Psychometric Evaluation of the Diary for Irritable Bowel Syndrome Symptoms-Constipation in a Prospective Observational Study.

OBJECTIVES: To evaluate the psychometric properties of the Diary for Irritable Bowel Syndrome Symptoms-Constipation (DIBSS-C), which was developed to support primary and secondary endpoints in irritable bowel syndrome (IBS) with predominant constipation (IBS-C) clinical trials. METHODS: Observational data were collected from 108 adults with IBS-C using a smartphone-type device for 17 days. DIBSS-C data regarding bowel movements (BMs) were collected for each event (along with the Bristol Stool Form Scale); abdominal symptoms were rated each evening. Global status items and the Gastrointestinal Symptom Rating Scale-IBS were completed on day 10 and day 17 and the IBS-Symptom Severity Scale on day 17. Item-level performance, internal consistency reliability, test-retest reliability, and construct validity were evaluated. RESULTS: The Abdominal Symptoms Domain score demonstrated high internal consistency reliability (Cronbach's alpha week 1 = 0.98; week 2 = 0.96) and test-retest reliability (intraclass correlation coefficient [ICC] = 0.93). Test-retest reliability was stronger for abdominal symptoms (ICC = 0.91-0.94) than for the frequency-based BM-related outcomes (ICC = 0.54-0.66). Key construct validity hypotheses were supported by moderate to strong correlations with the corresponding Gastrointestinal Symptom Rating Scale-IBS, IBS-Symptom Severity Scale, and Bristol Stool Form Scale items. All known-groups comparisons were statistically significant for the abdominal symptom items and domain score; evidence for known-groups validity of BM-related outcomes was supportive when based on constipation severity. CONCLUSIONS: The results of this study provided key psychometric evidence for the DIBSS-C, ultimately contributing to its qualification by the US Food and Drug Administration for use in IBS-C clinical trials.

Assessing asthma symptoms in children: qualitative research supporting the development of the Pediatric Asthma Diary-Child (PAD-C) and Pediatric Asthma Diary-Observer (PAD-O).

BACKGROUND: Pediatric asthma has been identified by regulators, clinicians, clinical trial sponsors, and caregivers as an area in need of novel fit-for-purpose clinical outcome assessments (COAs) developed in accordance with the U.S. Food and Drug Administration's (FDA's) regulatory guidance for evaluating clinical benefit in treatment trials. To address this gap, the Patient-Reported Outcome (PRO) Consortium's Pediatric Asthma Working Group has continued development of 2 COAs to assess asthma signs and symptoms in pediatric asthma clinical trials to support efficacy endpoints: a PRO measure, the Pediatric Asthma Diary-Child (PAD-C) for children 8-11 years old (y.o.) and an observer-reported outcome measure, the Pediatric Asthma Diary-Observer (PAD-O) for caregivers of children 4-11 y.o. This qualitative research aimed to generate evidence regarding the content validity of the PAD-C and PAD-O. METHODS: Semi-structured combined concept elicitation and cognitive interviews were conducted with a diverse sample of U.S. participants (15 children 8-11 y.o. and 30 caregivers of children 4-11 y.o.). All children had clinician-diagnosed mild to severe asthma. Interviews explored the experience of pediatric asthma and assessed the understanding and relevance of both measures. Interviews were conducted across 3 iterative rounds to allow for modifications. RESULTS: Concept elicitation findings demonstrated that the core sign/symptom and impact concepts assessed in the PAD-C (cough, hard to breathe, out of breath, wheezing, chest tightness, and nighttime awakenings/symptoms) and PAD-O (cough, difficulty breathing, short of breath, wheezing, and nighttime awakenings/signs) correspond to those most frequently reported by participants; concept saturation was achieved. All PAD-C and PAD-O instructions and core items were well understood and considered relevant by most participants. Feedback from participants, the Pediatric Asthma Working Group, advisory panel, and FDA supported modifications to the measures, including addition of 1 new item to both measures and removal of 1 caregiver item. CONCLUSIONS: Findings provide strong support for the content validity of both measures. The cross-sectional measurement properties of both measures and their user experience and feasibility in electronic format will be assessed in a future quantitative pilot study with qualitative exit interviews, intended to support the reliability, construct validity, final content, and, ultimately, FDA qualification of the measures.

