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Patient-reported outcome measures for systemic lupus erythematosus clinical trials: a review of content validity, face validity and psychometric performance

BackgroundDespite overall progress in treatment of autoimmune diseases, patients with systemic lupus erythematosus (SLE) experience many inflammatory symptoms representing an unmet medical need. This study aimed to create a conceptual model of the humanistic and economic burden of SLE, and review the patient-reported outcomes (PROs) used to measure such concepts in SLE clinical trials.MethodsA conceptual model for SLE was developed from structured review of published articles from 2007 to August 2013 identified from literature databases (MEDLINE, EMBASE, PsycINFO, EconLit) plus other sources (PROLabels, FDA/EMA websites, Clinicaltrials.gov). PROs targeting key symptoms/impacts were identified from the literature. They were reviewed in the context of available guidance and assessed for face and content validity and psychometric properties to determine appropriateness for use in SLE trials.ResultsThe conceptual model identified fatigue, pain, cognition, daily activities, emotional well-being, physical/social functioning and work productivity as key SLE concepts. Of the 68 articles reviewed, 38 reported PRO data. From these and the other sources, 15 PROs were selected for review, including SLE-specific health-related quality of life (HRQoL) measures (n = 5), work productivity (n = 1), and generic measures of fatigue (n = 3), pain (n = 2), depression (n = 2) and HRQoL (n = 2). The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue), Brief Pain Inventory (BPI-SF) and LupusQoL demonstrated the strongest face validity, conceptual coverage and psychometric properties measuring key concepts in the conceptual model. All PROs reviewed, except for three Lupus-specific measures, lacked qualitative SLE patient involvement during development. The Hospital Anxiety and Depression Scale (HADS), Short Form [36 item] Health Survey version 2 (SF-36v2), EuroQoL 5-dimensions (EQ-5D-3L and EQ-5D-5L) and Work Productivity and Activity Impairment Questionnaire: Lupus (WPAI:Lupus) showed suitability for SLE economic models.ConclusionsBased on the identification of key symptoms and impacts of SLE using a scientifically sound conceptual model, we conclude that SLE is a condition associated with high unmet need and considerable burden to patients. This review highlights the availability and need for disease-specific and generic patient-reported measures of relevant domains of disease signs and symptoms, HRQoL and work productivity, providing useful insight for SLE clinical trial design.

Assessing the impact of growth hormone deficiency and treatment in adults: development of a new disease-specific measure.

CONTEXT Approximately 50 000 adults in the United States are diagnosed with GH deficiency, which has negative impacts on cognitive functioning, psychological well-being, and quality of life. OBJECTIVE This paper presents development and validation of a patient-reported outcome measure (PRO), the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD). The TRIM-AGHD was developed to measure the impact of GH deficiency and its treatment. DESIGN AND SETTINGS The development and validation of the TRIM-AGHD was conducted according to the Food and Drug Administration guidance on the development of PROs. Concept elicitation, conducted in three countries included interviews with patients, clinical experts, and literature review. Qualitative data were analyzed based on grounded theory principles, and draft items were cognitively debriefed. The measure underwent psychometric validation in a US clinic-based population. An a priori statistical analysis plan included assessment of the measurement model, reliability, and validity. Item functioning was reviewed using item response theory analyses. PATIENTS OR OTHER PARTICIPANTS Forty-eight patients and six clinical experts participated in concept elicitation and 169 patients completed the validation study. MAIN OUTCOME MEASURE TRIM-AGHD was measured. RESULTS Factor analysis resulted in four domains: energy level, physical health, emotional health, and cognitive ability. The item response theory confirmed adequate item fit and placement within their domain. Internal consistency ranged from 0.82 to 0.95 and test-retest ranged from 0.80 to 0.92. All prespecified hypotheses for convergent validity and all but two for discriminant validity were met. CONCLUSIONS The final 26-item TRIM-AGHD can be considered a reliable and valid PRO of the impact of disease and treatment for adult GH deficiency.

