A Review of Labeling Based on Patient-Reported Outcome Endpoints for New Oncology Drugs Approved by the European Medicines Agency (2017-2021).

OBJECTIVE: A review of new oncology indications approved by the European Medicines Agency (EMA) for 2012-2016 showed that 33% of new drugs had labeling based on patient-reported outcomes (PROs). We reviewed labeling text based on PRO endpoints for new oncology indications approved during 2017-2021. METHODS: New oncology drugs approved by EMA to treat indications of cancers during 2017-2021 were identified from the EMA website. PRO-related language reported in EMA summaries of product characteristics (SmPCs) were summarized and compared with similar findings reported for oncology indications approved during 2012-2016. RESULTS: Review documents by the EMA during 2017-2021 were available for 49 new oncology drugs for 70 cancer indications. Submissions for 52 (74.3%) of the 70 indications included PRO data for EMA review. Of all submissions, 14 (20.0%) approvals contained PRO-related language in the SmPC. Broad concepts such as health-related quality of life were most common and found in 8 of 14 (57.1%) PRO-related labels. CONCLUSION: PRO-related language appeared in SmPCs for 20% of all indications of new oncology drugs approved by EMA during 2017-2021 compared with approximately 33% of EMA approvals during 2012-2016. PRO-related labeling during the same periods showed a greater decline (from 47% to 27%) for indications of new oncology drugs that also included PRO data. One possible reason for this decline may be the increase in open-label studies from 62% between 2012 and 2016 to approximately 79% between 2017 and 2021.

Is IQWiG's 15% Threshold Universally Applicable in Assessing the Clinical Relevance of Patient-Reported Outcomes Changes? An ISPOR Special Interest Group Report.

This article discusses a recent methodological change to assess the additional benefit of drug intervention by the German Federal Joint Committee (Gemeinsamer Bundesausschuss), a key stakeholder in EUnetHTA21 (European Network for Health Technology Assessment joint consortium for future EU HTA regulation), methodological workstream. The German Federal Joint Committee (Gemeinsamer Bundesausschuss) set a universal individual response threshold at ≥ 15% of the scale range of the measurement instrument, for all patient-reported outcomes, to achieve an additional benefit rating for a given pharmaceutical intervention. This approach is originally based on a corresponding recommendation from the Institute for Quality and Efficiency in Health Care. The merits of this approach are reviewed from various perspectives, including the evidence basis, statistical and psychometric considerations, and regulatory perspectives by the ISPOR Clinical Outcomes Assessment Special Interest Group's multistakeholder group of authors (academia, contract research organizations, and industry). Particular focus is placed on the patient perspective within the Institute for Quality and Efficiency in Health Care approach. The article development incorporated feedback from ISPOR members during well-attended ISPOR US and European conference presentations and 2 formal rounds of written review. The authors concluded that the ≥ 15% response threshold is incongruent with previously defined and scientifically established thresholds and is not well-suited for universal implementation. Further scientific evidence and discussion among all stakeholders are needed, especially should this universal rule be considered in the context of future joint clinical assessments of health technologies in the European Union scheduled from 2025 onward.