Pediatric asthma is one of the most common chronic diseases in children. However, there are problems of underdiagnosis, poor disease management, and undertreatment for many pediatric asthma patients, pressuring healthcare systems worldwide. Evaluating asthma symptoms is an important part of the development of treatments for pediatric asthma. However, there are few clinical outcome assessments (COAs) developed in line with regulatory guidance to directly assess symptom severity and evaluate the benefit of new treatments in children with asthma. In this study, we continued the development of the Pediatric Asthma Diary­Child (PAD-C) and the Pediatric Asthma Diary­Observer (PAD-O), according to regulatory guidance, to assess asthma signs and symptoms in children 4 through 11 years old and address this unmet need. The study aimed to explore the experience of pediatric asthma and assess how well-understood and relevant the measures are. Three rounds of qualitative interviews were conducted with 15 children 8 through 11 years old and 30 caregivers of children 4 through 11 years old with asthma. Results show that both measures are well-understood and assess the relevant and important aspects of pediatric asthma reported by children and caregivers. Findings provide evidence supporting the PAD-C and PAD-O as measures of symptom severity and their future use in pediatric asthma treatment trials. Further research is underway to evaluate their measurement properties and assess the user experience and feasibility of electronic completion, to ultimately support the PAD-C and PAD-O in an ongoing COA qualification process by the United States Food and Drug Administration.

Recommendations on the Selection, Development, and Modification of Performance Outcome Assessments: A Good Practices Report of an ISPOR Task Force.

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.

Updated Recommendations on Evidence Needed to Support Measurement Comparability Among Modes of Data Collection for Patient-Reported Outcome Measures: A Good Practices Report of an ISPOR Task Force.

The ISPOR Task Force on measurement comparability between modes of data collection for patient-reported outcome measures (PROMs) has updated the good practice recommendations from the 2009 ISPOR electronic patient-reported outcome and 2014 patient-reported outcome mixed modes Good Research Practices Task Force reports in light of accumulated evidence of measurement comparability among different modes of PROM data collection. Furthermore, with the increasing use of electronic formats of clinical outcome assessments in clinical trials and the US Food and Drug Administration's encouragement of electronic data collection, this new task force report provides stakeholders with best practice recommendations reflecting the current body of evidence and enables them to respond to future developments in research and technology. This task force recommends an evidence-based approach to determine whether new research is needed to evaluate measurement comparability for a given questionnaire or technology. The suitability of existing evidence depends upon whether it satisfactorily demonstrates that the change in data collection mode has not affected the PROM's measurement properties. In cases where sufficient evidence of measurement comparability exists and best practices for faithful migration are followed, this task force concludes that further testing of measurement comparability among the data collection modes is unnecessary, including cases of "mixing modes" within clinical trials such as bring your own device designs.

Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease.

OBJECTIVES: Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)-approved labeling claims that used these approaches. METHODS: A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. RESULTS: A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. CONCLUSIONS: Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.

Comparing patient global impression of severity and patient global impression of change to evaluate test-retest reliability of depression, non-small cell lung cancer, and asthma measures.

