Development of an Item Bank to Assess Patient-Reported Outcomes: Signs, Symptoms, and Impacts of COVID-19.

BACKGROUND AND OBJECTIVE: Patients experience a wide range of signs, symptoms, and impacts related to coronavirus disease 2019 (COVID-19). A patient-reported outcome (PRO) item bank that measures the most relevant patient experiences is needed to fully evaluate treatment benefit in COVID-19 clinical trials. METHODS: A review of the literature and social media informed a novel PRO item bank of COVID-19 signs, symptoms, and impacts and general pandemic impacts. Twenty 1:1 concept elicitation and cognitive debriefing interviews were conducted with adults in the US who had symptomatic COVID-19. A conceptual model was developed and the PRO item bank refined following interviews. RESULTS: A heterogenous set of signs, symptoms, and impacts of COVID-19, as well as impacts associated with the pandemic overall, was identified. Fifty-five short-term and long-term signs and symptom items, 26 items assessing disease-related impacts, and seven items evaluating pandemic-related impacts are included in the item bank. CONCLUSIONS: The novel and preliminarily content-valid IQVIA COVID-19 Daily Diary Item Bank© and the IQVIA COVID-19 Weekly Diary Item Bank© were developed to measure signs and symptoms, their associated severity, and disease-related and pandemic-related impacts. The items are arranged in seven groups and can be individually selected based on research needs.

Qualitative interviews to improve patient-reported outcome measures in late-onset Pompe disease: the patient perspective.

BACKGROUND: Late-onset Pompe Disease (LOPD) is a rare, heterogeneous disease manifested by a range of symptoms varying in severity. Research establishing the frequency of these symptoms and their impact on patients' daily lives is limited. The objective of this study was to develop a conceptual model that captures the most relevant symptoms and functional limitations experienced by patients with LOPD, to inform the development of new patient-reported outcome (PRO) tools. METHODS: A preliminary conceptual model was constructed following a literature review and revised through interviews with expert clinicians to identify important and relevant concepts regarding symptoms and impacts of LOPD. This preliminary model informed the development of a qualitative patient interview guide, which was used to gather the patient perspective on symptoms and impacts relating to LOPD or its treatment (including symptom/impact frequency and levels of disturbance). Patient interviews aided further refinement of the conceptual model. The findings from the patient interviews were triangulated with the literature review and clinician interviews to identify the most relevant and significant effects of LOPD from the patient perspective. RESULTS: Muscle weakness, fatigue, pain, and breathing difficulties (especially while lying down) were the most common and highly disturbing symptoms experienced by patients. Limitations associated with mobility (e.g., difficulty rising from a sitting position, getting up after bending) and activities of daily living, (e.g., reduced ability to participate in social/family activities or work/study) were the most frequently reported impacts with the highest levels of disturbance on the patient's daily life. These identified symptoms and impacts were included in the new conceptual model of disease. CONCLUSIONS: This qualitative patient interview study, also informed by a literature review and clinician interviews, identified the most frequent and relevant symptoms and the functional impact of LOPD on patients. The study interviews also captured the patient-preferred language to describe symptoms and impacts of LOPD. The results from this study can be used to develop future PRO instruments that are tailored to the specific symptoms and impacts experienced by patients with LOPD.

Patient Global Impression of Benefit-Risk (PGI-BR): Incorporating Patients' Views of Clinical Benefit-Risk into Assessment of New Medicines.

INTRODUCTION: There is a need to understand how patients assess perceived benefits and risks of treatments. OBJECTIVES: The study aimed to (i) elucidate how patients evaluate treatment experiences and (ii) develop a brief patient-reported outcome (PRO) instrument for use across disease areas for perceived benefit-risk evaluation of a new medicine in a clinical trial setting. METHODS: Concepts relating to patient-perceived benefit-risk were identified from literature reviews and qualitative concept elicitation interviews with patients across a variety of primary medical conditions. Draft instrument items were developed from identified concepts and evaluated for clarity, relevance and appropriateness of response options in cognitive interviews. Items were iteratively revised to address patient feedback. RESULTS: Qualitative interviews were conducted with 47 patients (primary condition: 20 oncological, 12 respiratory, 10 metabolic, 5 cardiovascular), of whom 32 contributed to concept elicitation and 42 to cognitive debriefing. Elicited concepts could be grouped into four medication-related categories: effectiveness of treatment, burden of side effects, convenience of use and overall acceptance/satisfaction. Cost, trial experience and altruism were additional concept categories unrelated to medication. The final instrument contained one item each on the medication's effectiveness, side effects and convenience, and an overall item capturing patient benefit-risk assessment. An upfront question was included to separate out non-medication aspects of patients' experiences. CONCLUSION: We developed a brief PRO instrument, the Patient Global Impression of Benefit-Risk (PGI-BR), which can be applied across disease areas to assess patient views of benefit-risk of a new medicine in the clinical trial setting.

