4FS) demonstrated stable test-retest scores, internal consistency, correlations with the scores produced by reference measures, and the ability to differentiate between different global health levels. Changes on the PMMSA 4FS were also related to change scores produced by the reference measures. PMMSA severity scores were higher for the symptom rated as "most bothersome" by each subject relative to the remaining nine PMMSA items (most bothersome symptom mean = 2.88 vs. 2.18 for other items). Distribution- and anchor-based evaluations suggested that reduction in weekly scores between 0.79 and 2.14 (scale range: 4-16) may represent a meaningful change on the PMMSA 4FS and reduction in weekly scores between 0.03 and 0.61 may represent a responder for each of the remaining six non-fatigue items, scored independently. CONCLUSIONS: Upon evaluation of its psychometric properties, the PMMSA, specifically the 4FS domain, demonstrated strong reliability and construct-related validity. The PMMSA can be used to evaluate treatment benefit in clinical trials with individuals with PMM. Trial registration ClinicalTrials.gov identifier, NCT02805790; registered June 20, 2016; https://clinicaltrials.gov/ct2/show/NCT02805790 .

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) in a phase 2 clinical study.

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 .

Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF©.

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.

Development and content validity of the Barth Syndrome Symptom Assessment (BTHS-SA) for adolescents and adults.

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.

Psychometric evaluation of the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF).

BACKGROUND: The Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) was developed to evaluate symptoms of advanced systemic mastocytosis (AdvSM). This study aimed to psychometrically evaluate AdvSM-SAF scores and provide score interpretation guidelines. METHODS: The 10-item AdvSM-SAF was administered daily (scored as a seven-day average) in EXPLORER, an open-label Phase 1 study in AdvSM. Score distribution, reliability, construct-related validity, sensitivity to change, and interpretation guidelines were evaluated for AdvSM-SAF items, gastrointestinal symptom score (GSS), skin symptom score (SSS), and total symptom score (TSS). RESULTS: Thirty-one patients contributed to the analyses. At Baseline, the GSS, SSS, and TSS had adequate internal consistency (α > 0.7) and test-retest reliability (intraclass correlation coefficients >0.7). AdvSM-SAF scores were moderately to strongly correlated with variables as expected, and distinguished among clinically distinct groups. Observed relationships between change scores in the AdvSM-SAF and other assessments reflect evidence that AdvSM-SAF scores change in concert with other assessments designed to measure similar constructs. The magnitude of AdvSM-SAF weekly TSS mean change scores based on different anchor groupings was as expected (improvement > stable > worsening). Candidate clinically meaningful between-group difference estimates (GSS = 2-4, SSS = 2-3, and TSS = 4-7 points) and within-person change estimates (GSS = 6-9, SSS = 1-4, TSS = 9-14) for AdvSM-SAF weekly scores were generated. CONCLUSION: The AdvSM-SAF produced reliable, construct-valid, and sensitive scores when administered in the target patient population. These results, along with its strong development history and evidence of content validity, indicate that the AdvSM-SAF is fit for the purpose of measuring treatment benefit in individuals with AdvSM.

Clinically Relevant Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 ALLEVIATE Trial.

