Outcome measures for migraine: Measuring the impact of migraine and results of migraine treatment.

The experience of migraine symptoms and the impacts of migraine on quality of life (QOL) are best reported by the person experiencing them. Therefore, patient-reported outcome (PRO) measures are often used to collect data about the experience and impact of migraine, and value of migraine treatments. PRO concepts that are assessed for the evaluation of migraine treatment outcomes are myriad and diverse (e.g., symptoms, impacts, satisfaction). The first step toward developing a precise strategy to evaluate the outcomes of a treatment is identifying WHAT to measure. This is followed by considerations around HOW to measure the concept. "Selecting What to Measure" section of this chapter discusses the important PRO concepts (WHAT) to measure the impact of migraine and to evaluate interventions for migraine. "Selecting How to Measure" section of this chapter focuses on HOW to collect data about these outcomes in the context of research to evaluate migraine treatments. PRO endpoints recommended in international migraine guidelines and examples of PRO measures that can be used for collecting data to support these endpoints are discussed. The final section of this chapter suggests considerations for selecting PRO measures for evaluating the impact of migraine and migraine treatments and for using these measures to collect data in clinical research.

Using Health-Related Social Media to Understand the Experiences of Adults With Lung Cancer in the Era of Immuno-Oncology and Targeted Therapies: Observational Study.

BACKGROUND: The treatment of non-small cell lung cancer (NSCLC) has evolved dramatically with the approval of immuno-oncology (IO) and targeted therapies (TTs). Insights on the patient experience with these therapies and their impacts are lacking. Health-related social media has been increasingly used by patients to share their disease and treatment experiences, thus representing a valuable source of real-world data to understand the patient's voice and uncover potential unmet needs. OBJECTIVE: This study aimed to describe the experiences of patients with NSCLC as reported in discussions posted on lung cancer-specific social media with respect to their disease symptoms and associated impacts. METHODS: Publicly available posts (2010-2019) were extracted from selected lung cancer- or NSCLC-specific websites. Social media users (patients and caregivers posting on these websites) were stratified by metastatic- and adjuvant-eligible subgroups and treatment received using natural language processing (NLP) and machine learning methods. Automated identification of symptoms was conducted using NLP. Qualitative data analysis (QDA) was conducted on random samples of posts mentioning pain-related, fatigue-related, respiratory-related, or infection-related symptoms to capture the patient experience with these and associated impacts. RESULTS: Overall, 1724 users (50,390 posts) and 574 users (4531 posts) were included in the metastatic group and adjuvant group, respectively. Among users in the metastatic group, pain, discomfort, and fatigue were the most commonly mentioned symptoms (49.7% and 39.6%, respectively), and in the QDA (258 posts from 134 users), the most frequent impacts related to physical impairments, sleep, and eating habits. Among users in the adjuvant group, pain, discomfort, and respiratory symptoms were the most commonly mentioned (44.8% and 23.9%, respectively), and impacts identified in the QDA (154 posts from 92 users) were mostly related to physical functioning. CONCLUSIONS: Findings from this exploratory observational analysis of social media among patients and caregivers informed the lived experience of NSCLC in the era of novel therapies, shedding light on most reported symptoms and their impacts. These findings can be used to inform future research on NSCLC treatment development and patient management.

The Severity of Chronic Cough Diary (SCCD): development and content validation of a novel patient-reported outcome instrument for evaluating the symptom experience of chronic cough.

BACKGROUND: Refractory chronic cough (RCC), a cough lasting longer than 8 weeks with an unexplained underlying etiology and unresponsive to conventional treatment, can have substantial effects on patients' quality of life. For assessment of the efficacy of antitussive medication in clinical trials in RCC, patient-reported outcome (PRO) instruments should be fit for purpose with appropriate content validity. Here we describe the qualitative testing of a newly developed PRO instrument: the Severity of Chronic Cough Diary (SCCD). METHODS: The SCCD was developed to assess patients' symptom experience of cough in patients with RCC. A preliminary version was tested and refined based on an iterative process in a qualitative study. In total, three rounds of interviews were conducted with adult participants diagnosed with RCC in the USA (n = 19) and UK (n = 10). Rounds 1-3 consisted of hybrid concept elicitation (CE) interviews and cognitive interviews (CIs), with Round 3 also including interviews in a subset of participants (n = 5) about the usability of the SCCD as administered on an electronic handheld device. RESULTS: The CE interviews identified concepts important to patients' experiences related to RCC that were broadly in line with the concepts in the preliminary version of the SCCD. Participants provided positive feedback on the draft SCCD across all CI rounds, reporting the instrument to be relevant and straightforward to complete, and containing a comprehensive set of concepts to evaluate their symptom experience of RCC. Participants demonstrated a good understanding of proposed item wording, response options, and the 24-hour recall period, and thought completion of the SCCD on the electronic device was easy. Following revisions based on results from each interview round, the SCCD at the end of this qualitative research study had 14 items assessing the concepts of: cough symptoms (five items), symptoms related to cough (four items), disruption to activities due to cough (three items), and disruption to sleep due to cough (two items). CONCLUSIONS: The results of this study provide qualitative evidence supporting the content validity of the SCCD as a PRO instrument for evaluating outcomes of therapies for RCC in clinical trials.