Development of the Pulmonary Hypertension Functional Classification Self-Report: a patient version adapted from the World Health Organization Functional Classification measure.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by progressive limitations on physical activity, right heart failure, and premature death. The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning, but no equivalent patient-reported version of PAH symptoms and activity limitations exists. We developed a version of the WHO-FC for self-completion by patients: the Pulmonary Hypertension Functional Classification Self-Report (PH-FC-SR). METHODS: Semistructured interviews were conducted with three health care providers (HCPs) via telephone to inform development of the draft PH-FC-SR. Two rounds of semi-structured interviews were conducted with 14 US patients with a self-reported PAH diagnosis via telephone/online to elicit concepts and iteratively refine the PH-FC-SR. RESULTS: HCPs reported that the WHO-FC was a useful tool for evaluating patients' PAH severity over time and for making treatment decisions but acknowledged that use of the measure is subjective. Patients in round 1 interviews (n = 6) reported PAH symptoms, including shortness of breath (n = 6), fatigue (n = 5), syncope (n = 5), chest pains (n = 3), and dizziness (n = 3). Round 1 patients identified challenges with the original WHO-FC, including comprehensibility of clinical terms and overlapping descriptions of class II and III, and preferred the Draft 1 PH-FC-SR over the original WHO-FC. After minor changes were made to Draft 2, round 2 interviews (n = 8) confirmed patients understood the PH-FC-SR class descriptions, interpreting them consistently. CONCLUSIONS: The HCP and patient interviews identified and confirmed certain limitations inherent within the clinician-rated WHO-FC, including subjective assessment and overlapping definitions for class II and III. The PH-FC-SR includes patient-appropriate language, symptoms, and physical activity impacts relevant to patients with PAH. Future research is recommended to validate the PH-FC-SR and explore its correlation with the physician-assessed WHO-FC and other outcomes.

Is the EQ-5D fit for purpose in asthma? Acceptability and content validity from the patient perspective.

BACKGROUND: The increasing emphasis on patient-reported outcomes in health care decision making has prompted greater rigor in the evidence to support the instruments used. Acceptability and content validity are important properties of any measure to ensure it assesses the relevant aspects of the target concept. The purpose of this study was to evaluate the acceptability and content validity of the EQ-5D 5-Level (EQ-5D-5L) to assess the impact of asthma on patients' lives. METHODS: Qualitative interviews were conducted with 40 adults with asthma in the United Kingdom. The first 25 interviews used cognitive-debriefing methods to assess the relevance and acceptability of the EQ-5D-5L and two asthma-specific measures for comparison: an asthma-specific, preference-based measure (the Asthma Quality of Life Utility Index-5 Dimensions) and an Asthma Symptom Diary. The final 15 interviews combined concept elicitation to identify patient-perceived asthma impact, and cognitive debriefing to assess relevance and acceptability of the EQ-5D-5L and the Asthma Symptom Diary. Cognitive-debriefing feedback on the content of the measures was collated and summarized descriptively. The concept-elicitation data were analyzed thematically. RESULTS: Participants were aged 20 to 57 years and 62.5% were female. Although some participants expressed positive opinions on aspects of the EQ-5D-5L, only the usual activities dimension was consistently considered relevant to participants' asthma experiences. The mobility and self-care dimensions prompted strong negative reactions from some participants. Variations in interpretation of the mobility dimension and difficulties with multiple concepts in the pain/discomfort and anxiety/depression dimensions also were noted. Concepts reported by participants as missing included environmental triggers, asthma symptoms, emotions, and sleep. The EQ-5D-5L was the least preferred measure to describe the impact of asthma on participants' lives. Participants reported shortness of breath and impact on activities as especially salient issues. CONCLUSIONS: The content of the EQ-5D-5L was poorly aligned with the patient-perceived impact of asthma, and the measure failed to meet basic standards for acceptability and content validity as a measure to assess the impact of asthma from the patient perspective. The shortcomings identified raise concerns regarding the appropriateness of the EQ-5D in asthma and further evaluation is warranted.

A Review of Patient-Reported Outcome Labeling in the United States (2011-2015).