PURPOSE: Score reproducibility is an important measurement property of fit-for-purpose patient-reported outcome (PRO) measures. It is commonly assessed via test-retest reliability, and best evaluated with a stable participant sample, which can be challenging to identify in diseases with highly variable symptoms. To provide empirical evidence comparing the retrospective (patient global impression of change [PGIC]) and current state (patient global impression of severity [PGIS]) approaches to identifying a stable subgroup for test-retest analyses, 3 PRO Consortium working groups collected data using both items as anchor measures. METHODS: The PGIS was completed on Day 1 and Day 8 + 3 for the depression and non-small cell lung cancer (NSCLC) studies, and daily for the asthma study and compared between Day 3 and 10. The PGIC was completed on the final day in each study. Scores were compared using an intraclass correlation coefficient (ICC) for participants who reported "no change" between timepoints for each anchor. RESULTS: ICCs using the PGIS "no change" group were higher for depression (0.84 vs. 0.74), nighttime asthma (0.95 vs. 0.53) and daytime asthma (0.86 vs. 0.68) compared to the PGIC "no change" group. ICCs were similar for NSCLC (PGIS: 0.87; PGIC: 0.85). CONCLUSION: When considering anchor measures to identify a stable subgroup for test-retest reliability analyses, current state anchors perform better than retrospective anchors. Researchers should carefully consider the type of anchor selected, the time period covered, and should ensure anchor content is consistent with the target measure concept, as well as inclusion of both current and retrospective anchor measures.

Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ): Measurement Properties and Estimated Clinically Meaningful Thresholds From a Phase 3 Study.

Introduction: The NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ) was developed to assess NSCLC symptom severity in accordance with Food and Drug Administration evidentiary expectations leading to Food and Drug Administration qualification in 2018. This study evaluated the NSCLC-SAQ's measurement properties within a clinical trial. Methods: The KEYNOTE-598 phase 3 study of participants with stage IV metastatic NSCLC with programmed death-ligand 1 tumor proportion score greater than or equal to 50% was used to assess the NSCLC-SAQ's reliability, construct validity, responsiveness, and estimate clinically meaningful within-person change. Other patient-reported outcome measures included patient global impression items of severity and change in lung cancer symptoms, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and lung cancer module, LC13. Results: Participants (N = 560) were mostly men (70%), had a mean age of 64 years, and had Eastern Cooperative Oncology Group performance status of 1 (64%) or 0 (36%). Internal consistency at baseline (Cronbach's α = 0.74) and test-retest reliability after 3 weeks (intraclass correlation coefficient = 0.79) were satisfactory. NSCLC-SAQ items, domains, and total score correlated moderately to highly with patient-reported outcome measures capturing similar content, and the total score differentiated among patient global impression of severity groups (p < 0.001). The total score detected improvement over time and the estimated clinically meaningful within-person change threshold for improvement ranged from three to five points on the 0 to 20 scale. Few participants exhibited symptom worsening (n = 38), limiting inferences in this group. Conclusions: The NSCLC-SAQ was found to be reliable, valid, responsive, and interpretable for assessing symptom improvement in NSCLC. Further evaluation is recommended in trial participants whose symptoms worsen over time.

Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD): Measurement Properties of Novel Patient-Reported Symptom Measures.

BACKGROUND: The Asthma Daytime Symptom Diary (ADSD) and the Asthma Nighttime Symptom Diary (ANSD) were developed to meet the need for standardized patient-reported measures of asthma symptoms to assess treatment trial outcomes in adults and adolescents. OBJECTIVE: To determine scoring and evaluate the measurement properties of the ADSD/ANSD. METHODS: Adolescents (12-17 years) and adults (18+ years) with asthma completed draft 8-item electronic versions of the ADSD/ANSD for 10 days alongside the Adult Asthma Symptom Daily Scales (AASDS) and a Patient Global Impression of Severity (PGIS). Using classical and modern psychometric methods, initial analyses evaluated the performance of ADSD/ANSD items to inform scoring. Subsequent analyses evaluated the reliability and validity of ADSD/ANSD scores. RESULTS: A demographically and clinically diverse sample (n = 130 adolescents; n = 89 adults) was recruited. Item performance was generally strong. However, items assessing chest pressure and mucus/phlegm demonstrated redundancy and poorer performance and were removed. Principal-components analysis, confirmatory factor analysis, and item response theory supported combining items to form 6-item total ADSD/ANSD scores. Internal consistency (α = 0.94-0.95) and test-retest reliability (intraclass correlation coefficient = 0.86-0.95) were strong. Strong correlations (r = 0.72-0.80) were observed between ADSD scores and AASDS items assessing asthma symptom frequency, bother, and impact on activities. Significant differences (P < .001) in mean ADSD/ANSD scores were observed between groups categorized by asthma severity (PGIS), asthma control, inhaler use, nebulizer use, activity limitations, and nighttime awakenings. CONCLUSIONS: The ADSD/ANSD items and scores demonstrated strong reliability and validity. Implementation of the measures in interventional studies will enable the evaluation of responsiveness and meaningful within-patient change.