Developing a Conceptual Disease Model of Patient Experiences and Identifying Patient-Reported Clinical Outcome Assessments for Use in Trials of Treatments for Focal Onset Seizures.

Purpose: To identify concepts important to understanding the experiences of adults with focal onset seizures (FOS) and evaluate clinical outcome assessments (COAs) for measuring these concepts in clinical trials of treatments for FOS. Methods: A search of published qualitative research, clinical trials, and approved product labels for FOS treatments was performed to develop a conceptual disease model (CDM) of patients' experience of living with FOS. Concepts of interest (COI) were selected, and a second literature search was conducted to identify COAs measuring these concepts. Ten COAs were selected and reviewed to document their development process, evidence of measurement properties, and methods for interpreting change scores using criteria proposed in regulatory guidelines for patient-reported outcomes to support label claims. Results: Concepts identified from the published literature (13 articles, 1 conference abstract), 24 clinical trials, and 8 product labels were included in a novel CDM. Impacts on physical, cognitive, and social and emotional function were chosen as COI for evaluating treatment outcomes for FOS; the additional concept of social support and coping strategies was chosen to understand patients' lived experiences. From 51 unique COAs identified, 10 were selected based on their potential coverage of the COI; some symptom severity and health-related quality of life (HRQoL) COAs covered multiple COI. Of these 10, 8 COAs evaluated impacts/limitations on physical function, 8 measured social and emotional impacts, and 5 assessed social support and coping strategies. While most assessments had gaps in evidence validating their measurement properties, 2 COAs measuring symptom severity and 1 COA measuring HRQoL had evidence confirming their potential utility in clinical trials to support label claims. Conclusion: This research provides insights into the experience of patients with FOS and identifies COAs that measure concepts considered to support endpoints in clinical trials for FOS.

Reducing the physical, social, and emotional impact of episodic migraine: Results from erenumab STRIVE and ARISE phase III randomized trials.

OBJECTIVE: The purpose of this study was to examine changes in the functional impact of migraine following treatment with erenumab, as measured by the Migraine Functional Impact Questionnaire (MFIQ). BACKGROUND: The MFIQ, a novel patient-reported outcome (PRO) measuring the impact of migraine on four domains (physical function, social function, and emotional function [PF, SF, and EF]; usual activities [UAs]) and a single item assessing overall impact on UA, was included in phase III trials evaluating erenumab 70 and 140 mg monthly for migraine prevention among people with episodic migraine (EM). METHODS: In the ARISE study, 577 patients with EM were randomized to erenumab 70 mg or placebo. In the STRIVE study, 955 patients with EM were randomized to erenumab, 70 mg or 140 mg or placebo. Pairwise comparisons of least-squares mean (LSM) change from baseline in MFIQ scores (with associated 95% confidence interval [CI]) were assessed for each active treatment versus placebo. RESULTS: In ARISE, greater reductions from baseline to month 3 were observed for 70 mg versus placebo for PF (LSM [95% CI]: -3.2 [-6.4 to -0.1]; p = 0.046) and EF (-4.0 [-7.3 to -0.7]; p = 0.019) domain scores. In STRIVE, between-group differences also reflected reductions from baseline to the average of months 4-6 that favored erenumab on all four MFIQ domain scores. Reductions in impact for 70 mg compared to placebo were -4.3 (95% CI: -6.8 to -1.7; p < 0.001) for PF, -4.0 (-6.3 to -1.7; p < 0.001) for UA, -3.7 (-6.1 to -1.2; p = 0.003) for SF, and -5.3 (-7.9 to -2.6; p < 0.001) for EF domain scores. Improvements were also observed for 140 mg versus placebo with between-group differences of -5.7 (95% CI: -8.2 to -3.2; p < 0.001) in PF, -5.1 (-7.5 to -2.8; p < 0.001) in UA, -5.0 (-7.4 to -2.6; p < 0.001) in SF, and -7.2 (-9.9 to -4.5; p < 0.001) in EF domain scores. There were also greater improvements in the overall impact on UA score for 70 mg (LSM [95% CI]: -4.3 [-7.0 to -1.7]; p = 0.001) and 140 mg (-5.3 [-8.5 to -3.2]; p < 0.001) versus placebo. CONCLUSIONS: The MFIQ measures the frequency of impacts and level of difficulty on multiple functional domains that provide a more complete picture of the effects of migraine. MFIQ scores showed that in comparison with placebo, patients treated with erenumab had greater reductions in the functional impact of migraine, providing insight into treatment benefits that extend beyond improvements in clinical status and health-related quality of life previously reported based on clinical end points and other PROs.