BACKGROUND: A review of new drug approvals (NDAs) by the Food and Drug Administration (FDA) for 2006 to 2010 showed that 24.1% of new drugs had patient-reported outcome (PRO) labeling. OBJECTIVES: To review PRO labeling for NDAs for 2011 to 2015 and to compare key findings reported previously. METHODS: A review of the FDA drug approval reports for NDAs was conducted using the FDA Web site to determine the number of NDAs for the period 2011 to 2015. For all identified NDAs, drug approval package and product labeling were reviewed to identify PRO end-point status and PRO labeling. NDAs for the period 2006 to 2015 were grouped by disease category as per the International Classification of Diseases, Tenth Revision. Data were summarized for all NDAs and for approvals in diseases that traditionally rely on PROs for evaluating treatment benefit (PRO-dependent). Results were compared with NDAs for the period 2006 to 2010. RESULTS: In the period 2011 to 2015, 16.5% of the 182 NDAs had PRO labeling. For PRO-dependent NDAs, this figure was 46.9% and 46.0% for the period 2006 to 1010 and the period 2011 to 2015, respectively. Most of the PRO labeling for the period 2011 to 2015 was based on primary end points (76.7%). Almost all PRO labeling was for concepts proximal to the disease. CONCLUSIONS: There is potential for increased PRO labeling, especially for drug approvals in diseases that traditionally rely on PROs for evaluating treatment benefit to satisfy regulatory needs. Less PRO labeling based on secondary end points may be indicative of drug manufacturers' reluctance to aid and enhance the value propositions of their products to all stakeholders, including patients.

Estimating Health-State Utility for Economic Models in Clinical Studies: An ISPOR Good Research Practices Task Force Report.

Cost-utility models are increasingly used in many countries to establish whether the cost of a new intervention can be justified in terms of health benefits. Health-state utility (HSU) estimates (the preference for a given state of health on a cardinal scale where 0 represents dead and 1 represents full health) are typically among the most important and uncertain data inputs in cost-utility models. Clinical trials represent an important opportunity for the collection of health-utility data. However, trials designed primarily to evaluate efficacy and safety often present challenges to the optimal collection of HSU estimates for economic models. Careful planning is needed to determine which of the HSU estimates may be measured in planned trials; to establish the optimal methodology; and to plan any additional studies needed. This report aimed to provide a framework for researchers to plan the collection of health-utility data in clinical studies to provide high-quality HSU estimates for economic modeling. Recommendations are made for early planning of health-utility data collection within a research and development program; design of health-utility data collection during protocol development for a planned clinical trial; design of prospective and cross-sectional observational studies and alternative study types; and statistical analyses and reporting.

Assessment of PRO label claims granted by the FDA as compared to the EMA (2006-2010).

BACKGROUND: The US Food and Drug Administration (FDA) provides formal guidance for the use of patient-reported outcomes (PROs) in support of labeling claims, whereas the European Medicines Agency (EMA) offers insight in a reflection paper relating to health-related quality of life in lieu of formal guidance. OBJECTIVES: PRO label claims granted for new molecular entities and biologic license applications from 2006 through 2010 were reviewed to evaluate consistencies and discrepancies in PRO label claims granted by the FDA and the EMA and to highlight trends in the acceptance of PRO claims across agencies. METHODS: Products approved by both the FDA and the EMA were identified. By using US Drug Approval Packages and European Public Assessment Reports packages, any PRO label claims made for the same product by the same company were compared. RESULTS: Both agencies approved a total of 75 products. Of these, 35 (47%) had at least one EMA-granted PRO label claim compared with 14 (19%) by the FDA. Most FDA-grated claims focused on symptoms; however, EMA-granted claims were more likely to include higher order concepts. Few (~12%) were granted the same label claims. Despite this discordance between the two agencies, where PRO label claims were granted by both the FDA and the EMA, there was similarity in the type of label claim. CONCLUSIONS: The EMA is more likely than the FDA to grant PRO claims and for higher order constructs. On a macro level, there appears to be poor concordance between claims granted by both agencies. On close examination, however, there appears to be greater concordance than previously recognized, which may be instructive in formulating future PRO strategies. Further research to create strategic alignment across agencies may be beneficial.

The Patient Experience of Acute Lymphoblastic Leukemia and Its Treatment: Social Media Review.

