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.

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.

Best Practice Recommendations: User Acceptance Testing for Systems Designed to Collect Clinical Outcome Assessment Data Electronically.

Implementing clinical outcome assessments electronically in clinical studies requires the sponsor and electronic clinical outcome assessment (eCOA) provider to work closely together to implement study-specific requirements and ensure consensus-defined best practices are followed. One of the most important steps is for sponsors to conduct user acceptance testing (UAT) using an eCOA system developed by the eCOA provider. UAT provides the clinical study team including sponsor or designee an opportunity to evaluate actual software performance and ensure that the sponsor's intended requirements were communicated clearly and accurately translated into the system design, and that the system conforms to a sponsor-approved requirements document based on the study protocol. The components of an eCOA system, such as the study-specific application, customization features, study portal, and custom data transfers should be tested during UAT. While the provider will perform their own system validation, the sponsor or designee should also perform their due diligence by conducting UAT. A clear UAT plan including the necessary documentation may be requested by regulatory authorities depending on the country. This paper provides the electronic patient-reported outcome (ePRO) Consortium's and patient-reported outcome (PRO) Consortium's best practice recommendations for clinical study sponsors or their designee for conducting UAT with support from eCOA providers to ensure data quality and enhance operational efficiency of the eCOA system. Following these best practice recommendations and completing UAT in its entirety will support a high quality eCOA system and ensure more reliable and complete data are collected, which are essential to the success of the study.

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.

Development and Validation of the FSIQ-RMS: A New Patient-Reported Questionnaire to Assess Symptoms and Impacts of Fatigue in Relapsing Multiple Sclerosis.

OBJECTIVES: A new patient-reported outcome (PRO) instrument to measure fatigue symptoms and impacts in relapsing multiple sclerosis (RMS) was developed in a qualitative stage, followed by psychometric validation and migration from paper to an electronic format. METHODS: Adult patients with relapsing-remitting multiple sclerosis (RRMS) were interviewed to elicit fatigue-related symptoms and impacts. A draft questionnaire was debriefed in cognitive interviews with further RRMS patients, and revised. Content confirmation interviews were conducted with patients with progressive-relapsing multiple sclerosis (PRMS) and relapsing secondary-progressive multiple sclerosis (RSPMS). Psychometric analyses used data from adult patients with different RMS subtypes and matched non-RMS controls in a multicenter, observational study. After item reduction, the final instrument was migrated to a smartphone (eDiary) and usability was confirmed in interviews with additional adult RMS patients. RESULTS: The qualitative stage included 37 RRMS, 5 PRMS, and 5 RSPMS patients. Saturation of concepts was reached during concept elicitation. Cognitive interviews confirmed that participants understood the instructions, items, and response options of the instrument-named FSIQ-RMS-as intended. Psychometric validation included 164 RMS and 74 control patients. Internal consistency and test-retest reliability were demonstrated. The symptoms domain discriminated along the RMS symptom-severity continuum and between patients and controls. Patients were able to attribute fatigue-related symptoms to RMS. Usability and conceptual equivalence of the eDiary were confirmed (n = 10 participants). CONCLUSIONS: With 7 symptom items and 13 impact items (in 3 impacts subdomains: physical, cognitive and emotional, and coping) after item reduction, the FSIQ-RMS is a comprehensive, valid, and reliable measure of fatigue-related symptoms and impacts in RMS patients.

Emerging good practices for Translatability Assessment (TA) of Patient-Reported Outcome (PRO) measures.

This paper presents emerging Good Practices for Translatability Assessment (TA) of Patient-Reported Outcome (PRO) Measures. The ISOQOL Translation and Cultural Adaptation Special Interest Group (TCA-SIG) undertook the review of several TA approaches, with the collaboration of organizations who are involved in conducting TA, and members of the TCA-SIG. The effort led to agreement by the writing group on Good Practices for 1) the terminology to be used in referring to translatability process, 2) the best definition of TA, 3) the methodology that is recommended at each step of the process, 4) the persons involved in TA, 5) the timing of assessment, 6) the review criteria for TA, and 7) the recommendations to be made at the end of the TA process. With input from the TCA-SIG membership and in consultation with experts in the field, these emerging good practices can guide the future use of TA in the development of PROs.

Development and validation of the functional assessment of cancer therapy nasopharyngeal cancer subscale.