Non-Small Cell Lung Cancer Symptom Assessment Questionnaire: Psychometric Performance and Regulatory Qualification of a Novel Patient-Reported Symptom Measure.

BACKGROUND: The Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) was developed to incorporate the patient's perspective into evaluation of clinical benefit in advanced non-small cell lung cancer trials and meet regulatory expectations for doing so. Qualitative evidence supported 7 items covering 5 symptom concepts. OBJECTIVE: This study evaluated measurement properties of the NSCLC-SAQ's items, overall scale, and total score. METHODS: In this observational cross-sectional study, a purposive sample of patients with clinician-diagnosed advanced non-small cell lung cancer, initiating or undergoing treatment, provided sociodemographic information and completed the NSCLC-SAQ, National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lung Symptom Index (FLSI-17), and a Patient Global Impression of Severity item. Rasch analyses, factor analyses, and assessments of construct validity and reliability were completed. RESULTS: The 152 participants had a mean age of 64 years, 57% were women, and 87% where White. The majority were Stage IV (83%), 51% had an Eastern Cooperative Oncology Group performance status of 1 (32% performance status 0 and 17% performance status 2), and 33% were treatment naïve. Rasch analyses showed ordered thresholds for response options. Factor analyses demonstrated that items could be combined for a total score. Internal consistency (Cronbach  α = 0.78) and test-retest reliability (intraclass correlation coefficient = 0.87) were quite satisfactory. NSCLC-SAQ total score correlation was 0.83 with the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lung Symptom Index-17. The NSCLC-SAQ was able to differentiate between symptom severity levels and performance status (both P values < .001). CONCLUSIONS: The NSCLC-SAQ generated highly reliable scores with substantial evidence of construct validity. The Food and Drug Administration's qualification supports the NSCLC-SAQ as a measure of symptoms in drug development. Further evaluation is needed on its longitudinal measurement properties and interepretation of meaningful within-patient score change. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).

Agreement Among Paper and Electronic Modes of the EQ-5D-5L.

INTRODUCTION: While the EQ-5D-5L has been migrated to several electronic modes, evidence supporting the measurement equivalence of the original paper-based instrument to the electronic modes is limited. OBJECTIVES: This study was designed to comprehensively examine the equivalence of the paper and electronic modes (i.e., handheld, tablet, interactive voice response [IVR], and web). METHODS: As part of the foundational work for this study, the test-retest reliability of the paper-based, UK English format of the EQ-5D-5L was assessed using a single-group, single-visit, two-period, repeated-measures design. To compare paper and electronic modes, three independent samples were recruited into a three-period crossover study. Each participant was assigned to one of six groups to account for order effects. Descriptive statistics, mean differences (i.e., split-plot analysis of variance [ANOVA]), and intraclass correlation coefficients (ICCs) were calculated. RESULTS: The test-retest results showed mean differences near zero and ICC values > 0.90 for both the index and the EQ VAS scores. For the electronic comparisons, mean difference confidence intervals (CIs) for the EQ-5D index scores and EQ VAS scores reflected equivalence of the means across all modes, as the CIs were wholly contained inside the equivalence interval. Further, the ICC 95% lower CIs for the index and EQ VAS scores showed values above the thresholds for denoting equivalence across all comparisons in each sample. No significant mode-by-order interactions were present in any ANOVA model. CONCLUSIONS: Overall, our comparisons of the paper, screen-based, and phone-based formats of the EQ-5D-5L provided substantial evidence to support the measurement equivalence of these modes of data collection.