The patient's perspective on treatment with dacomitinib: patient-reported outcomes from the Phase III trial ARCHER 1050.

Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.

Prospective development of a patient-reported outcomes instrument for desmoid tumors or aggressive fibromatosis.

BACKGROUND: Desmoid tumors (or aggressive fibromatosis) are locally infiltrative connective-tissue tumors that can arise in any anatomic location; they can be asymptomatic, or they can result in pain, deformity, swelling, and loss of mobility and/or threaten visceral organs with bowel perforation, hydronephrosis, neurovascular damage, and other complications. Existing clinical trial endpoints such as the Response Evaluation Criteria in Solid Tumors (version 1.1) and progression-free survival are inadequate in capturing treatment efficacy. This study was designed to develop a novel clinical trial endpoint by capturing patient-reported outcomes (PROs). METHODS: Following best practices in qualitative methodology, this study used concept elicitation (CE) interviews to explore desmoid patients' perspectives on key disease-related symptoms and impacts. Qualitative analysis was performed to determine the relative frequency and disturbance of symptoms and impacts as well as other characteristics of these concepts. A draft PRO scale was then developed and tested with cognitive interviewing. Information from the interviews was subsequently incorporated into the refined PRO scale. RESULTS: CE interviews with desmoid patients (n = 31) helped to identify salient concepts and led to a draft scale that included symptom and impact scales. Cognitive interviews were completed with additional patients (n = 15) across 3 phases. Patient input was used to refine instructions, revise and/or remove items, and modify the response scale. This resulted in an 11-item symptom scale and a 17-item impact scale. CONCLUSIONS: This is the first disease-specific PRO instrument developed for desmoid tumors. The instrument is available as an exploratory endpoint in clinical trials. This study highlights the feasibility and challenges of developing PRO instruments for rare diseases.

Conceptual Model to Illustrate the Symptom Experience and Humanistic Burden Associated With Atopic Dermatitis in Adults and Adolescents.

Atopic dermatitis (AD) is a pruritic or painful dermatologic disease characterized by xerosis and eczema lesions. The symptoms/signs of AD can significantly impact patients' health-related quality of life (HRQoL). This study aimed to qualitatively explore the adult and adolescent experience of AD. A targeted literature review and qualitative concept elicitation interviews with clinicians (n = 5), adult AD patients (n = 28), and adolescent AD patients (n = 20) were conducted to elicit AD signs/symptoms and HRQoL impacts experienced. Verbatim transcripts were analyzed using thematic analysis. Twenty-nine symptoms/signs of AD were reported, including pruritus, pain, erythema, and xerosis. Atopic dermatitis symptoms/signs were reported to substantially impact HRQoL. Scratching was reported to influence the experience of symptoms and HRQoL impacts. Four proximal impacts (including discomfort and sleep disturbance) were reported. Ten domains of distal impact were reported, including impacts on psychological and social functioning and activities of daily living. A conceptual model was developed to summarize these findings. This study highlights the range of symptoms and HRQoL impacts experienced by adults and adolescents with AD. To our knowledge, this study was first to explore the lived experience of AD in both adult and adolescent patients, providing valuable insight into the relatively unexplored adolescent experience of AD.

Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial.