BACKGROUND: Adult patients with acute lymphoblastic leukemia (ALL) report substantial disease- and treatment-related impacts on their health-related quality of life (HRQOL). Patient-reported information (PRI) shared on social media may provide a distinct opportunity to understand the patient experience outside of formal research contexts and help inform the development of novel therapies. OBJECTIVE: This qualitative social media review aimed to assess PRI shared on social media websites to gain a better understanding of the symptom, HRQOL, and treatment impacts on individuals with ALL. METHODS: We identified English-language posts on 3 patient advocacy websites (Patient Power, The Patient Story, and Leukaemia Care) and YouTube that included PRI about experiences with ALL or ALL treatments shared by adults (aged ≥18 years) with a self-reported ALL diagnosis. Patients' demographic and disease characteristics were extracted from posts (where available), and the posts were analyzed thematically. A network analysis was conducted to delineate possible associations among ALL symptoms, HRQOL impacts, and treatment-related symptoms and impacts. RESULTS: Of the 935 social media posts identified, 63 (7%) met the review criteria, including 40 (63%) videos, 5 (8%) comments posted in response to videos, and 18 (29%) blog posts. The 63 posts were contributed by 41 patients comprised of 21 (51%) males, 18 females (44%), and 2 (5%) whose gender was not reported. Among the patients, 13 (32%) contributed >1 source of data. Fatigue (n=20, 49%), shortness of breath (n=13, 32%), and bruising (n=12, 29%) were the symptoms prior to treatment most frequently discussed by patients. Patients also reported impacts on personal relationships (n=26, 63%), psychological and emotional well-being (n=25, 61%), and work (n=16, 39%). Although inpatient treatment reportedly restricted patients' independence and social functioning, it also provided a few patients with a sense of safety. Patients frequently relied on their doctors to drive their treatment decisions but were also influenced by family members. The network analysis indicated that disease-related symptoms were primarily associated with patients' physical functioning, activities of daily living, and ability to work, while treatment-related symptoms were primarily associated with emotional well-being. CONCLUSIONS: This social media review explored PRI through a thematic analysis of patient-contributed content on patient advocacy websites and YouTube to identify and contextualize emergent themes in patient experiences with ALL and its treatments. To our knowledge, this is the first study to leverage this novel tool to generate new insights into patients' experiences with ALL. Patients' social media posts suggest that inpatient care for ALL is associated with restricted independence and social functioning. However, inpatient care also provided a sense of safety for some patients. Studies such as this one that capture patients' experiences in their own words are valuable tools to further our knowledge of patient outcomes with ALL.

Validation of NASH-CHECK: a novel patient-reported outcome measure for nonalcoholic steatohepatitis.

BACKGROUND: Standardized measures for evaluating patients' experiences with nonalcoholic steatohepatitis (NASH) and their perceived changes with treatment in clinical trials have been limited. To meet this need, a patient-reported outcome (PRO) measure, NASH-CHECK, was developed to evaluate symptoms and health-related quality of life for patients with NASH. The objective of this study was to conduct a quantitative evaluation of the psychometric properties of NASH-CHECK. METHODS: The study used data from a phase 2, randomized controlled trial of adult patients with NASH (NCT02855164). Analyses were conducted to determine the optimal scoring of NASH-CHECK and to evaluate reliability, construct validity, and ability to detect change in NASH-CHECK scale scores. RESULTS: Data were available for 253 patients with NASH (61% female; mean [standard deviation] age = 53 [12] years). Following initial item-level analyses, including correlations and exploratory factor analysis, three items were removed from the measure. Confirmatory factor analysis supported the formation of four multi-item scales (Cognitive Symptoms, Activity Limitations, Social Impact, and Emotional Impact) and five single-item scales (Abdominal Pain, Abdominal Bloating, Fatigue, Sleep, and Itchy Skin). Psychometric analyses of the final NASH-CHECK scales provided support for their internal reliability, test-retest reliability, construct validity, and ability to detect change. CONCLUSION: The results support NASH-CHECK as a reliable, valid, and responsive measure to assess patients' perspectives of symptoms and the health-related quality of life impact of NASH in clinical trials and in routine practice.

Correction: The Patient Experience of Acute Lymphoblastic Leukemia and Its Treatment: Social Media Review.

[This corrects the article DOI: 10.2196/39852.].