BACKGROUND: We aimed to develop a quality-of-life subscale for nasopharyngeal carcinoma (NPC) and validate the functional assessment of cancer therapy-nasopharyngeal (FACT-NP). METHODS: The FACT-NP was tested cross-sectionally in survivors of postirradiated NPC (n = 357) and was administered to newly diagnosed patients (n = 160) before, at the end of, and 3 months after radiotherapy (RT). RESULTS: Each FACT-NP domain was internally consistent (Cronbach's alpha = 0.87-0.90). The test-retest reliability for each subscale was satisfactory (intraclass correlation coefficient = .73-.88). Concurrent validity was suggested by the moderate to strong correlations between the FACT-NP and the Quality of Life-Radiation Therapy Instrument-Head and Neck (QOL-RTI-H&N) subscales (Pearson r = .39-.84). The FACT-NP was responsive to clinical changes from pretreatment to 3 months after RT (effect sizes > 0.6 for clinically relevant subscales). The pooled data for multitrait scaling analysis showed satisfactory item internal consistency and item discriminant validity (100% and 90% scaling success, respectively). CONCLUSION: The FACT-NP is a reliable and valid instrument for measuring QOL in patients with NPC.

Cross-cultural validation of the Japanese version of the lung cancer subscale on the functional assessment of cancer therapy-lung.

BACKGROUND: The Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, which consists of a core questionnaire (the General Measure of FACT [FACT-G]) and a 9-item Additional Concerns comprised of a 7-item Lung Cancer Subscale (LCS), was developed in an English-speaking culture. The validation of the Japanese FACT-G was reported previously, and this report describes the cross-cultural validation of the LCS. METHODS: The Japanese version of the LCS was developed through an iterative forward-backward translation sequence used throughout the FACT Multilingual Translation Project. In evaluating psychometric performance, its construct validity was investigated with Cronbach's alpha coefficient and factor analysis. Clinical validities of a known-groups comparison and longitudinal validity were also investigated. RESULTS: The FACT-L was administered twice to 180 patients with lung cancer within 2 weeks. The Japanese LCS had borderline values for Cronbachs alpha coefficients (0.62-0.67). Factor analysis indicated that the LCS had the three dimensions of respiratory symptoms, appetite plus body weight, and clear thinking. For clinical validity, a known-groups comparison showed that the LCS could differentiate patients according to truth disclosure, as Japanese doctors sometimes do not fully inform terminally ill patients. However, responsiveness was not proved when performance status was used as an anchor, probably owing to the short interval between the administration of the two measures. CONCLUSION: The Japanese version of the LCS asked questions about multiple symptoms of patients with lung cancer, as did the original English LCS. The longitudinal clinical validity of the Japanese version should be investigated in future clinical trials.

Korean translation and validation of the functional assessment of cancer therapy-lung (FACT-L) version 4.

In this study, we have translated and cross-culturally adapted the Functional Assessment of Cancer Therapy-Lung (FACT-L) version 4 into Korean, and we have evaluated its reliability and validity. The FACT-L version 4 was translated into Korean following the standard Functional Assessment of Chronic Illness Therapy (FACIT) translation methodology. The psychometric properties of the FACT-L were evaluated in 122 lung cancer patients (mean age, 60.88 years). Pre-testing was performed in 22 patients, and these results indicated good content coverage and overall comprehensibility. In validating the FACT-L version 4, our results indicated high internal consistency of the FACT-L scales, with Cronbach's alpha coefficients ranging from 0.52 to 0.84. The FACT-L also demonstrated good convergent and divergent validity when correlated with the Functional Living Index-Cancer (FLIC) and the shortened forms of the Profile of Mood States (POMS). This reliable and valid instrument can now be used to properly evaluate the quality of life of Korean lung cancer patients.

Korean translation and validation of the functional assessment of cancer therapy-breast (FACT-B) scale version 4.

We undertook to translate and cross-culturally adapt the Functional Assessment of Cancer Therapy-Breast (FACT-B) scale into Korean and to evaluate its reliability and validity. The translation procedure followed the standard Functional Assessment of Chronic Illness Therapy translation methodology. A total of 201 breast cancer patients (mean age, 43.87 years) were studied for psychometric properties of the FACT-B scale. A pre-test of 20 Korean breast cancer patients indicated that the Korean FACT-B scale provided good content coverage and overall comprehensibility. Our results indicated high internal consistency of the FACT-B scale, with Cronbach's alpha coefficients ranging from 0.79 to 0.90. The only exception was the Breast Cancer Scale (BCS), which had a Cronbach's alpha coefficient of 0.67. We can consider that most of the patients in this study had not resumed sexual activity after surgery and found it difficult to comment on this aspect. We also considered that contents of the BCS may have been somewhat heterogeneous. After performing a factor analysis of the BCS data from this study, we identified three factors, accounting 58.8%: psychological distress (5 items, with explained variances of 27.5%), feminine satisfaction (2 items, with explained variances of 17.1%), and physical complaints (2 items, with explained variances of 14.2%). The FACT-B scale also demonstrated good convergent and divergent validity when correlated with the shortened forms of the Profile of Mood States and the Functional Living Index-Cancer (FLIC). We can now evaluate the Quality of Life (QoL) of Korean breast cancer patients using this reliable and valid instrument. Nevertheless our study has the limitation that it did not evaluate the sensitivity to the changes of the patients' QoL in the long term follow-up, and we will supplement it in our further study.