BACKGROUND: In the ongoing phase 3, CheckMate 214 trial, nivolumab plus ipilimumab improved overall survival compared with sunitinib in patients with intermediate or poor risk, previously untreated, advanced renal cell carcinoma. We aimed to assess whether health-related quality of life (HRQoL) could be used to further describe the benefit-risk profile of nivolumab plus ipilimumab versus sunitinib. METHODS: In the phase 3, randomised, controlled, CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg/day for 4 weeks of each 6-week cycle. Randomisation was done with a block size of four and stratified by risk status and geographical region. Patient-reported outcomes (PROs) were assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five dimensional three level (EQ-5D-3L) instruments. The coprimary endpoints of the trial, reported previously, were overall survival, progression-free survival, and the proportion of patients who had an objective response in those categorised as at intermediate or poor risk. PROs in all randomised participants were assessed as an exploratory endpoint; here we report this exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but is now closed to recruitment. FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) were randomly assigned to treatment, of whom 847 (77%) were at intermediate or poor risk and randomly assigned to nivolumab plus ipilimumab (n=425) or sunitinib (n=422). Median follow-up was 25·2 months (IQR 23·0-27·4). PROs were more favourable with nivolumab plus ipilimumab than sunitinib throughout the first 103 weeks after baseline, with mean change from baseline at week 103 for FKSI-19 total score being 4·00 (95% CI 1·91 to 6·09) for nivolumab plus ipilimumab versus -3·14 (-6·03 to -0·25) for sunitinib (p<0·0001), and for FACT-G total score being 4·77 (1·73 to 7·82) for nivolumab plus ipilimumab versus -4·32 (-8·54 to -0·11) for sunitinib (p=0·0005). Significant differences were also seen for four of five FKSI-19 domains (disease-related symptoms, physical disease-related symptoms, treatment side-effects, and functional wellbeing) and FACT-G physical and functional wellbeing domains. However, there was no significant difference between the treatment groups at week 103 in EQ-5D-3L visual analogue rating scale (VAS) scores, with mean change from baseline to week 103 of 10·07 (95% CI 4·35 to 15·80) for nivolumab plus ipilimumab and 6·40 (-1·36 to 14·16) for sunitinib (p=0·45). Compared with sunitinib, nivolumab plus ipilimumab reduced risk of deterioration in FKSI-19 total score (hazard ratio [HR] 0·54; 95% CI 0·46-0·63), FACT-G total score (0·63, 0·52-0·75), and EQ-5D-3L VAS score (HR 0·75, 95% CI 0·63-0·89) and UK utility scores (0·67, 0·57-0·80). INTERPRETATION: Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL. FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.

Symptoms and Impacts in Metastatic Castration-Resistant Prostate Cancer: Qualitative Findings from Patient and Physician Interviews.

BACKGROUND: There is little information available on health-related quality of life in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. This study aimed to develop a conceptual model that describes patients' experiences of living with this condition. METHODS: This was a cross-sectional, non-interventional qualitative research study. Sixty-minute semi-structured interviews were conducted with physicians experienced in treating metastatic castration-resistant prostate cancer and with chemotherapy-naïve patients with metastatic castration-resistant prostate cancer. Interviews were audio-recorded and transcripts were analysed to identify the key symptoms and impacts on quality of life. Results were used to expand a previously published conceptual model for non-metastatic castration-resistant prostate cancer. RESULTS: Three physicians and 19 patients with metastatic castration-resistant prostate cancer were interviewed. Physicians identified several symptoms frequently mentioned by their patients: fatigue, bone pain, anxiety, stress, depression and interference with daily activities. The most salient symptoms emerging from the patient interviews were urinary frequency and urgency, fatigue, pain/stiffness and sexual dysfunction. The most salient impacts were interference with daily activities, frustration, anxiety and sleep problems. Compared with non-metastatic castration-resistant prostate cancer, some symptoms and impacts in metastatic castration-resistant prostate cancer were more common and rated as more disturbing (e.g. fatigue, pain, urinary frequency, interference with daily activities and frustration). New concepts that were added to the non-metastatic castration-resistant prostate cancer model, to more accurately reflect the experiences of patients with metastatic disease, were enlarged breasts, muscle loss/deconditioning, inability to focus/mental slowing, body image perception, interference with work and lack of ambition/motivation. CONCLUSIONS: Chemotherapy-naïve patients with metastatic castration-resistant prostate cancer experience a substantial burden from their condition. Furthermore, as castration-resistant prostate cancer progresses from the non-metastatic stage to the early metastatic (pre-chemotherapy) stage, certain symptoms become more common and disturb patients' lives to a greater extent. The resulting conceptual model for metastatic castration-resistant prostate cancer highlights areas that are not adequately assessed with current patient-reported outcome instruments.

The Potential Role of Individual-Level Benefit-Risk Assessment in Treatment Decision Making: A DIA Study Endpoints Community Workstream.