Patient Perspectives and Experiences of Preventive Treatments and Self-Injectable Devices for Migraine: A Focus Group Study.

BACKGROUND: Although several self-injectable preventive treatments for migraine have become available, they are not yet widely used. Thus, understanding patients' perceptions towards them is limited. OBJECTIVE: This study aimed to inform the design of a preference-elicitation instrument, which is being developed to quantify preventive treatment preferences of people with migraine. METHODS: We conducted a qualitative study involving nine in-person focus groups (three per country) in the United States, the United Kingdom, and Germany. Participants were adults (n = 47) with episodic or chronic migraine who were currently using or had used a prescription preventive treatment for migraine within the previous 5 years. During the focus groups, participants described their experiences of migraine and preventive treatments; handled and simulated self-injection using five different unbranded, fired demonstration auto-injectors and prefilled syringes; and ranked different aspects of preventive treatments by importance. Focus groups were analyzed with a focus on themes that would be feasible or meaningful to include in a subsequent preference-elicitation instrument. RESULTS: Reducing the frequency and severity of migraine attacks was consistently ranked as the most important aspect of preventive treatment. Participants expressed dissatisfaction with available daily oral preventive treatments for migraine they had previously used because they were ineffective or caused intolerable adverse events. Many participants were willing to self-inject a treatment that was effective and tolerable. When presented with devices for self-injecting a preventive treatment for migraine, participants generally preferred autoinjectors over prefilled syringes. Participants especially valued safety features such as the unlocking step and automated needle insertion, and audible and visual dose confirmation increased confidence in autoinjector use. Autoinjector needle protection mechanisms were also appreciated, especially by participants averse to needles, as the needles are not visible. CONCLUSIONS: This study highlights the fact that many people with migraine still lack access to a preventive treatment that is effective and tolerable. In addition to efficacy and safety considerations, treatment decisions may be guided by the mode of administration. In the case of self-injectable preventive treatments, key device characteristics affecting these decisions may be ease of use, comfort, and confidence in self-injection. Insights gained from this study were used to help develop a preliminary set of attributes and levels for a preference-elicitation instrument.

Development of the SMA independence scale-upper limb module (SMAIS-ULM): A novel scale for individuals with Type 2 and non-ambulant Type 3 SMA.

BACKGROUND: The amount of assistance required to perform daily activities for individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA) is often cited as meaningful for quality of life, and important to routinely assess. METHODS: The SMA Independence Scale (SMAIS), a patient-reported outcome measure for individuals with SMA aged ≥12 years, and an observer-reported outcome measure for caregivers of individuals aged ≥2 years, was developed and evaluated in two phases. In Phase 1, 30 draft items were developed following review of the literature. Semi-structured interviews were then conducted with individuals with SMA and caregivers to establish content validity, resulting in a 29-item measure. In Phase 2, classical test theory and Rasch measurement theory methods were used to examine the cross-sectional and longitudinal measurement performance of the SMAIS in two independent datasets. RESULTS: Phase 1 qualitative findings supported the relevance, acceptability, and comprehensibility of 29 items. In Phase 2, psychometric analyses indicated that the five response options were poorly discriminated and were thus collapsed to three options for subsequent analyses. Items showed statistical misfit, implying that the SMAIS was not assessing a single underlying construct. Based on conceptual evaluation of the items, and assessment of item performance, a more targeted 22-item upper limb score was derived. Reliability and validity analyses confirmed acceptable measurement properties of this score. CONCLUSIONS: Qualitative and quantitative analyses support the use of the 22-item SMAIS-Upper Limb Module in individuals with Type 2 and non-ambulant Type 3 SMA, aged ≥2 years.

Impact and burden of acid sphingomyelinase deficiency from a patient and caregiver perspective.

Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease (NPD) types A, A/B, and B, is a rare, progressive, potentially fatal lysosomal storage disease with a spectrum of phenotypes. Little is known about how ASMD symptoms affect the lives of patients and their caregivers. In a cross-sectional qualitative study conducted in the US and UK, and in collaboration with the National Niemann-Pick Disease Foundation (US) and Niemann-Pick UK, we investigated the symptom experience of patients with ASMD types B and A/B and explored how the disease impacts their and their caregivers' lives. The study included 17 adult patients (mean age 38.7 years, 12 female), three caregivers of adults with ASMD, 12 pediatric/adolescent patients with ASMD (mean age 10.5 years, six female), and 12 caregivers of pediatric/adolescent patients with ASMD. The most commonly reported disease manifestations were respiratory (n = 26, 89.7%), abdominal (n = 25, 86.2%), and musculoskeletal symptoms (n = 23, 79.3%); excessive bleeding or bruising (n = 20, 69%); fatigue (n = 20, 69%); gastrointestinal symptoms (n = 18, 62.1%); and headache (n = 15, 51.7%). ASMD was reported to negatively impact patients' physical function (n = 23, 79.3%), self-esteem (n = 18, 62.1%), emotions (n = 16, 55.2%), social function and relationships (n = 16, 55.2%), and personal care (n = 9, 31%). Providing care for individuals with ASMD negatively affected caregivers' emotional well-being (n = 12, 80%), social function (n = 4, 26.7%), relationships (n = 6, 40%), and financial security (n = 7, 46.7%). The physical toll of providing care, the need for lifestyle changes, and the responsibility for making medical decisions added to the burden for caregivers. Alternatively, some caregivers noted that caring for a loved one enhanced their spirituality, providing them with a different outlook on life and a deeper personal resolve. This study showed that ASMD is a substantial burden for patients and caregivers, with long-term physical, emotional, social, and financial impacts. The study confirmed commonly known manifestations of ASMD, especially respiratory problems, but also identified less recognized ones, such as dermatological complications. The data collected and insight gained from this study should enhance clinical care, help evaluate new treatments, and inform health care decision making for patients with ASMD.

Evaluating functional disability in clinical trials of lisdexamfetamine dimesylate in binge eating disorder using the Sheehan Disability Scale.

OBJECTIVES: This study examined Sheehan Disability Scale (SDS) performance in binge eating disorder (BED) and explored relationships between SDS and BED outcomes using data from three placebo-controlled lisdexamfetamine (LDX) studies (two short-term, dose-optimized studies and one double-blind, randomized-withdrawal study) in adults with Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR)-defined BED. METHODS: Analyses evaluated the psychometric properties of the SDS. RESULTS: Confirmatory factor analysis supported a unidimensional total score in the short-term studies, with internal consistency (Cronbach's α) being 0.878. Total score exhibited good construct validity, with moderate and statistically significant correlations observed with Yale-Brown Obsessive Compulsive Scale modified for binge eating, Binge Eating Scale (BES), and EuroQol Group 5-Dimension 5-Level health status index scores. Known-groups validity analysis for the short-term studies demonstrated a significantly lower total score at end of study in participants considered "not ill" versus "ill" based on Clinical Global Impressions-Severity scores. SDS total score changes in the short-term studies were greater in responders than nonresponders based on binge eating abstinence or BES score. In the randomized-withdrawal study, SDS scores increased relative to baseline to a greater extent in participants randomized to placebo than LDX. CONCLUSIONS: These analyses support the reliability, validity, and responsiveness to change of the SDS in individuals with BED.

Defining Patient Engagement in Research: Results of a Systematic Review and Analysis: Report of the ISPOR Patient-Centered Special Interest Group.

OBJECTIVES: Lack of clarity on the definition of "patient engagement" has been highlighted as a barrier to fully implementing patient engagement in research. This study identified themes within existing definitions related to patient engagement and proposes a consensus definition of "patient engagement in research." METHODS: A systematic review was conducted to identify definitions of patient engagement and related terms in published literature (2006-2018). Definitions were extracted and qualitatively analyzed to identify themes and characteristics. A multistakeholder approach, including academia, industry, and patient representation, was taken at all stages. A proposed definition is offered based on a synthesis of the findings. RESULTS: Of 1821 abstracts identified and screened for eligibility, 317 were selected for full-text review. Of these, 169 articles met inclusion criteria, from which 244 distinct definitions were extracted for analysis. The most frequently defined terms were: "patient-centered" (30.5%), "patient engagement" (15.5%), and "patient participation" (13.4%). The majority of definitions were specific to the healthcare delivery setting (70.5%); 11.9% were specific to research. Among the definitions of "patient engagement," the most common themes were "active process," "patient involvement," and "patient as participant." In the research setting, the top themes were "patient as partner," "patient involvement," and "active process"; these did not appear in the top 3 themes of nonresearch definitions. CONCLUSION: Distinct themes are associated with the term "patient engagement" and with engagement in the "research" setting. Based on an analysis of existing literature and review by patient, industry, and academic stakeholders, we propose a scalable consensus definition of "patient engagement in research."

Assessing the impact on caregivers caring for patients with rare pediatric lysosomal storage diseases: development of the Caregiver Impact Questionnaire.

