Incorporating development of a patient-reported outcome instrument in a clinical drug development program: examples from a heart failure program.

BackgroundPatient-reported outcome (PRO) measures can be used to support label claims if they adhere to US Food & Drug Administration guidance. The process of developing a new PRO measure is expensive and time-consuming. We report the results of qualitative studies to develop new PRO measures for use in clinical trials of omecamtiv mecarbil (a selective, small molecule activator of cardiac myosin) for patients with heart failure (HF), as well as the lessons learned from the development process.MethodsConcept elicitation focus groups and individual interviews were conducted with patients with HF to identify concepts for the instrument. Cognitive interviews with HF patients were used to confirm that no essential concepts were missing and to assess patient comprehension of the instrument and items.ResultsDuring concept elicitation, the most frequently reported HF symptoms were shortness of breath, tiredness, fluid retention, fatigue, dizziness/light-headedness, swelling, weight fluctuation, and trouble sleeping. Two measures were developed based on the concepts: the Heart Failure Symptom Diary (HF-SD) and the Heart Failure Impact Scale (HFIS). Findings from cognitive interviews suggested that the items in the HF-SD and HFIS were relevant and well understood by patients. Multiple iterations of concept elicitation and cognitive interviews were needed based on FDA request for a broader patient population in the qualitative study. Lessons learned from the omecamtiv mecarbil PRO/clinical development program are discussed, including challenges of qualitative studies, patient recruitment, expected and actual timelines, cost, and engagement with various stakeholders.ConclusionDevelopment of a new PRO measure to support a label claim requires significant investment and early planning, as demonstrated by the omecamtiv mecarbil program

Ultimate pH values and bacteriological condition of meat and stress metabolites in blood of transported reindeer bulls

Twenty-three reindeer bulls, aged 2-3 years, fed during two winter months at the Vuolda reindeer research station in Arjeplog, Sweden, were used in the study. The first group of eight reindeer was moved from their feeding corral to a selection corral, captured by lasso and stunned with a captive bolt outside the selection corral. The second group of seven reindeer was moved to the selection corral, captured by lasso and restrained, after which they were loaded onto a lorry- and transported for 1 hour and then slaughtered. The third group of eight reindeer was moved to the selection corral and herded directly onto the lorry, without any manual handling. They were transported for 5 h and then slaughtered. In both transport groups, four reindeer were fitted with pre-programmed automatic blood sampling equipment (ABSE). ABSE sampled blood at predetermined times via a jugular vein catheter. Ultimate pH-values in three muscles (Mm. longissimus, triceps brachii and biceps femoris) were significantly lower in the group carefully handled and transported for 5 h compared with the other two groups. The physiological mechanisms behind these results are discussed. Samples from M. semimembranosus were collected at slaughter and after 2, 6 and 10 days of refrigerated storage (+4 °C). The samples were analysed for total counts of aerobic bacteria (pour-plated in Tryptone Glucose Extract Agar, Difco, incubated at 20 °C and 30 °C, respectively for 72 h), coliform bacteria 37 °C (pour-plated in Violet Red Bile Agar, Oxoid, incubated at 37 °C for 24 h), Enterococci (surface-plated onto Slantez and Bartley Agar, Oxoid, incubated at 44 °C for 48 h) and Bacillus cereus (surface-plated onto Blood Agar Plates (Blood Agar Base, Difco, supplemented with 5% defibrinated horse blood) 30 °C for 24 h). All samples fell in the range 'fit for consumption'. At slaughter, there was no difference in ASAT activity, urea and Cortisol concentrations between the two transported groups. However, the plasma ASAT activity and urea concentrations at slaughter were significantly lower in the non-transported group. In both transport groups, the plasma Cortisol concentrations increased during loading onto and unloading from the lorry. Abomasal lesions were observed in all treatment groups. It was concluded that reindeer showed an acute stress response to manual handling and transport

Development and validation of the short version of the Psychological General Well-Being Index (PGWB-S)

BACKGROUND: The PGWBI is a 22-item health-related Quality of Life (HRQoL) questionnaire developed in US which produces a self-perceived evaluation of psychological well-being expressed by a summary score. The PGWBI has been validated and used in many countries on large samples of the general population and on specific patient groups. Recently a study was carried out in Italy to reduce the number of items of the original questionnaire, yielding the creation of a shorter validated version of the questionnaire (PGWB-S). The purpose of the present paper is to describe the methods adopted and to report and discuss the relevance of results. METHODS: Data for this study were collected from 4 different population samples: two general population samples a student and a patient sample. On the basis of the results of the first (development) sample population, six relevant items were identified statistically from the original questionnaire and grouped to assemble a new summary scale. Following the newly created 6-item questionnaire was administered in three independent population samples. Descriptive statistics, correlation coefficients, univariate and multivariate regression analyses were used to compare the performance of the long and short questionnaire, within and between population samples and across relevant subgroups. A further independent sample extracted by an ongoing cancer clinical trial served as final validation step. RESULTS: Overall, the questionnaires were administered to 1443 subjects. Six items were selected by a step-wise approach to explain 90% of the variance of the summary measure of the original questionnaire. Response rates reached 100%, while missing items were not observed. University students (n = 400) showed the highest mean value of the summary measure (75.3); while the patient sample (n = 28) had the lowest score (71.5). The correlation coefficients between the summary measures and the single items according to the different studies were satisfactory, reaching the highest estimates in the student sample. The internal consistency showed high values of the Cronbach's alpha coefficient (range 0.80 – 0.92) for all three study samples, coming close to the value of the coefficient established for the original questionnaire (0.94). A cross-validation in an independent sample of 755 cancer patients confirmed the item selection procedure and amount of variance explained by the new shorter questionnaire (ranging from 90. 2 to 95.1 %, across age and sex strata). CONCLUSION: The newly identified PGWB-S showed good acceptability and validity for the use in various settings in Italy. The translation of the PGWB-S into different languages, and its use in other linguistic settings will add evidence about its cross-cultural validity