Benefit-risk assessment is the cornerstone of decision making in medical care, playing a critical role in bringing treatments to market by informing decisions regarding drug development, licensing and reimbursement, and informing treatment decisions made by health care professionals and patients in clinical practice. In regulatory approval decision making, benefit and risk attributes are identified and defined based on available, aggregated clinical data from registration trials. In the context of major developments in recent years for involvement of patients as partners in all phases of drug development and in health care improvement, decision makers increasingly recognize the importance of informing treatment decisions by patient needs, values, experiences, and preferences. Using this as a basis, a DIA workstream was convened to explore the potential of individual-level benefit-risk assessment as a supplement to traditional group-level benefit-risk assessment for evaluating treatment. Various approaches as to how this information could be collected, including via patient-reported outcome measures, open-ended questioning, and stated-preference methods are presented. The utility of this information for various stakeholders is discussed.

Development and content validation of a patient-reported endometriosis pain daily diary.

BACKGROUND: Endometriosis is a common gynecological disorder that causes inflammation and pelvic pain. Endometriosis-related pain is best captured with patient-reported outcome (PRO) measures, however, assessment of endometriosis-related pain in clinical trials has been difficult in the absence of a reliable and valid PRO instrument. We describe the development of the Endometriosis Pain Daily Diary (EPDD), an electronic PRO developed as a survey instrument to assess endometriosis-related pain and its impact on patients' lives. METHODS: The EPDD was initially developed on the basis of an existing Endometriosis Pain and Bleeding Diary, a targeted review of relevant literature, clinical expert interviews, and open-ended (concept elicitation) patient interviews in the United States (US) and Japan which captured patients' experience with endometriosis. Cognitive interviews of patients with endometriosis were conducted to evaluate patient comprehension of the EPDD items. A conceptual model of endometriosis was developed, and meetings with US and European regulatory authorities provided feedback for validating the EPDD in the context of clinical trials. Translatability assessments of the EPDD were conducted to confirm its appropriate interpretation and ease of completion across 17 languages. RESULTS: The iterative development progressed through three versions of the instrument. The EPDDv1 included 18 items relating to dysmenorrhea/pelvic pain, dyspareunia and sexual activity, bleeding, hot flashes, daily activities, and use of rescue medication. The EPDDv2 was a larger 43-item survey tested in cognitive interviews and subsequently revised to yield the current 11-item EPDDv3, consisting of five core items relating to dysmenorrhea, non-menstrual pelvic pain, and dyspareunia, and six extension items relating to sexual activity, daily activities, and use of rescue medication. CONCLUSIONS: The EPDD is a PRO for the evaluation of endometriosis-related pain and its associated impacts on patients' lives. The EPDD represents an important step in providing a PRO that is relevant to patients with endometriosis-related pain in the context of a clinical study setting (ie, fit-for-purpose), designed to evaluate pain associated with endometriosis, including regulatory agency support for its further exploration in clinical trials.

Understanding polycystic ovary syndrome from the patient perspective: a concept elicitation patient interview study.

BACKGROUND: The aim of this study was to explore the need for a new disease-specific patient reported outcome (PRO) measure for use in clinical trials of drugs designed to target the underlying causes of polycystic ovary syndrome (PCOS), and in the process contribute to our understanding of the symptoms and impacts that define the patient experience with PCOS. METHODS: Semi-structured interviews were conducted in 20 women diagnosed with PCOS according to the Rotterdam criteria who had not menstruated in the previous month. The relative importance of PCOS symptoms and impact concepts to patients was determined by analyzing the frequency of their expression in the interview transcripts. These insights were compared to clinicians' perceptions of PCOS. RESULTS: Pain- and discomfort-related symptoms accounted for the highest proportion (27.6%) of the 735 patient expressions, although clinicians did not consider pain to be important to patients with PCOS. The most frequently expressed individual symptoms were cramping (70% of patients; 14.7% of concepts), irregular menstruation (95% of patients; 12.2% of concepts), facial hair growth (75% of patients; 10.6% of concepts), heavy bleeding (70% of patients; 8.8% of concepts), infertility (70% of patients; 5.4% of concepts), and bloating (60% of patients; 5.2% of concepts). Cramping, heavy bleeding, and bloating were not identified by clinicians as being important to patients with PCOS. The impacts most frequently reported by patients with PCOS related to emotional well-being (e.g. anxiety/stress) and coping behaviors (e.g. acne medication, hair removal). CONCLUSIONS: The only validated PCOS-specific PRO, the PCOSQ, does not capture some key PCOS symptoms and impacts expressed by patients with PCOS, most notably those related to pain and discomfort, bleeding intensity and coping behaviours. Furthermore, some key PCOS symptoms may be under-recognized in the clinic.