Patient Perceptions Regarding Ciltacabtagene Autoleucel Treatment: Qualitative Evidence From Interviews With Patients With Relapsed/Refractory Multiple Myeloma in the CARTITUDE-1 Study.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation. METHODS: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study. RESULTS: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments. CONCLUSION: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments.

The patient experience of relapsed refractory multiple myeloma and perspectives on emerging therapies.

BACKGROUND: Relapsed refractory multiple myeloma (RRMM) is a disease that is nonresponsive or progressive on therapy, and although patients can achieve remission, relapse is common. As more treatment options become available for multiple myeloma (MM), it is important to understand patients' experiences of current and emerging therapies. AIMS: This study aimed to better understand patient experiences with treatment and therapies for MM using qualitative interviews and patient-reported information (PRI) shared on social media. METHODS: Semistructured qualitative interviews were conducted with adults with RRMM who resided in the United States. In addition to the interviews, PRI was collected from YouTube and a patient advocacy website. Key themes from the interviews and PRI were summarized, and illustrative quotes were extracted. RESULTS: Twenty participants were interviewed; 11 were female, and mean (standard deviation) age was 60 (7.0) years. The PRI included 14 posts and 19 unique contributors (10 were female). Similar treatment-related symptoms were reported in the interviews and PRI. Fatigue and pain were the most frequently reported symptoms while receiving treatment in both the interviews and PRI. These symptoms had a meaningful impact on health-related quality of life (HRQOL); being off treatment and returning to normal living was described as an ideal treatment outcome. Nearly all interview participants (n = 18) preferred a treatment that would allow for a treatment-free interval, if it had the same efficacy and safety profile as a continuous treatment. CONCLUSION: The symptom experience reported in this study is consistent with known RRMM symptoms and HRQOL impacts. Additionally, this study highlighted that patients' treatment expectations are changing relative to their past treatment experience. Individuals living with RRMM strongly desire therapies with a treatment-free interval and minimal impact on their HRQOL.

Development and validation of the living with chronic obstructive pulmonary disease questionnaire.

PURPOSE: Available patient-reported outcome (PRO) measures for chronic obstructive pulmonary disease (COPD) focus primarily on impairment (symptoms) and activities (functioning). The purpose of the study was to develop a patient-based PRO measure for COPD that captures the overall everyday impact of living with COPD from the patient's perspective. METHODS: LCOPD items (Living with COPD Questionnaire) were generated from qualitative interviews in the U.K. and focus groups in the U.S.A. The draft measure was tested for face and content validity in both countries. Item reduction and testing for reproducibility and construct validity was conducted via Rasch and traditional psychometric analyses. RESULTS: The draft LCOPD was found to be relevant and acceptable to patients in the U.K. (N = 19) and U.S. (N = 16). Application of Rasch analysis to data collected in validation studies (n = 162 in the U.K. and 145 in U.S.) identified a 22-item scale that measured a single construct in both countries. Psychometric analyses indicated that this version was internally consistent and reproducible. Scores on the measure were related as expected to clinician ratings of disease severity and patient ratings of COPD severity and general health. CONCLUSIONS: The LCOPD is a new measure examining the everyday impact of living with COPD. It demonstrates good scaling properties and may prove valuable in understanding treatment benefits.

Qualitative study: burden of menopause-associated vasomotor symptoms (VMS) and validation of PROMIS Sleep Disturbance and Sleep-Related Impairment measures for assessment of VMS impact on sleep.