BACKGROUND: Capturing the impact of caring for patients with debilitating rare disease is important for understanding disease burden. We aimed to develop and validate an instrument to measure the impact on caregivers of caring for children with three lysosomal storage diseases (LSDs): metachromatic leukodystrophy (MLD), neuronopathic mucopolysaccharidosis type II (MPS II) and mucopolysaccharidosis type IIIA (MPS IIIA). METHODS: A draft instrument was developed based on targeted literature searches and revised through sequential qualitative interviews with caregivers of patients first with MLD (n = 16), then with MPS II (n = 22), and finally with MPS IIIA (n = 8). The instrument, which covered domains of physical, emotional, social and economic burden, was refined at each stage of development based on caregiver feedback. Saturation of major concepts was reached during concept elicitation (MLD and MPS II). RESULTS: It was confirmed that caring for a patient with an LSD impacts social functioning, emotional/psychological functioning, physical functioning, daily activities, and finances/work productivity. Results from cognitive debriefing of the draft questionnaires were considered during each round of interviews, resulting in a final set of items that caregivers found clear and easy to understand. The Caregiver Impact Questionnaire (CIQ) has 30 items in five domains: (1) social functioning (7 items); (2) impact on daily activities (5 items); (3) emotional/psychological functioning (10 items); (4) physical functioning (6 items); and (5) financial impact (2 items). CONCLUSIONS: These findings demonstrate that the content of the CIQ is relevant for determining the impact of caring on caregivers of patients with MLD, MPS II and MPS IIIA.

Evaluating the Psychometric Properties of the Migraine Functional Impact Questionnaire (MFIQ).

BACKGROUND: Migraine is a chronic neurologic disease that can be associated with significant migraine-related impact, disability, and burden. Patient-reported outcome measures (PRO) are included in clinical trials of migraine interventions to capture treatment effects from a patient perspective. Clinical and regulatory guidelines also encourage use of PROs in trials. The Migraine Functional Impact Questionnaire (MFIQ) is a novel PRO measure, assessing the impact of migraine on Physical Function (PF), Usual Activities (UA), Social Function (SF), and Emotional Function (EF), in the past 7 days. Scientific methods recommended to meet the requirements of the U.S. Food and Drug Administration were followed, to ensure that the MFIQ content included outcomes that were relevant to adults with migraine and were clinically relevant, specifically to evaluate preventive treatments for migraine. OBJECTIVE: The objective of this study was to conduct item analyses informing item reduction and scoring, and to evaluate the psychometric properties of the MFIQ. METHODS: In a prospective, observational study, adults with migraine completed the MFIQ as well as additional clinical and PRO instruments, including the Headache Impact Test (HIT-6TM ), Patient-Reported Outcomes Measurement Information System Physical Function Short Form 10a (PROMIS-PF), Migraine-Specific Quality-of-Life Questionnaire (MSQ), and Patient Global Rating of Change (PGIC). Item-level evaluation, item response theory (IRT), and factor analysis were used to select final MFIQ items, identify domains, and inform scoring. Psychometric properties of the MFIQ were evaluated to assess reliability (internal consistency and test-retest), validity (construct and known-groups), and responsiveness. RESULTS: The study enrolled 569 adults with migraine. Subjects had an average age of 39.9 years (SD 12.0), 87.2% were female, and 80.8% were white. Five items were dropped from the draft version based on results of item-level analyses reviewed in the context of previous qualitative research to produce the final 26-item MFIQ (v.2). Four domain scores (PF, UA, SF, and EF) and a global item score for impact on UA were identified. Higher scores on a 0-100 scale represent greater impact. All scores exhibited high internal consistency (α ≥ 0.89) and moderate test-retest reliability among stable subjects (ICCs ≥ 0.47). Construct validity was demonstrated by significant correlations (all P < .0001) between MFIQ domain scores, related PRO scores, and the frequency of migraine days and headache days. All domain scores differentiated between subgroups ("known groups") defined based on established levels of clinical severity: number of monthly migraine and headache days, migraine interference levels and scores on other PRO instruments (P < .05). Improvements in MFIQ scores corresponded with clinical improvement (percent reduction in monthly migraine days), improvement in migraine interference with daily activities, and related improvements in PRO scores (P < .05), demonstrating that the MFIQ was responsive to changes in migraine impact. CONCLUSIONS: The MFIQ is a reliable and valid measure that can be used to collect data about migraine impact. The MFIQ is being used to evaluate outcomes of migraine interventions in clinical trials and observational studies. It could potentially also be used in clinical practice both for initial and ongoing assessments for monitoring outcomes and to enhance communication between patients and healthcare professionals for the management of migraine.

Development of a New Tool for Evaluating the Benefit of Preventive Treatments for Migraine on Functional Outcomes - The Migraine Functional Impact Questionnaire (MFIQ).