Why Reinvent the Wheel? Use or Modification of Existing Clinical Outcome Assessment Tools in Medical Product Development.

Assessment of clinical benefit in treatment trials can be made through report by a clinician, a patient, or a nonclinician observer (eg, caregiver) or through a performance-based assessment. The US Food and Drug Administration (FDA) published a final guidance for industry for one type of clinical outcome assessment (COA)-patient-reported outcome (PRO) measures-in 2009 that described how FDA reviews PRO measures for their adequacy to support medical product-labeling claims. Many of the principles described in the PRO Guidance could be applicable to the other types of COAs, including instruments completed by clinicians (ie, clinician-reported outcome assessments) and nonclinician observers (ie, observer-reported outcome assessments). FDA guidance describing the regulatory expectations for all COA types including performance outcome assessments, which are based on the patient's performance of a defined task or activity, is in progress to meet requirements described within the 21st Century Cures Act and PDUFA VI. This communication highlights potential ways in which existing instruments might be modified or used "as is" to conform to good measurement principles. An industry and a regulatory perspective are described.

Symptoms of Major Depressive Disorder Scale: Performance of a Novel Patient-Reported Symptom Measure.

BACKGROUND: The Symptoms of Major Depressive Disorder Scale (SMDDS) was expressly developed on the basis of qualitative data to directly incorporate patients' voices into evaluation of treatment benefit in major depressive disorder (MDD) clinical trials. OBJECTIVES: To collect quantitative data necessary to refine/optimize the SMDDS and document its psychometric properties. METHODS: In this multicenter, observational study, participants with clinically diagnosed MDD completed questionnaires in 2 waves. Wave 1 was designed to refine the SMDDS using Rasch measurement evaluations and item reduction analyses. On a subset of wave 1 subjects, 7 to 12 months later, wave 2 further examined item performance and measurement properties. Exploratory factor analyses and assessments of construct validity and reliability (internal consistency and reproducibility) were completed. RESULTS: Using wave 1 data (N = 315; females = 71%, white = 81%, mean age = 44 years), the SMDDS was revised from 36 to 16 items. The Rasch item threshold map indicated that all but 1 item (suicidal ideation) were appropriately ordered. The 207 wave 2 participants were 74% females, 82% white, with a mean age of 45 years. The exploratory factor analyses resulted in a single component (all standardized factor loadings >0.46). Cronbach α was 0.93 and the 7-day test-retest intraclass correlation coefficient (n = 93) was 0.84 (95% confidence interval 0.77-0.89). SMDDS scores discriminated between MDD severity levels. CONCLUSIONS: The 16-item SMDDS generated highly reliable scores with substantial evidence of construct validity. On the basis of the evidence of appropriate content validity and sound psychometric performance, the Food and Drug Administration qualified the SMDDS as an outcome measure to support exploratory efficacy endpoints in MDD clinical trials.

Developing and Implementing Performance Outcome Assessments: Evidentiary, Methodologic, and Operational Considerations.

The use of performance outcome (PerfO) assessments to measure cognitive or physical function in drug trials presents several challenges for both sponsors and regulators, owing in part to a relative lack of scientific guidance on their development, implementation, and interpretation. In December 2016, the Duke-Margolis Center for Health Policy convened a 2-day workshop to explore the evidentiary, methodologic, and operational challenges associated with PerfO measures, and to identify potential paths to addressing these challenges. This paper presents both a summary of the discussion as well as additional input from a working group of experts from FDA, industry, academia, and public-private consortia. It is intended to advance the discussion around the development and use of PerfO measures to assess patient functioning in clinical trials intended to support registration of new treatments, and to highlight the key gaps in knowledge where additional research, collaboration, and discussion are needed.

Assessing test-retest reliability of patient-reported outcome measures using intraclass correlation coefficients: recommendations for selecting and documenting the analytical formula.