PURPOSE: We evaluated the impact of menopause-associated vasomotor symptoms (VMS) on sleep. We also sought to establish the content validity of Patient-Reported Outcomes Measurement Information System (PROMIS) short form Sleep-Related Impairment and Sleep Disturbance measures in postmenopausal women with moderate to severe VMS. METHODS: Cross-sectional, in-person, qualitative interviews were conducted in the United States (Texas, Illinois) and European Union (UK, France) with women aged 40-64 years experiencing moderate to severe VMS (≥35/wk). Main outcomes were impact of VMS on sleep based on concept elicitation and content validity of PROMIS Sleep-Related Impairment and Sleep Disturbance short forms via cognitive debriefing. RESULTS: Thirty-two women (US: n = 16; EU: n = 16) participated. A majority (US: 93.8%; EU: 93.8%) said VMS affected sleep; specifically, they had sleep interrupted by sweating or overheating and had difficulty returning to sleep. Sleep disturbance was the most bothersome aspect of VMS (US: 75%; EU: 50%). VMS-associated sleep disturbance affected next-day work productivity, mood, relationships, daily activities, concentration, social activities, and physical health. Participants found both PROMIS sleep measures relevant and easy to answer; the Sleep Disturbance measure was considered the most relevant. Participants had no difficulty remembering their experiences over the 7-day recall period and found the response options to be distinct. CONCLUSION: VMS associated with menopause significantly interferes with sleep and next-day functioning (e.g., work productivity), supporting assessment of sleep outcomes in studies evaluating treatment of VMS. Women with moderate to severe VMS found that the PROMIS Sleep-Related Impairment and Sleep Disturbance short forms assessed constructs important to understanding sleep in the context of menopause-associated VMS.

Development of a Patient-Reported Outcome Measure for Non-Alcoholic Steatohepatitis (NASH-CHECK): Results of a Qualitative Study.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease characterized by excessive liver fat accumulation, inflammation, cell injury, and fibrosis. It is viewed as largely asymptomatic in its earlier (non-cirrhotic) stages, and information on the patient-perceived impact of NASH is scarce. OBJECTIVE: This study aimed to develop a NASH-specific patient-reported outcome (PRO) measure (NASH-CHECK) for use as a trial endpoint, using methods compliant with regulatory expectations. METHODS: A NASH conceptual model was developed based on the literature and clinical/patient expert review. The model guided concept elicitation (CE) interviews in patients with non-cirrhotic NASH recruited via a US tertiary care center. NASH-CHECK content was generated via thematic analysis of CE data and review by clinical/patient experts. Cognitive debriefing (CD) interviews with US patients evaluated content validity. RESULTS: The literature review confirmed that NASH impacts on functioning and health-related quality of life (HRQoL). Overall, 23 CE and 20 CD interviews were conducted. Key symptoms reported in CE interviews included pain in the upper-right abdomen (n = 14), fatigue (n = 18), poor sleep quality (n = 12), impaired memory (n = 13), and reduced focus (n = 11); key HRQoL impacts included impaired physical functioning, reduced ability to conduct daily living tasks, reduced quality of relationships, low mood, anxiety, and self-consciousness. The 52-item first-draft NASH-CHECK was reduced to 31 items based on patient feedback on item relevance, acceptability, and comprehension. CONCLUSIONS: The interviews revealed key symptoms and broad HRQoL impacts of NASH. As a disease-specific PRO measure assessing symptoms and HRQoL, the NASH-CHECK is relevant, comprehensive, and acceptable to patients and clinicians.

International development of the patient-reported outcome indices for multiple sclerosis (PRIMUS).

BACKGROUND: The Patient-Reported Indices for Multiple Sclerosis (PRIMUS) comprises a suite of three scales for assessing symptoms, activity limitations, and quality of life in multiple sclerosis (MS). It was developed in the UK and has been shown to have excellent psychometric properties. This study describes the adaptation of eight language versions for Canadian English, Canadian French, French, German, Italian, Spanish, Swedish, and US English. METHODS: The PRIMUS was translated using the dual-panel process. Cognitive debriefing interviews conducted with MS patients assessed face and content validity. Psychometric and scaling properties were assessed via a two-administration postal survey conducted in each country involving the PRIMUS, the Nottingham Health Profile (NHP), the Unidimensional Fatigue Impact Scale (U-FIS), and demographic questions. RESULTS: Cognitive debriefing interviews demonstrated the acceptability of the new language versions. Analysis of survey data showed that the new language versions of the three PRIMUS scales were unidimensional (as indicated by fit to the Rasch model) and that they had good internal consistency and reproducibility. PRIMUS scale scores correlated as expected with those on the NHP and the U-FIS. The scales in all countries were able to discriminate between groups of patients on the basis of their self-reported MS severity, general health, and employment status. CONCLUSIONS: The PRIMUS was successfully adapted into eight new languages. Most of the tests showed the PRIMUS to have good unidimensionality and to have good internal consistency, reproducibility, and construct validity. The measure is now available for use in clinical studies and trials involving these countries and the UK. Further work is required to assess the measure's responsiveness.