Development of a conceptual model evaluating the humanistic and economic burden of Crohn’s disease: implications for patient-reported outcomes measurement and economic evaluation

The primary objective of this review is to develop a conceptual model for Crohn’s disease (CD) outlining the disease burden for patients, healthcare systems and wider society, as reported in the scientific literature. A search was conducted using MEDLINE, PsycINFO, EconLit, Health Economic Evaluation Database and Centre for Reviews and Dissemination databases. Patient-reported outcome (PRO) measures widely used in CD were reviewed according to the US FDA PRO Guidance for Industry. The resulting conceptual model highlights the characterization of CD by gastrointestinal disturbances, extra-intestinal and systemic symptoms. These symptoms impact physical functioning, ability to complete daily activities, emotional wellbeing, social functioning, sexual functioning and ability to work. Gaps in conceptual coverage and evidence of reliability and validity for some PRO measures were noted. Review findings also highlight the substantial direct and indirect costs associated with CD. Evidence from the literature confirms the substantial burden of CD to patients and wider society; however, future research is still needed to further understand burden from the perspective of patients and to accurately understand the economic burden of disease. Challenges with existing PRO measures also suggest the need for future research to refine or develop new measures.

Assessing the impact of non-severe hypoglycemic events and treatment in adults: development of the Treatment-Related Impact Measure—Non-severe Hypoglycemic Events (TRIM-HYPO)

PurposeNon-severe hypoglycemic events (NSHEs) are commonly experienced by diabetes patients, particularly among insulin users, and can have serious impacts on daily functioning, emotional well-being, sleep, work productivity, and treatment adherence. Currently, no PRO measures are available to assess the impacts of non-severe hypoglycemia. To address this gap, the Treatment-Related Impact Measure-Non-severe Hypoglycemic Events (TRIM-HYPO) was developed. This paper describes the TRIM-HYPO development and validation.MethodsThe creation of the TRIM-HYPO followed FDA’s guideline for PRO development. Concept elicitation data were gathered from literature review, clinical expert interviews, and focus groups of patients with Type 1 or 2 diabetes in four countries. Based on the qualitative analysis, draft items were generated and cognitively debriefed. Psychometric validation included factor analysis, item response theory analysis, and assessment of psychometric characteristics for the TRIM-HYPO.ResultsEight clinical experts and 167 patients participated in concept elicitation. The validation study included 407 patients. Thirteen of the 46 items from the preliminary measure were dropped due to ceiling/floor effects and high correlations between conceptually similar items. Factor analysis confirmed five domains in the TRIM-HYPO: daily function, emotional well-being, diabetes management, sleep disruption, and work productivity. All scores were internally consistent (0.86–0.95) and reproducible with a test–retest range of 0.75–0.98. All but one a priori hypothesized associations for validity were confirmed.ConclusionsStudy findings demonstrate that the final, 33-item TRIM-HYPO is reliable and valid and may be useful for assessing impacts related to NSHEs in research and clinical practice.

Development of the Weight-Related Sign and Symptom Measure

BackgroundOverweight and obesity have been associated with physical and emotional signs & symptoms. Research has shown that modest weight loss can mitigate some symptoms in individuals with overweight or obesity. This study’s purpose was to conduct concept elicitation (CE) interviews to provide documented qualitative support for the development of the Weight-Related Sign and Symptom Measure (WRSSM) to assess weight-related signs/symptoms in U.S. adults with overweight or obesity, with or without type 2 diabetes (T2DM).Eight focus groups were conducted in the U.S. with adults with overweight or obesity to understand weight-related sign/symptom impact from the patient perspective. Individual interviews were conducted with clinical experts to understand the impact of overweight or obesity on patient signs and symptoms. Transcripts were analyzed to identify symptoms and observable signs. A clinical challenge was conducted with clinical experts to confirm the signs/symptoms were clinically relevant, important to patients, and would improve with modest weight loss. Cognitive debriefing (CD) was conducted with individuals with overweight or obesity to confirm readability and symptom relevance.ResultsCE interviews were conducted with four clinical experts, and 61 people, 32% of whom had T2DM, participated in the focus groups. Analyses identified two major areas of obesity impacts: weight-related physical signs/symptoms, and emotional impacts. The most frequently reported physical signs/symptoms were feeling tired (74%), shortness of breath (69%), and joint pain (64%). The most often reported emotional impacts included poor self-image (72%) and depression (51%). Twelve signs/symptoms were identified during item generation and included on the preliminary measure. Twelve adults with overweight/obesity, who were not part of the focus groups, participated in CD. After the CD, a validation-ready, 10-item WRSSM measure was generated.ConclusionsFindings provide evidence of content validity for the validation-ready WRSSM in U.S. adults with overweight or obesity, including people with and without T2DM.