Quality of life in colorectal cancer patients with colectomy and the validation of the Functional Assessment of Cancer Therapy-Colorectal (FACT-C), Version 4.

The purpose of this study was to determine whether the Functional Assessment of Cancer Therapy-Colorectal (the FACT-C), a disease-specific tool for the assessment of colorectal cancer patients' QOL, is a valid assessment tool for measuring QOL changes. Ninety-eight colorectal cancer patients performed the assessment at baseline and 52 of these patients completed the instrument at one month and six months after colectomy. In addition to the FACT-C, the shortened forms of the Profile of Mood States, the Eastern Cooperative Oncology Group Performance Status Rating, Neuroticism Scale in the Eysenck Personality Questionnaire, and Functional Living Index-Cancer were completed. We found convergent and divergent validity and good reliability of the FACT-C. Patients' overall QOL was lower at one month after colectomy and recovered to the pre-surgery level at six months after colectomy.

Cross-cultural validation of the Japanese Functional Assessment of Cancer Therapy-Anemia (FACT-An).

BACKGROUND: The Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire, which consists of a core questionnaire named the General Measure of the Functional Assessment of Cancer Therapy (FACT-G) and the Anemia additional concerns subscale, was developed in an English-speaking culture. The validation of the Japanese FACT-G was reported previously (Fumimoto et al., 2001), and, in this report, a cross-cultural validation for the subscale was performed. METHODS: The Japanese version was developed through an iterative forward-backward translation sequence used throughout the Functional Assessment of Chronic Illness Therapy (FACIT) Multilingual Translation Project. In evaluating psychometric performance, its construct validity was investigated by exploratory factor-analyses, and confirmed by Cronbach's alpha coefficient. RESULTS: The FACT-An was given to 180 patients with lung cancer. Using the 20 items of the Anemia subscale, a factor analysis extracted four factors of fatigue, chest condition, activities and headache. When analyzed as two extracted factors, fatigue, chest condition and headache were combined to be a major factor, although the minor factor of activities still remained. Thirteen of the 20 items construct the Fatigue additional concerns subscale. Cronbach's alpha coefficients for the Fatigue subscale (0.93) and the Anemia subscale (0.88) confirmed that, although these subscales had items that focus on different aspects of anemia or fatigue, each subscale was unidimensional. Clinical validity was indicated by moderate values of Spearman's correlation coefficients between Eastern Cooperative Oncology Group performance status rating (ECOG PSR) and the Anemia subscale (-0.50) or the Fatigue subscale (-0.48). CONCLUSION: Both the Fatigue subscale and the Anemia subscale are valid in Japan, indicating that FACT-An is an instrument that is applicable across cultures and particularly with a Japanese cancer population.

Reliability & validity of the Malayalam Functional Assessment of Cancer Therapy for Head & Neck Cancer.

BACKGROUND & OBJECTIVES: The need for quality over quantity in cancer survival is increasingly being recognised in the developing countries, and the efforts to monitor quality of life (QOL) are increasing. However, the non-availability of a valid and reliable tool in the local language is a common problem. Cross-culturally sensitive tools enable the researchers to compare different patient populations and identify cultural differences and variations. The present study was carried out to translate, validate and test for reliability a reliable QOL tool for the head and neck cancer patient population in a tertiary care hospital in south India. METHODS: The functional assessment of cancer therapy for head and neck cancer (FACT-H&N) was translated into the local language (Malayalam) and tested for reliability in 140 patients of head and neck cancer. RESULTS: The translated tool showed substantial psychometric sensitivity. The Cronbach's alpha for the total FACT-H&N was 0.94. The alpha scores for the five subscales ranged from 0.81-0.92. Significant correlations were observed amongst the total QOL and subscale scores and patient's demographic, disease and treatment variables. INTERPRETATION & CONCLUSION: The Malayalam translation of the FACT-H&N questionnaire was developed, tested and validated. It was found to satisfactorily measure QOL in head and neck cancer patients.