OBJECTIVE: The objective of this study was to develop a method for evaluating patient-relevant outcomes of interventions for preventing migraine attacks, followed by an assessment of the content validity of a new patient-reported outcome (PRO) instrument: the Migraine Functional Impact Questionnaire (MFIQ). BACKGROUND: The aim of preventive treatments for migraine is not only to reduce migraine frequency, but also to restore patients' ability to function and improve quality of life. METHODS: A multi-stage process based on best practice methods and regulatory guidelines for ensuring content validity of PRO instruments for evaluating treatment benefit was followed. Qualitative concept elicitation interviews conducted to understand the experiences of adults with migraine underpinned the development of the instrument. The initial stage included the development of a conceptual disease model (CDM) based on information from these interviews. This CDM was used to identify the concepts of interests (COI) to evaluate outcomes of preventive treatments. The results of the interviews were also used in stage 2, to develop a measurement framework for collecting data about these COI. In the third stage, existing instruments were reviewed for coverage of the concepts in the framework and evidence of concept elicitation to the point of saturation, to support content validity. In the fourth stage, an instrument was drafted to evaluate concepts in the framework, based on the qualitative data collected from the interviews. Following a review by clinical and translation experts, the new instrument was tested in adults with migraine in the fifth stage using 2 rounds of cognitive interviews, and was modified based on interview feedback. In the last stage, the instrument was linguistically adapted, using methods recommended for PRO instruments, to ensure conceptual equivalence of language versions for use in international studies. Each language version was tested in at least 5 native speakers using cognitive interviews. RESULTS: Results from the concept elicitation interviews suggested that migraine had an impact on various aspects of functioning. A conceptual framework for evaluating functional outcomes was developed for the concept selected based on a review of the CDM - physical and emotional functioning, every day activities, and social/leisure activities. Existing PROs lacked coverage of some concepts in the conceptual framework, had recall periods that were inappropriate for capturing the experience of COI or did not have evidence of content validity. A novel PRO instrument, the MFIQ, was developed to address these gaps. Cognitive interviews with 9 adults with migraine resulted in minor changes to the items of the MFIQ, and a final round of 8 interviews confirmed the changes were acceptable and supported its validity. The interviews conducted to test linguistic adaptations confirmed conceptual equivalence in the 25 countries evaluated. CONCLUSIONS: Development of the MFIQ followed best measurement practices to ensure content validity and followed regulatory guidelines for PRO instruments to evaluate benefits of treatments. The MFIQ was developed for use in clinical trials or clinical practice settings to track outcomes of preventive treatments that are most relevant to adults with migraine.

Evaluation of the psychometric properties of the Early Morning Symptoms of COPD Instrument (EMSCI).

Background: Early morning respiratory symptoms impact quality of life and are often the most troublesome for patients with COPD. Reduction in symptoms and their impact are important treatment outcomes for COPD. The Early Morning Symptoms of COPD Instrument (EMSCI) is a daily diary designed to collect patients' report of the occurrence, severity, and impact of morning COPD symptoms. Methods: To assess the psychometric properties of the EMSCI, a split-half sample of data from a COPD clinical trial where participants completed the EMSCI daily was used for conducting descriptive statistics, factor analyses, and Rasch model analyses to examine item performance and inform scoring. Once the final scoring algorithm was determined, data from the second split-half sample were used to examine the properties of the EMSCI. Test-retest reliability was assessed using intraclass correlation coefficient (ICC). Correlations with other study assessments were used to evaluate convergent and known-groups validity. Results: Data from 1,663 patients with COPD aged 40-93 years were analyzed. Factor analysis and Rasch analysis confirmed a one-factor structure for the 6 individual symptom items. Item analyses supported the generation of 4 scores. All scores demonstrated good test-retest reliability: 6-item symptom severity (ICC, 0.84); overall morning symptom severity (ICC, 0.84); activity limitation (ICC, 0.85); and rescue medication (ICC, 0.62). Significant correlations between EMSCI scores, St George's Respiratory Questionnaire scores, and EXAcerbations of Chronic pulmonary disease Tool (EXACT)-Respiratory Symptoms scores supported the tool's convergent validity. Significant differences (p<0.0001) in all EMSCI domain scores were found between known-groups based on median split St George's Respiratory Questionnaire and EXACT-Respiratory Symptoms scores. Conclusion: The EMSCI consists of 4 scores: 6-item symptom severity, overall symptom severity, activity limitation, and rescue medication. The EMSCI is a reliable and valid instrument for evaluating patients' experience of early morning COPD symptoms.

Beyond study participants: a framework for engaging patients in the selection or development of clinical outcome assessments for evaluating the benefits of treatment in medical product development.

BACKGROUND: Patients are participating more actively in health care decision-making with regard to their health, as well as in the broader realm of assessing the value of medical products and influencing decisions about their registration and reimbursement. There is an increasing trend to include patients' perspectives throughout the stages of medical product development by broadening the traditional study-participant role to that of an active partner throughout the process. Including patients in the selection and development of clinical outcome assessments (COAs) to evaluate the benefit of treatment is particularly important. Still, despite widespread enthusiasm, there is substantial uncertainty regarding how and when to engage patients in this process. PURPOSE: This manuscript proposes a methodological framework for engaging patients at varying levels in the selection and development of COAs for medical product development. FRAMEWORK: The framework builds on the Food and Drug Administration's roadmap for patient-focused COA. Methods for engaging patients across each stage in this roadmap are summarized by levels of engagement. Opportunities and examples of patient engagement (PE) in the selection and/or development of COAs are summarized, together with best practices and practical considerations. CONCLUSION: This paper offers a framework for understanding, planning, and implementing methods to advance PE in the selection and/or development of COAs for evaluating the benefit of medical products. The intent is to further this important discussion and enhance the process and outcome of PE in this context.