Interactive Voice Response and Text-based Self-report Versions of the Electronic Columbia-Suicide Severity Rating Scale Are Equivalent.

Objectives: Our study objective was to compare the equivalence of a new version of the electronic Columbia-Suicide Severity Rating Scale that was administered on a tablet device with the existing interactive voice response version in order to support the prospective monitoring of suicidal ideation and behavior in clinical trials and clinical practice. Design: This was a randomized, crossover-equivalence study with no treatment intervention. Setting: The study setting was a psychiatric hospital. Participants: Fifty-eight recently admitted psychiatric inpatients and 28 employees of the hospital site were included in the study. Mean age was 41.0 years (standard deviation=12.5), and 59 percent were female. Measurements: Participants completed both tablet and interactive voice response versions in randomized order, with a 25-minute break between administrations. Finally, participants completed a second administration of the first administered version. Intraclass correlation coefficients (ICCs) and Kappa coefficients were used to evaluate agreement across modalities. Results: High levels of agreement were observed for most severe lifetime (ICC=0.88) and recent (ICC=0.79) ideation, occurrence of actual lifetime (Kappa=0.81) and recent (Kappa=0.73) suicide attempts, and occurrence of lifetime interrupted attempts (Kappa=0.78), aborted attempts (Kappa=0.54), and preparatory behaviors (Kappa=0.77), as well as non-suicidal self-injurious behavior (Kappa=0.73). Scores from both modes significantly differentiated psychiatric patients and hospital employee controls, and the test-retest reliability of both modes was excellent. Conclusions: These results support the validity and reliability of the new tablet-based electronic Columbia-Suicide Severity Rating Scale. This will allow the inclusion of the electronic Columbia-Suicide Severity Rating Scale in a wider range of clinical studies, particularly where a tablet is also being used to collect other study data.

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.

Talking About Breast Cancer: Which Symptoms and Treatment Side Effects are Important to Patients with Advanced Disease?

BACKGROUND: Patients' experience of symptoms and associated treatment is an increasingly important consideration in both regulatory and health technology assessments, and can inform treatment decisions. OBJECTIVE: This study aimed to gain insight directly from patients with advanced breast cancer about which symptoms and treatment side effects are important to them. METHODS: Women with locally advanced or metastatic breast cancer were interviewed individually by trained interviewers, using a semi-structured interview guide. Verbatim transcripts were analyzed qualitatively, including whether symptoms were mentioned spontaneously (indicating their importance to patients) or only when questioned directly. RESULTS: Sixteen women (aged 38-74 years) participated. The most commonly reported symptom aspects were: pain (16/16 [all reported spontaneously]); feeling tired/fatigued (15/16 [12 spontaneously]); changes in weight (15/16 [2 spontaneously]); hair loss (15/16 [5 spontaneously]); changes in appetite (11/16 [8 spontaneously]); nausea (9/16 [all spontaneously]). Pain was attributed mostly to the disease or to its treatment. Tiredness, changes in weight/appetite, and hair loss were attributed mostly to the treatment. All women (14 spontaneously) reported that the cancer affected their emotional well-being and their ability to perform daily activities. CONCLUSIONS: Further qualitative research is needed to understand how patients distinguish cancer-related symptoms from treatment-related side effects, to gain insight into which patient experiences should be measured and how best to measure them.

Content Validity for the VVSymQ® Instrument: A New Patient-Reported Outcome Measure for the Assessment of Varicose Veins Symptoms.

BACKGROUND: Varicose veins are common and can impact patients' quality of life, but consensus regarding the evaluation of varicose vein symptoms is lacking and existing measures have limitations. OBJECTIVE: This research aimed to develop and establish the content validity of a new electronic patient-reported outcome (PRO) measure, the VVSymQ® instrument, to assess symptoms of superficial venous insufficiency (varicose veins) in clinical trials. METHODS: The development of the VVSymQ® instrument began with qualitative interviews with patients based on the symptom domain of the VEINES-QOL/Sym, an existing PRO instrument for chronic venous disorders of the leg. Three phases of qualitative research were conducted to examine the relevance and importance of the symptoms to patients with varicose veins, and the patients' ability to understand and use the VVSymQ® instrument. The development included evaluating questions that had 1-week and 24-h recall periods, and paper and electronic versions of the new instrument. RESULTS: Five symptoms (heaviness, achiness, swelling, throbbing, and itching [HASTI™]) were consistently reported by patients across all sources of qualitative data. The final version of the VVSymQ® instrument queries patients on the HASTI™ symptoms using a 24-h recall period and a 6-point duration-based response scale ranging from "None of the time" to "All of the time," and is administered daily via an electronic diary. Cognitive interviews demonstrated varicose vein patients' understanding of and their ability to use the final version of the VVSymQ® instrument. CONCLUSION: Content validity was established for the VVSymQ® instrument, which assesses the five HASTI™ symptoms of varicose veins daily via an electronic diary and has promise for use in research and practice.