International development of the Unidimensional Fatigue Impact Scale (U-FIS).

OBJECTIVE: The 22-item Unidimensional Fatigue Impact Scale (U-FIS) provides an index of the impact of fatigue on patients with multiple sclerosis (MS). The objective is to produce eight new language versions of the U-FIS: Canadian-English, Canadian-French, French, German, Italian, Spanish, Swedish, and US-English. METHODS: The U-FIS was translated via two translation panels. Cognitive debriefing interviews conducted with patients in each country assessed face and content validity. Scaling and psychometric properties were assessed via survey data with patients in each country completing the U-FIS, Nottingham Health Profile (NHP), and demographic questions. RESULTS: Cognitive debriefing interviews demonstrated U-FIS acceptability. Analysis of postal survey data showed all new language versions to be unidimensional. Reliability was high, with test-retest correlations and internal-consistency coefficients exceeding 0.85. Initial evidence of validity was provided by moderate to high correlations with NHP scales. The U-FIS was able to discriminate between groups based on employment status, perceived MS severity, and general health. CONCLUSION: The U-FIS is a practical new measure of the impact of fatigue. It was successfully adapted into eight new languages to broaden availability for researchers. Psychometric analyses indicated that the new language versions were unidimensional and reproducible with promising construct validity.

Patient reported outcomes: looking beyond the label claim.

The use of patient reported outcome scales in clinical trials conducted by the pharmaceutical industry has become more widespread in recent years. The use of such outcomes is particularly common for products developed to treat chronic, disabling conditions where the intention is not to cure but to ameliorate symptoms, facilitate functioning or, ultimately, to improve quality of life. In such cases, patient reported evidence is increasingly viewed as an essential complement to traditional clinical evidence for establishing a product's competitive advantage in the marketplace. In a commercial setting, the value of patient reported outcomes is viewed largely in terms of their potential for securing a labelling claim in the USA or inclusion in the summary of product characteristics in Europe. Although, the publication of the recent US Food and Drug Administration guidance makes it difficult for companies to make claims in the USA beyond symptom improvements, the value of these outcomes goes beyond satisfying requirements for a label claim. The European regulatory authorities, payers both in the US and Europe, clinicians and patients all play a part in determining both the availability and the pricing of medicinal products and all have an interest in patient-reported data that go beyond just symptoms. The purpose of the current paper is to highlight the potential added value of patient reported outcome data currently collected and held by the industry for these groups.

Interpreting scores on multiple sclerosis-specific patient reported outcome measures (the PRIMUS and U-FIS).