Development and exploration of the content validity of a patient-reported outcome measure to evaluate the impact of migraine- the migraine physical function impact diary (MPFID).

BACKGROUND: Adults with migraine experience substantial reductions in quality of life during and in-between migraine attacks. Clinical and regulatory guidelines encourage the inclusion of patient reported outcomes for the evaluation of benefits of interventions for migraine. METHODS: The conceptual framework and items for a new patient-reported outcome (PRO) instrument, the Migraine Physical Function Impact Diary (MPFID), were developed using scientific methods recommended to ensure content validity of PRO instruments. The MPFID was developed to measure the impact of migraine on physical functioning based on themes raised in concept elicitation (CE) interviews (conducted previously) with adults with migraine. Cognitive interviews were conducted with adults with migraine to further explore content validity. The instrument was modified following an interim analysis of a first round of cognitive interviews, to assess comprehensiveness and clarity of items, instructions, and response options. Refinements were subsequently tested in additional cognitive interviews. RESULTS: The conceptual framework included impacts on physical functioning experienced by most adults with migraine and deemed clinically relevant for measuring the outcome of an intervention for migraine. Concepts in the framework included the impact of migraine on physical impairments (acts) and ability to complete day-to-day activities and perform everyday activities (tasks). MPFID items were generated to evaluate functioning over the past 24 h and to collect data daily, to capture experiences on days with migraine as well as the days in-between migraines. Items asked about needing to rest or lie down; ability to get out of bed, stand up, bend over, walk, perform household chores, do tasks outside the home, keep routines or schedules, get ready for the day, do activities that require concentration or clear thinking; difficulty moving head and body, doing activities requiring physical effort; avoiding interacting with others. Initial modifications based on the first round of cognitive interviews (n = 8) included clarifying instructions, updating three items to enhance specificity and clarity, and revising one item to include gender-neutral language. The second round of interviews (n = 9) confirmed acceptability of revisions and supported content validity. CONCLUSIONS: The results provide qualitative evidence supporting the content validity of the MPFID for evaluating outcomes of interventions for migraine.

Psychometric Evaluation of a Novel Instrument Assessing the Impact of Migraine on Physical Functioning: The Migraine Physical Function Impact Diary.

OBJECTIVE: The objective of this study was to evaluate the measurement properties of the Migraine Physical Function Impact Diary (MPFID), a novel patient-reported outcome (PRO) measure for assessing the impact of migraine on physical functioning. METHODS: In a prospective, observational study, adults with episodic migraine (EM) or chronic migraine (CM) used an eDiary to complete the MPFID (assessing daily impacts of migraine on physical function) and a headache diary (capturing migraine days, migraine pain intensity, and migraine interference) each day, and other PRO instruments related to migraine. Item-level evaluation, item response theory (IRT), and exploratory factor analysis (EFA) methods were applied to identify domains, select final MPFID items, and develop scoring procedures. Psychometric properties of the final 13-item MPFID were evaluated using confirmatory factor analysis and tests of reliability (Cronbach's α for internal consistency and intra-class correlation [ICC] for test-retest) and validity (convergent and known-groups). RESULTS: The study enrolled 569 adults with chronic or episodic migraine, mean (SD) age 39.9 (12.0) years and 87.2% female. Item-level analyses based on interim data informed selection of a set of 13 items for the MPFID, through evaluation of floor/ceiling effects, item-to-item correlations, factor loadings, and IRT-based fit/misfit statistics. Two domain scores (EA: Impact on Everyday Activities; PI: Physical Impairment) and a global item score for impact on everyday activities were identified. EA and PI domains exhibited high internal consistency (α = 0.97; α = 0.93) and good test-retest reliability among stable subjects (ICCs = 0.74 and 0.77). Convergent validity was demonstrated by moderate correlations (r = ±0.50-0.68; P < .0001) between MPFID domain scores and number of migraine days, headache days, bed days, and other migraine-related PRO instruments. EA and PI scores differentiated between groups who varied by number of migraine days, migraine interference levels, migraine pain intensity, and median split groups of scores based on other PROs instruments (P < .05). CONCLUSIONS: The MPFID has robust psychometric properties (ie, reliability and validity). Findings supported two distinct domains about the impact of migraine on physical functioning: Impact on Everyday Activities and Physical Impairment. Both domain scores showed evidence of excellent reliability and construct validity in assessing the impacts of migraine on physical functioning.