Psychometric Evaluation of a New Patient-Reported Outcome (PRO) Symptom Diary for Varicose Veins: VVSymQ(®) Instrument.

OBJECTIVE: To evaluate the psychometric properties of the VVSymQ(®) instrument, a new 5-item patient-reported outcome (PRO) measure for symptoms of varicose veins. METHOD: The VVSymQ(®) electronic daily diary was administered to outpatients who received routine treatment for varicose veins (N = 40). Compliance with diary administration and item score variability, reliability, construct validity, sensitivity to change, and clinically meaningful change were evaluated. RESULTS: Patients completed >97 % of scheduled diary assessments (at screening, baseline, and week 8). The VVSymQ(®) instrument captured patients' pre-treatment symptoms (all VVSymQ(®) symptoms were endorsed by ≥75 % of patients at baseline), and the change post-treatment (mean change in score -6.1), with a large Cohen effect size (1.6). Test-retest reliability was high (intraclass correlation coefficient 0.96); internal consistency was good (Cronbach's alpha ≥0.76; baseline, week 8). VVSymQ(®) scores were more strongly associated with PRO scores that reflect symptoms and symptom impact (the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms [VEINES-QOL/Sym] instrument and the Chronic Venous Insufficiency Quality-of-Life Questionnaire [CIVIQ-20]) than with PRO scores that reflect appearance (the Patient Self-Assessment of Appearance of Visible Varicose Veins [PA-V(3)]) or clinician-reported outcome scores (the Clinical-Etiology-Anatomy-Pathophysiology [CEAP] Classification of Venous Disorders and Venous Clinical Severity Score [VCSS]), demonstrating construct validity. Patients reporting that symptoms were "moderately" or "much improved" on the Patient Global Impression of Change (PGIC) anchor (i.e., >97 % of patients) had mean improvements of -6.3 VVSymQ(®) points, while a cumulative distribution curve showed that 50 % of patients improved by ≥-5.8 points; thus, a score change of approximately -6 demonstrated a clinically meaningful change in this study. The clinically meaningful change in the VVSymQ(®) score was greater in patients with a greater baseline VVSymQ(®) symptom burden, and the VVSymQ(®) instrument captured clinically meaningful treatment benefit even in patients with a low baseline symptom burden. CONCLUSION: The 5-item VVSymQ(®) instrument is a brief, psychometrically sound, useful tool for evaluating patient-reported varicose veins symptoms.

Practical Considerations for the Use of Clinical Outcome Assessments (COAs) in Pediatric Clinical Research: Examples From Pediatric Gastroenterology.

Clinical outcome assessments (COAs), including patient-reported outcome (PRO) measures, are routinely used in drug development and other clinical research initiatives to assess the impact of treatment on patient health and well-being. The FDA Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (2009), the European Medicines Agency's Reflection Paper on the Regulatory Guidance for the Use of Health-Related Quality of Life Measures in the Evaluation of Medicinal Products (2005), and the International Society for Pharmacoeconomics and Outcomes Research PRO Good Research Practices for the Assessment of Children and Adolescence Task Force (2013) outline key considerations and good measurement principles that are relevant to the selection and use of COAs in a pediatric population. However, challenges remain in the appropriate selection and use of COAs to assess treatment benefit in pediatric clinical research. The purpose of this paper is to summarize proceedings from a panel presentation at the Critical Path Institute's 2015 Annual PRO Consortium Workshop. This paper underscores the importance of considering children's specific needs and the numerous challenges faced when developing and implementing well-defined and reliable COAs in pediatric clinical trials evaluating medical products, and describes some approaches to addressing these unique needs and challenges.