PURPOSE: To assess the post-acute activity and clinical utility of reproxalap, a novel reactive aldehyde species (RASP) inhibitor, versus vehicle in patients with seasonal allergic conjunctivitis. DESIGN: Parallel-group, double-masked, randomized Phase 3 trial. METHODS: Two topical ocular reproxalap concentrations (0.25% and 0.5%) were evaluated versus vehicle in patients with allergic conjunctivitis randomized 1:1:1 and treated with test article 10 minutes prior to conjunctival seasonal allergen challenge. The primary endpoint was area under the post-acute ocular itching score (range = 0-4) curve from 10 to 60 minutes after challenge. The key secondary endpoint was the proportion of subjects with ≥2 points improvement from their peak ocular itching score at baseline. RESULTS: A total of 318 patients were randomized at 11 US sites. Both concentrations of reproxalap (0.25% and 0.5%) achieved the primary endpoint (P < .0001 and P = .003, respectively) and the key secondary endpoint (P = .0005 and P = .02, respectively). Time to complete resolution of ocular itching was statistically faster for both reproxalap concentrations than for vehicle (P < .0001 and P = .001, respectively). No safety or tolerability concerns were noted. The most common adverse event was mild and transient instillation site irritation. CONCLUSION: Reproxalap was effective at reducing ocular itching in patients with allergic conjunctivitis. Reproxalap activity was clinically relevant, as assessed by responder-based and distributional analyses. ALLEVIATE represents one of the first allergic conjunctivitis Phase 3 trials of a novel mechanism of action in decades, and is unique among conjunctival allergen challenge trials in assessing clinical relevance with standard and validated techniques.

FABry Disease Patient-Reported Outcome-GastroIntestinal (FABPRO-GI): A new Fabry disease-specific gastrointestinal outcomes instrument.

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 FABry disease Patient-Reported Outcome-GastroIntestinal (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.

Development of a Patient-Reported Outcome Questionnaire to Evaluate Primary Mitochondrial Myopathy Symptoms: The Primary Mitochondrial Myopathy Symptom Assessment.

OBJECTIVES: Primary mitochondrial myopathy (PMM) is a genetic condition characterized by life-limiting symptoms such as muscle weakness, fatigue, and pain. Because these symptoms are best reported by individuals with PMM, the objective of this qualitative research study was to develop a PMM-specific patient-reported outcome (PRO) questionnaire. METHOD: Individuals with PMM were interviewed, identifying the most salient symptoms of PMM and assessing the resulting questionnaire's relevance and comprehensibility. RESULTS: Developed based on patient interviews, the 10-item Primary Mitochondrial Myopathy Symptom Assessment assesses patients' symptom experiences at their worst in the last 24 hours. Individuals with PMM confirmed the concepts of the questionnaire as relevant and comprehensive to their symptom experiences and responded to the items consistently with developers' intentions. CONCLUSIONS: The Primary Mitochondrial Myopathy Symptom Assessment is a content-valid PRO questionnaire with qualitative and quantitative support as a valuable tool to evaluate and monitor the day-to-day experience of PMM symptoms from the patient perspective.

Development and Psychometric Evaluation of the Life Interference Questionnaire for Growth Hormone Deficiency (LIQ-GHD) to Assess Growth Hormone Injection Burden in Children and Adults.