Impact of gastroesophageal reflux disease on patients' daily lives: a European observational study in the primary care setting

<p>Abstract</p> <p>Background</p> <p>The impact of gastroesophageal reflux disease (GERD) on the daily lives of patients managed in primary care is not well known. We report the burden of GERD in a large population of patients managed in primary care, in terms of symptoms and impact on patients' daily lives.</p> <p>Methods</p> <p>RANGE (<it>R</it>etrospective <it>AN</it>alysis of <it>GE</it>RD) was an observational study that was conducted at 134 primary care sites across six European countries. All adult subjects who had consulted their primary care physician (PCP) during a 4-month identification period were screened retrospectively and those consulting at least once for GERD-related reasons were identified. From this population, a random sample of patients was selected to enter the study and attended a follow-up appointment, during which the Reflux Disease Questionnaire (RDQ), the GERD Impact Scale (GIS) and an extra-esophageal symptoms questionnaire were self-administered. Based on medical records, data were collected on demographics, history of GERD, its diagnostic work-up and therapy.</p> <p>Results</p> <p>Over the 4-month identification period, 373,610 subjects consulted their PCP and 12,815 (3.4%) did so for GERD-related reasons. From 2678 patients interviewed (approximately 75% of whom reported taking medication for GERD symptoms), symptom recurrence following a period of remission was the most common reason for consultation (35%). At the follow-up visit, with regard to RDQ items (score range 0–5, where high score = worse status), mean Heartburn dimension scores ranged from 0.8 (Sweden) to 1.2 (UK) and mean Regurgitation dimension scores ranged from 1.0 (Norway) to 1.4 (Germany). Mean overall GIS scores (range 1–4, where low score = worse status) ranged from 3.3 (Germany) to 3.5 (Spain). With regard to extra-esophageal symptoms, sleep disturbance was common in all countries in terms of both frequency and intensity.</p> <p>Conclusion</p> <p>In this large European observational study, GERD was associated with a substantial impact on the daily lives of affected individuals managed in the primary care setting.</p

Impact of gastroesophageal reflux disease on work absenteeism, presenteeism and productivity in daily life: a European observational study

<p>Abstract</p> <p>Background</p> <p>The RANGE (<it>R</it>etrospective <it>AN</it>alysis of <it>G</it>astro<it>E</it>sophageal reflux disease [GERD]) study assessed differences among patients consulting a primary care physician due to GERD-related reasons in terms of: symptoms, diagnosis and management, response to treatment, and effects on productivity, costs and health-related quality of life. This subanalysis of RANGE determined the impact of GERD on productivity in work and daily life.</p> <p>Methods</p> <p>RANGE was conducted at 134 primary care sites across six European countries (Germany, Greece, Norway, Spain, Sweden and the UK). All subjects (aged ≥18 years) who consulted with their primary care physician over a 4-month identification period were screened retrospectively, and those consulting at least once for GERD-related reasons were identified (index visit). From this population, a random sample was selected to enter the study and attended a follow-up appointment, during which the impact of GERD on productivity while working (absenteeism and presenteeism) and in daily life was evaluated using the self-reported Work Productivity and Activity Impairment Questionnaire for patients with GERD (WPAI-GERD).</p> <p>Results</p> <p>Overall, 373,610 subjects consulted with their primary care physician over the 4-month identification period, 12,815 for GERD-related reasons (3.4%); 2678 randomly selected patients attended the follow-up appointment. Average absenteeism due to GERD was highest in Germany (3.2 hours/week) and lowest in the UK (0.4 hours/week), with an average of up to 6.7 additional hours/week lost due to presenteeism in Norway. The average monetary impact of GERD-related work absenteeism and presenteeism were substantial in all countries (from €55/week per employed patient in the UK to €273/patient in Sweden). Reductions in productivity in daily life of up to 26% were observed across the European countries.</p> <p>Conclusion</p> <p>GERD places a significant burden on primary care patients, in terms of work absenteeism and presenteeism and in daily life. The resulting costs to the local economy may be substantial. Improved management of GERD could be expected to lessen the impact of GERD on productivity and reduce costs.</p