PURPOSE: The US Food and Drug Administration (FDA) 2009 guidance for industry on patient-reported outcome (PRO) measures describes how the Agency evaluates the psychometric properties of measures intended to support medical product labeling claims. An important psychometric property is test-retest reliability. The guidance lists intraclass correlation coefficients (ICCs) and the assessment time period as key considerations for test-retest reliability evaluations. However, the guidance does not provide recommendations regarding ICC computation, nor is there consensus within the measurement literature regarding the most appropriate ICC formula for test-retest reliability assessment. This absence of consensus emerged as an issue within Critical Path Institute's PRO Consortium. The purpose of this project was to generate thoughtful and informed recommendations regarding the most appropriate ICC formula for assessing a PRO measure's test-retest reliability. METHODS: Literature was reviewed and a preferred ICC formula was proposed. Feedback on the chosen formula was solicited from psychometricians, biostatisticians, regulators, and other scientists who have collaborated on PRO Consortium initiatives. RESULTS AND CONCLUSIONS: Feedback was carefully considered and, after further deliberation, the proposed ICC formula was confirmed. In conclusion, to assess test-retest reliability for PRO measures, the two-way mixed-effect analysis of variance model with interaction for the absolute agreement between single scores is recommended.

Selection of and Evidentiary Considerations for Wearable Devices and Their Measurements for Use in Regulatory Decision Making: Recommendations from the ePRO Consortium.

BACKGROUND: Wearable devices offer huge potential to collect rich sources of data to provide insights into the effects of treatment interventions. Despite this, at the time of writing this report, limited regulatory guidance on the use of wearables in clinical trial programs has been published. OBJECTIVES: To present recommendations from the Critical Path Institute's Electronic Patient-Reported Outcome Consortium regarding the selection and evaluation of wearable devices and their measurements for use in regulatory trials and to support labeling claims. METHODS: The evaluation group was composed of Critical Path Institute's clinical outcome assessment (COA) scientists and COA specialists from pharmaceutical trial eCOA solution providers, including COA development and validation specialists. The resulting recommendations were drawn from a broad range of backgrounds, perspectives, and expertise that enriched the development of this report. Recommendations were developed through analysis of existing regulatory guidance relating to COA development and use in clinical trials, medical device certification/clearance regulations, literature-reported best practice, and practical experience of wearable technology application in clinical trials. RESULTS: We identify the essential properties of fit-for-purpose wearables and propose evidence needed to support their use. In addition, we overview the activities required to establish clinical endpoints derived from wearables data. CONCLUSIONS: Using this framework, we believe there is enough current understanding to promote the appropriate use of wearables in study protocols. We hope this will provide a basis for discussion among clinical trial stakeholders and catalyze the development of more robust regulatory guidance.

Informing the Tolerability of Cancer Treatments Using Patient-Reported Outcome Measures: Summary of an FDA and Critical Path Institute Workshop.

The US Food and Drug Administration and the Critical Path Institute's Patient-Reported Outcome (PRO) Consortium convened a cosponsored workshop on the use of PRO measures to inform the assessment of safety and tolerability in cancer clinical trials. A broad array of international stakeholders involved in oncology drug development and PRO measurement science provided perspectives on the role of PRO measures to provide complementary clinical data on the symptomatic side effects of anticancer agents. Speakers and panelists explored the utility of information derived from existing and emerging PRO measures, focusing on the PRO version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Panelists and speakers discussed potential ways to improve the collection, analysis, and presentation of PRO data describing symptomatic adverse events to support drug development and better inform regulatory and treatment decisions. Workshop participants concluded the day with a discussion of possible approaches to the patient-reported assessment of an investigational drug's overall side effect burden as a potential clinical trial end point. The Food and Drug Administration reiterated its commitment to collaborate with international drug development stakeholders to identify rigorous methods to incorporate the patient perspective into the development of cancer therapeutics.

Development of a harmonized patient-reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials.