BACKGROUND: Current recombinant human growth hormone (r-hGH) replacement therapy involves long-term daily subcutaneous injections to treat growth hormone deficiency (GHD) in children and adults. Daily r-hGH injections can be burdensome, often resulting in poor treatment compliance. Clinical outcome assessments (COAs) can capture the burden of these injections from the patient (and caregiver) perspective and may demonstrate the benefit of a less-frequent r-hGH injection regimen, which may ultimately improve treatment compliance and long-term outcomes. OBJECTIVE: To address this knowledge gap, qualitative research was conducted to inform the development of a new Life Interference Questionnaire for Growth Hormone Deficiency (LIQ-GHD), designed to measure the experiences of patients taking r-hGH GHD injections. A second objective was to evaluate the hypothesized factor structure and preliminary performance of the LIQ-GHD in a cross-sectional observational study. METHODS: An empirical literature review and expert advice meetings were conducted to inform development of the draft LIQ-GHD (pediatric and adult versions). In-person concept elicitation and cognitive debriefing interviews were conducted with GHD patients (and patient dyads including caregivers) to explore and confirm concept coverage and evaluate respondents' ability to understand the questionnaire. The draft LIQ-GHD was then tested in a cross-sectional field study involving pediatric and adult patients receiving daily r-hGH injections for GHD. The factor structure, reliability, and validity were analyzed for the overall sample and for pediatric, adolescent, and adult subgroups. RESULTS: Results from the literature review and input from six experts were used to develop and refine the LIQ-GHD, with content covering pen ease of use; regimen convenience; life interference due to regimen; benefit/satisfaction/willingness to continue treatment; regimen choice/preference; intent to comply with regimen; injection-related signs/symptoms; and reasons for missed injections. Twenty-one patient interviews confirmed comprehensive concept coverage and patient/caregiver comprehension of the LIQ-GHD. A total of 224 patients (n = 70 children/caregiver dyads, n = 79 adolescents/caregiver dyads, n = 75 adults) participated in the field study. While most items showed floor effects, confirmatory factor analysis fit statistics were good for the overall sample (root mean square error of approximation = 0.07, comparative fit index = 0.98) and for the full pediatric sample after dropping co-dependent questions from the model. Cronbach's alpha (α) ranged from 0.746 to 0.905 and intra-class correlation coefficients ranged from 0.761 to 0.918 for the overall sample on LIQ-GHD domains. Scores correlated as predicted with an existing criterion measure in the overall sample and LIQ-GHD domain scores distinguished known groups as expected. CONCLUSIONS: The LIQ-GHD is a new COA for the measurement of r-hGH injection treatment burden. This research provides evidence supporting its content validity, hypothesized factor structure, score reliability, and construct validity in pediatric and adult populations.

Understanding the life experience of Barth syndrome from the perspective of adults: a qualitative one-on-one interview study.

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.

Development of a symptom assessment in patients with myelofibrosis: qualitative study findings.

BACKGROUND: The goal of the research reported here was to understand the patient experience of living with myelofibrosis (MF) and establish content validity of the Modified Myeloproliferative Neoplasm Symptom Assessment Diary (MPN-SD). METHODS: Qualitative interviews were performed in patients with MF, including both concept elicitation and cognitive debriefing. Patients with MF were asked to spontaneously report on their signs, symptoms, and impacts of MF, as well as their understanding of the MPN-SD content, and use of the tool on an electronic platform. A supplementary literature review and meetings with MF experts were also performed. RESULTS: Twenty-three patients with MF participated in qualitative interviews. Signs and symptoms most commonly reported by ruxolitinib-experienced patients (n = 16) were: fatigue and/or tiredness (n = 16, 100%), shortness of breath (n = 11, 69%), pain below the ribs on the left side and/or stomach pain and/or abdominal pain (n = 9, 56%), and enlarged spleen (n = 9, 56%) and for ruxolitinib-naïve patients (n = 7) were: fatigue and/or tiredness (n = 6, 86%), pain below the ribs on the left side (n = 6, 86%), enlarged spleen (n = 4, 57%), full quickly/filling up quickly (n = 4, 57%), night sweats and/or general sweats (n = 4, 57%), and itching (n = 4, 57%). Patients demonstrated that they were able to read, understand, and provide meaningful responses to the MPN-SD. The final version of the MPN-SD includes the 10 most commonly reported concepts from the MF patient interviews. CONCLUSIONS: The findings demonstrate the comprehensiveness of the MPN-SD in assessing MF symptoms in both ruxolitinib-experienced and ruxolitinib-naïve patients, while remaining easy for patients to understand and complete.

Informing a priori Sample Size Estimation in Qualitative Concept Elicitation Interview Studies for Clinical Outcome Assessment Instrument Development.