Measuring the impact of migraine for evaluating outcomes of preventive treatments for migraine headaches.

BACKGROUND: Migraine is characterized by headache with symptoms such as intense pain, nausea, vomiting, photophobia, and phonophobia that significantly impact individuals' lives. The objective of this study was to develop a strategy to measure outcomes from the patients' perspectives for use in evaluating preventive treatments for migraine. METHODS: This study used a multi-stage process. The first stage included concept identification research through literature review, patient-reported outcome (PRO) instrument content review, and clinician interviews, and resulted in a list of concepts relevant to understand the migraine experience. These results informed the design of the subsequent concept elicitation stage that involved qualitative interviews of adults with migraine to understand their experiences. Information from these two stages was used to develop a conceptual disease model (CDM) of the migraine experience. This CDM was used to identify concepts of interest (COI) to evaluate patient-relevant outcomes for assessing treatment benefit of migraine prophylactics. In the final stage, existing PRO instruments were reviewed to assess coverage of concepts related to the selected COI. RESULTS: Nine articles from 563 screened abstracts underwent full review to identify migraine-relevant concepts. This concept identification and subsequent concept elicitation interviews (N = 32; 21 episodic migraine; 11 chronic migraine) indicated that people with migraine experience difficulties during and between migraine attacks with considerable day-to-day variability in the impact on movement, ability to perform every day and social activities, and emotion. The CDM organized concepts as proximal to and more distal from disease-defining migraine symptoms, and was used to identify impact on physical function as the key COI. The item level review of PRO instruments revealed that none of the existing PRO instruments were suitable to collect data on impact of migraine on physical functioning, to evaluate treatment benefit. CONCLUSIONS: The impact of migraine includes impairments in functioning during and between migraine attacks that vary considerably on a daily basis. There is a need for novel PRO instruments that reflect patients' migraine experience to assess treatment benefit of migraine prophylactics. These instruments must evaluate the concepts identified and be able to capture the variability of patients' experience.

The effect of aclidinium bromide on daily respiratory symptoms of COPD, measured using the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) diary: pooled analysis of two 6-month Phase III studies.

BACKGROUND: Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD). We evaluated the effect of aclidinium bromide 400 µg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS(™): COPD) scale (formerly EXACT-RS). METHODS: Data were pooled from the aclidinium 400 µg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction. Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D. Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed. RESULTS: Of 1210 patients, 1167 had data available for GOLD classification. Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted. Compared with placebo, aclidinium 400 µg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group. The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 µg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D. CONCLUSIONS: Aclidinium 400 µg BID significantly improved respiratory symptoms regardless of the patients' level of symptoms at baseline. Net treatment benefit was similar in patients with low or high levels of symptoms. TRIAL REGISTRATION: ATTAIN (ClinicalTrials.gov identifier: NCT01001494 ) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397 ).

Evaluating functional outcomes in adolescents with attention-deficit/hyperactivity disorder: development and initial testing of a self-report instrument.

BACKGROUND: Engaging adolescents in decisions about their health may enhance their compliance with treatment and result in better health outcomes. Treatment outcomes in attention-deficit/hyperactivity disorder (ADHD) are rarely evaluated from the adolescents' point of view. There is also concern that adolescents with ADHD may not have insight about the impacts of their disease. This article describes research conducted to understand the experiences of adolescents with ADHD and how the research was used to develop an adolescent self-report instrument. METHODS: This research involved an iterative process to ensure content validity and was conducted in the following stages: concept identification from literature reviews and interviews with teachers and clinicians; concept elicitation interviews with adolescents with ADHD and their caregivers, review of existing instruments; development of a new instrument and cognitive interviews. Experts in instrument development and translation and clinical practitioners in ADHD also participated. RESULTS: A conceptual framework to measure the impact of ADHD on adolescent functioning identified from concept identification research informed concept elicitation interviews with 60 adolescents with ADHD and their primary caregivers. In the interviews, adolescents discussed difficulties with performing activities in various contexts: school, home, leisure activities and social interactions. Caregivers provided additional insights. The instrument review revealed that none of the existing instruments were suitable to collect data on the elicited concepts; therefore, a new instrument was developed. Revisions were made to the format and content of the instrument (a daily diary) based on feedback received from cognitive testing with 15 adolescents. CONCLUSIONS: Our research helped to obtain a comprehensive understanding of the impacts of ADHD on adolescent functioning, to inform the development of a new instrument for measuring outcomes. Adolescents were able to discuss the impact of ADHD on their lives in concept elicitation interviews and report the impacts of ADHD on a self-report instrument. The new instrument developed to reflect the perspective of adolescents with ADHD can be used to supplement outcome assessments in clinic and research settings. Scientific advocacy for the use of such measures can be valuable to measure outcomes meaningful to adolescents with ADHD and the clinical community.