BACKGROUND: The PRIMUS is a Multiple Sclerosis (MS)-specific suite of outcome measures including assessments of QoL (PRIMUS QoL, scored 0-22) and activity limitations (PRIMUS Activities, scored 0-30). The U-FIS is a measure of fatigue impact (scored 0-66). These measures have been fully validated previously using an MS sample with mixed diagnoses. The aim of the present study was to validate the measures further in a specifically Relapse Remitting MS (RRMS) sample and to provide preliminary evidence of the responder definitions (RD; also known as minimal important difference) for these instruments. METHODS: Data were derived from a multi-country efficacy trial of MS patients with assessments at baseline and 12 months. Baseline data were used to assess the internal reliability and validity of the measures. Both anchor-based and distribution-based approaches were employed for estimating RD. Anchor-based estimates were based on published RD values for the EQ-5D and were assessed for those improving and deteriorating separately. Distribution-based estimates were based on standard error of measurement (SEM), change score equivalent to 0.30, and change score equivalent to 0.50, effect sizes (ES). RESULTS: The sample included 911 RRMS patients (67.3% female, age mean (SD) 36.2 (8.4) years, duration of MS mean (SD) 4.8 (5.2) years). Results showed that the PRIMUS and U-FIS had good internal consistency. Appropriate correlations were observed with comparator instruments and both measures were able to distinguish between participants based on Expanded Disability Status Scale scores and time since diagnosis. The anchor-based and distribution-based RD estimates were: PRIMUS Activities range = 1.2-2.3, PRIMUS QoL range = 1.0-2.2, and U-FIS range = 2.4-7.0. CONCLUSIONS: The results show that the PRIMUS and U-FIS are valid instruments for use with RRMS patients. The analyses provide preliminary information on how to interpret scores on the scales. These data will be useful for assessing treatment efficacy and for powering clinical studies. TRIAL REFERENCE NUMBER: ClinicalTrials.gov Identifier NCT00340834.

Exploring the Impact of Fatigue in Progressive Multiple Sclerosis: A Mixed-Methods Analysis.

BACKGROUND: Patient-focused literature on fatigue in progressive forms of multiple sclerosis (MS) is sparse. This study aimed to explore progressive MS patients' experiences of fatigue. METHODS: Adult patients in the United States with primary progressive MS (n=21) and secondary progressive MS (n=23), recruited from research panels, completed the following PRO measures: Patient Global Impression of Severity (Fatigue) (PGI-F); Fatigue Scale of Motor and Cognitive Functions (FSMC); Modified Fatigue Impact Scale (MFIS); Patient Health Questionnaire, two-item version (PHQ-2); and Patient Determined Disease Steps (PDDS). Patients subsequently participated in a 45-minute semistructured telephone interview and were asked to describe their MS symptoms and to comment on how MS affected their day-to-day lives. More detailed questions followed on the nature of their fatigue, including symptoms, impacts, frequency, and bothersomeness. RESULTS: Patients' mean age was 52.5 years, mean time since diagnosis was 14.7 years, and 81.8% were female. 79.5% of patients were unemployed and/or receiving disability benefits. Of all spontaneously reported MS symptoms, fatigue was the most common (n=38, 86.4%), followed by ambulation problems (n=31, 70.5%) and muscle weakness (n=25, 56.8%). Patients used the words "tired," "exhausted," "wiped out," and having "little or no energy" to describe their fatigue. More patients rated fatigue as their "most troubling symptom" (n=17, 38.6%) compared with other MS-related symptoms. Half of patients reported feeling constantly fatigued, and more than 90% reported experiencing fatigue at least daily. The top three most frequently reported negative impacts of fatigue were social functioning, emotional well-being, and cognitive functioning (all >80%). Patients described themselves as "homebodies," as fatigue limited their social interactions with friends and family and impacted the types of activities they could participate in. Patients attributed their inability to think clearly or focus for long periods of time to their fatigue. Patients also reported experiencing depression and anxiety because of their fatigue, which would often have further negative effects on their relationships with friends and family. On the fatigue PRO measures, mean (standard deviation) scores were 75.2 (14.7) on the FSMC and 55.0 (15.2) on the MFIS. Most participants scored in the "high" fatigue category on the FSMC (84.1%) and above the clinically significant fatigue threshold (86.4%). MFIS and FSMC total scores correlated with PGI-F (polyserial correlations r=0.74 and r=0.62, both p<0.01) and PHQ-2 (r=0.56 and r=0.57, both p<0.01), but not with PDDS (r=0.09 and r=0.02, both p>0.05). CONCLUSIONS: Fatigue is a common, troublesome, and disabling symptom which has a profound impact on patients' daily lives, as evidenced by qualitative analyses and high scores on established fatigue measures observed in this sample. These findings provide insights into the burden of fatigue and can inform its measurement in both clinical and research settings. Treatments that improve the symptoms of fatigue or prevent exacerbations are needed for patients with progressive MS.