The Patient Perspective on Living with Acute Myeloid Leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) imposes significant burden on patients, their families, and the healthcare system. Published literature has reported many AML signs and symptoms, as well as their impact on patients. However, there are no publications on the experience of living with AML from the patient's perspective. In this study, we performed qualitative interviews with patients with AML to understand their experience. METHODS: Participants were recruited from the US and Japan. All patients were screened to assess eligibility, and were divided into four subgroups (i.e., newly-diagnosed, high-intensity chemotherapy; newly-diagnosed, low-intensity chemotherapy; relapse/refractory; and post-transplant). Patients were interviewed over the phone by a trained researcher and asked about their day-to-day experience with AML. Signs/symptoms and impacts were coded, analyzed using Atlas.ti software, and reported as frequencies, with the medians of patient-reported disturbance levels (0-10) computed for each symptom and impact. RESULTS: The most commonly reported sign/symptom in the US was fatigue (95.7%), followed by bruising and weakness (both 78.3%), and in Japan, nausea (94.4%), followed by fatigue and headache (both 88.9%). The most commonly reported impact in the US was a decreased ability to maintain social/familial roles (91.3%), followed by anxiety and a decreased ability to function (both 87.0%), and most commonly reported in Japan was anxiety, a decreased ability to function, and remission uncertainty (94.4%). CONCLUSION: Although the frequency of signs/symptoms and their level of disturbance varied between the US and Japan, there was remarkable consistency in the types of signs/symptoms and impacts reported across all patients. The consistency in the experience of the disease across patients suggests that measurement of AML experience can be achieved by using the same tool for most, if not all, of these patients. FUNDING: Astellas Pharma Inc., Northbrook, IL, USA.

The VVSymQ® instrument: Use of a new patient-reported outcome measure for assessment of varicose vein symptoms.

INTRODUCTION: No existing patient-reported outcome instrument focuses solely on assessment of varicose veins symptoms that are bothersome to patients. METHODS: The VVSymQ® instrument is a five-item patient-reported outcome that assesses symptoms most important to patients with varicose veins (heaviness, achiness, swelling, throbbing and itching). This paper describes how the VVSymQ® instrument was incorporated into an electronic daily diary to monitor key outcomes over time and capture treatment benefit in two randomized, controlled, phase 3 clinical trials. RESULTS: Patients were highly compliant in completing the electronic daily diary, and the VVSymQ® instrument demonstrated ability to detect overall change and ability to detect change that is meaningful to patients. CONCLUSION: The VVSymQ® instrument is a reliable, valid instrument responsive to measuring change in the patient experience of varicose vein symptoms pre- and post-intervention, and is uniquely focused on patient-reported symptoms compared with other widely used questionnaires completed by clinicians.

Electronic bladder diaries of differing duration versus a paper diary for data collection in overactive bladder.

AIMS: This observational study compared data values, reliability, consistency and compliance collected by electronic and paper diaries of differing durations. METHODS: Subjects ≥18 years with overactive bladder (OAB) on stable antimuscarinic treatment for ≥12 weeks were assigned to one of five, 15-week diary schedules in this randomized, parallel-group observational study. Sample size was sufficient to assess reliability and consistency of diary data with adequate precision. Reliability was assessed via intraclass correlation coefficients, variability with ANCOVAs, and consistency using Cronbach's alpha. RESULTS: Demographic characteristics of randomized subjects were representative of OAB trial populations. For mean volume voided, reliability was comparable across diary groups. For incontinence, reliability improved with increasing diary duration. For micturition frequency, electronic 7-day diary results had highest reliability and lowest variability. Lowest overall reliability was observed in the 3-day paper diary. Consistency was highest in the electronic continuous groups; Cont A (daily measurements throughout the study period [fully Continuous]) and Cont B (daily measurements for some but not all endpoints of interest [Partially Continuous]). Compliance was generally high; across groups ≥90% of diaries had at least one entry per day. There was no significant change in average micturition frequency with diary duration, suggesting no diary fatigue. One-third of subjects in the electronic Cont B group also reported micturitions as incontinence when they only needed to report incontinence; they also reported lowest satisfaction with the study. The electronic 7-day and electronic Cont A schedules (who reported incontinence and micturitions throughout the study) had lowest residual errors. CONCLUSIONS: For future OAB trials, 7-day or continuous electronic diaries may improve accuracy and reliability of micturition and incontinence frequency data compared with shorter collection periods and paper diaries. Neurourol. Urodynam. 35:743-749, 2016. © 2015 Wiley Periodicals, Inc.