Understanding burden of illness for child growth hormone deficiency

PurposeResearch demonstrates that children and adolescents with growth hormone deficiency (GHD) are impacted in multiple ways beyond their short stature; however, there are no disease-specific measures to assess these impacts. The purpose of this study was to examine the burden of GHD on children and adolescents, and to conduct concept elicitation to develop a model of the impact of GHD to support a disease-specific outcome measure.MethodsFour focus groups and 52 telephone interviews were conducted with children with GHD and parents/guardians of children with GHD to understand the experience and impacts from the child’s perspective, reported by children or parent-observers about the impact on the child. The interviews and focus groups were conducted in Germany, the United Kingdom, and the United States. Interview transcripts were analyzed thematically based on modified grounded theory principles.ResultsThere were 73 descriptions of patient’s experiences elicited from 70 respondents, as three respondents spoke for two children each. A majority of GHD descriptive narratives refer to boy children (n = 51, 69.9%) and a majority of children had taken GHD treatment (n = 64, 89%). Analysis identified four major areas of GHD impact: Signs and Symptoms (beyond short stature), Physical Aspects of Daily Life, Social Well-Being, and Emotional Well-Being.ConclusionsThe burden of GHD in children and adolescents is considerable and not limited to short stature. The severity of GHD impact on children and adolescents appears to be variable and individualized, but these data indicate that early identification and growth hormone treatment may lead to fewer impacts.

PROMs for Systemic Lupus Erythematosus

Patients with active Systemic Lupus Erythematosus (SLE) experience a large variation of symptoms and manifestations. The symptoms and manifestations of SLE impact the patients’ health-related quality of life (HRQoL). Many of the patients’ SLE symptoms are not always adequately captured by objective clinical outcome measures or laboratory assessments alone. Therefore in addition to well-established clinical outcome measures used in clinical practice, the patient perspective should be captured through patient reported outcome measures (PROMs). Key concepts/domains derived from a recently developed conceptual model published by Holloway et al. (Qual Life Outcomes. 2014;12:116) are the basis for the recommendations of PROMs. Recommendations for PROMs to apply in clinical practice are based on the face and content validity as well as psychometric properties of each of the PROMs. In the conceptual model, fatigue, pain, and emotional well-being/depression were identified as key domains impacting the lives of patients with SLE. Appropriate PROMs to use in clinical practice capturing the key domains are the Functional Assessment of Chronic Illness Therapy—Fatigue scale (FACIT-Fatigue), Brief Pain Inventory (BPI-SF), and Hospital Anxiety and Depression Scale (HADS). In addition the generic HRQoL measure Short Form (36 item) Health Survey version 2 (SF-36v2) and the disease-specific HRQoL measure LupusQoL can be applied in clinical practice. It might be favorable in standard clinical practice to consider including one cohesive PROM for the assessment of patient reported key symptoms and impacts in SLE, however, further research and validation studies are needed. PROMs capturing key symptoms of SLE such as fatigue, pain, and HRQoL supplement objective clinical outcome measures and laboratory assessments providing clinicians with a valuable patient perspective on the impact of SLE.