OBJECTIVE: Evidence-based recommendations for the a priori estimation of sample size are needed for qualitative concept elicitation (CE) interview studies in clinical outcome assessment (COA) instrument development. Saturation is described as the point at which no new data is expected to emerge from the conduct of additional qualitative interviews. STUDY DESIGN: A retrospective evaluation of 26 CE interview studies conducted with patients between 2006 and 2013 was completed to assess the point at which saturation of concept was achieved in each study. METHODS: For each of the 26 interview studies, saturation of symptom concepts was assessed by dividing the sample into quartiles and then comparing the number of responses elicited from the first 25% of participants to the next 25% of participants, from the first 50% of participants to the next 25% of participants, and then from the first 75% of participants to the last 25% of participants. The number of interviews required to achieve saturation was documented for each study and then summarized across studies. RESULTS: Findings indicate that 84% of symptom concepts emerged by the 10th interview, 92% emerged by the 15th interview, 97% emerged by the 20th interview, and 99% by the 25th interview. CONCLUSIONS: Results provide practical guidance for estimating the number of interviews that may be needed to achieve saturation in a qualitative CE interview study for COA instrument development; address an important gap in qualitative research for the development of COAs in the context of medical product development; and offer useful information for study design and implementation.

Development of a Symptom-Focused Patient-Reported Outcome Measure for Functional Dyspepsia: The Functional Dyspepsia Symptom Diary (FDSD).

OBJECTIVES: The Functional Dyspepsia Symptom Diary (FDSD) was developed to address the lack of symptom-focused, patient-reported outcome (PRO) measures designed for use in functional dyspepsia (FD) patients and meeting Food and Drug Administration recommendations for PRO instrument development. METHODS: Concept elicitation interviews were conducted with FD participants to identify symptoms important and relevant to FD patients. A preliminary version of the FDSD was constructed, then completed by FD participants on an electronic device in cognitive interviews to evaluate the readability, comprehensibility, relevance, and comprehensiveness of the FDSD, and to preliminarily evaluate its measurement properties. RESULTS: During concept elicitation interviews, 45 participants spontaneously reported 19 symptom concepts. Of those, seven symptoms were selected for assessment by the eight-item FDSD. Cognitive interviews with 57 participants confirmed that participants were able to comprehend and provide meaningful responses to the FDSD, and that the handheld electronic FDSD format was suitable for use in the target population. Scores of the FDSD were well-distributed among response options, item discrimination indices suggested that the FDSD items differentiate among patients with varying degrees of FD severity, and inter-item correlations suggested that no items of the FDSD were capturing redundant information. Internal consistency estimates (0.87) and construct-related validity estimates using known-groups methods were within acceptable ranges. CONCLUSIONS: The FDSD is a content-valid PRO measure, with preliminary psychometric evidence providing support for the FDSD's items and total score. Further psychometric evaluations are recommended to more fully test the FDSD's score performance and other measurement properties in the target patient population.

Development and initial psychometric evaluation of patient-reported outcome questionnaires to evaluate the symptoms and impact of hidradenitis suppurativa.

BACKGROUND: Two patient-reported outcome (PRO) questionnaires, the Hidradenitis Suppurativa Symptom Assessment (HSSA) and Hidradenitis Suppurativa Impact Assessment (HSIA), were developed to measure signs, symptoms and impacts of HS in treatment efficacy studies. METHODS: In accordance with FDA guidelines and published best practices, four stages of research were conducted to create the questionnaires: concept elicitation, questionnaire construction, content evaluation and psychometric evaluation. RESULTS: Subjects (N = 20) who participated in the concept elicitation stage reported 15 unique HS-related signs and symptoms and 51 impacts. Following this, eight sign and symptom concepts and 21 impacts were selected for construction of the HSSA and HSIA, respectively. During content evaluation, cognitive debriefing interviews with HS subjects (N = 20) confirmed subjects could read, comprehend and meaningfully respond to both questionnaires. Modifications made after this stage of work resulted in a nine-item HSSA and a 17-item HSIA. The HSSA and HSIA were subsequently entered into a US-based observational study (N = 40), and the scores produced by each were found to be reliable, construct valid, and able to distinguish among clinically distinct groups. CONCLUSIONS: The HSSA and HSIA are content-valid, HS-specific, PRO questionnaires with demonstrated ability to generate reliable, valid scores when administered to patients with HS in a research setting.