Along with reducing spleen size, relieving symptom severity is a key objective of the treatment of myelofibrosis (MF). Several questionnaires have been developed for patient self-report of MF symptoms in clinical trials and each includes unique instructions, items, and/or response scales. This variability in questionnaire content increases uncertainty; it is unclear which questionnaire is the most appropriate for assessing MF symptoms and it makes comparisons across trials difficult. The Patient-Reported Outcome (PRO) Consortium's MF Working Group (WG) was established to review existing MF symptom questionnaires and to develop a harmonized, consensus-based PRO questionnaire for use in future MF trials. The WG focused on the seven core symptoms of MF: fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain. The resulting Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) asks respondents to report symptom severity at its worst for each of the seven items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale. The MFSAF v4.0, for which there are 24-h and 7-day recall formats, will be maintained and licensed by the Critical Path Institute and made publicly available for use in future clinical trials.

Development of the Diary for Irritable Bowel Syndrome Symptoms to Assess Treatment Benefit in Clinical Trials: Foundational Qualitative Research.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and alterations in bowel habits. Three subtypes are defined on the basis of stool patterns: diarrhea-predominant IBS, constipation-predominant IBS, and alternating or mixed IBS. OBJECTIVES: To develop patient-reported outcome measures for qualification by the Food and Drug Administration to support product approvals and labeling in IBS; the article focuses on the qualitative research that provided the foundation for the new measures. METHODS: Forty-nine concept elicitation and 42 cognitive debriefing interviews were conducted with subjects meeting Rome III criteria; additional criteria were imposed to yield a sample representative of the target patient population. RESULTS: Although incomplete bowel movements, abnormal stool frequency and consistency, and abdominal pain, discomfort, and bloating were reported most frequently across concept elicitation interviews, the relative importance of specific symptoms varied by subtype. Among their five symptoms most important to treat, diarrhea-predominant and alternating or mixed IBS subjects frequently identified urgency, loose/watery stools, abdominal pain, and cramping, whereas constipation-predominant IBS subjects commonly included infrequent and incomplete bowel movements, bloating, and abdominal pain. The cognitive debriefing interviews facilitated refinement of each item set, supported minor modifications following translatability assessment, and suggested improvements to the electronic interface. Furthermore, subjects reported that every item was relevant and no concepts of importance were missing. CONCLUSIONS: Results support the content validity of the IBS patient-reported outcome measures. A pilot study was recently initiated to inform item reduction, develop scoring algorithms, and provide preliminary psychometric information. Comprehensive psychometric evaluation and responder definition development will follow.

Clinically Meaningful Outcomes in Early Alzheimer Disease: A Consortia-Driven Approach to Identifying What Matters to Patients.

BACKGROUND: Numerous statistically derived composite measures have recently been proposed as clinical outcome assessments (COAs) for clinical trials in the early stages of Alzheimer disease. Critical Path Institute's Coalition Against Major Diseases (CAMD) advanced a proposed statistically derived composite measure to regulatory agencies with the goal of qualifying it as a COA for pre-dementia trials. In response to FDA's requirement to demonstrate that proposed COAs are meaningful to patients, this project aimed to identify the most important cognition-related concerns patients and informants report early in the disease and determine how this information maps to what is assessed by several statistically derived composite measures. METHODS: Leveraging qualitative research completed by Critical Path Institute's Patient-Reported Outcome Consortium, CAMD utilized a summary report that included frequency grids of reported concerns of amnestic mild cognitive impairment patients and their informants, as well as the narrative transcripts from focus groups. Transcripts were reviewed and analyzed to identify which cognitive domains the patient- and informant-reported concerns mapped onto. The results were then compared to see how well these cognitive domains were represented in various statistically derived composite measures. RESULTS: The patient- and informant-reported concerns primarily mapped to the cognitive domains of episodic memory and, secondarily, orientation and language. Depending on the specified composite, there were varying levels of alignment between their subcomponents and these cognitive domains. CONCLUSION: Through secondary analyses of existing qualitative data, this study examined several statistically derived composite measures and found that they generally capture cognitive domains that reflect aspects of day-to-day functioning that patients and informants consider meaningful.