Search

To characterize a US population of patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) using CONTOR, a real-world longitudinal research platform that deterministically linked administrative claims data with patient-reported outcomes data among patients with these conditions.Patients with IBS-C or CIC were identified using diagnosis and treatment codes from administrative claims. Potential respondents received a mailed survey followed by 12 monthly online follow-up surveys and 2 mailed diaries. Surveys collected symptom severity, treatment use, quality of life, productivity, and condition/treatment history. Comorbidities and healthcare costs/utilization were captured from claims data. Diaries collected symptoms, treatments, and clinical outcomes at baseline and 12 months. Data were linked to create a patient-centric research platform.Baseline surveys were returned by 2,052 respondents (16.8% response rate) and retention rates throughout the study were high (64.8%-70.8%). Most participants reported burdensome symptoms despite having complex treatment histories that included multiple treatments over many years. More than half (55.3%) were dissatisfied with their treatment regimen; however, a higher proportion of those treated with prescription medications were satisfied.The study sample may have been biased by patients with difficult-to-treat symptoms as a result of prior authorization processes for IBS-C/CIC prescriptions. Results may not be generalizable to uninsured or older populations because all participants had commercial insurance coverage.By combining administrative claims and patient-reported data over time, CONTOR afforded a deeper understanding of the IBS-C/CIC patient experience than could be achieved with 1 data source alone; for example, participants self-reported burdensome symptoms and treatment dissatisfaction despite making few treatment changes, highlighting an opportunity to improve patient management. This patient-centric approach to understanding real-world experience and management of a chronic condition could be leveraged for other conditions in which the patient experience is not adequately captured by standardized data sources.

Objectives The Diary for Irritable Bowel Syndrome Symptoms–Constipation (DIBSS-C) has been developed to assess the core signs and symptoms of irritable bowel syndrome with constipation (IBS-C). This article presents the psychometric evaluation of the DIBSS-C abdominal score. Methods Data for these analyses are from a multicenter phase IIb study in IBS-C patients (NCT02559206). Subjects completed a number of assessments via handheld electronic diary throughout the study. The analyses used the intent-to-treat population and were blinded to randomized treatment group. The analyses evaluated the reliability, validity, and responsiveness of the DIBSS-C abdominal score; identified an appropriate scoring algorithm; and determined thresholds for interpreting clinically meaningful changes at the individual level. Results The correlations between the DIBSS-C abdominal symptom items (ie, abdominal pain, discomfort, and bloating) were strong (>0.75). Cronbach’s alpha for the abdominal symptom severity items was very strong (.94), indicating that the 3 abdominal symptom items produce a reliable score. The intraclass correlation coefficient for the abdominal score was 0.82, exceeding the threshold of 0.70 and indicating good test–retest reliability. Guyatt’s responsiveness statistic values all exceeded the threshold for a large effect of 0.80, so the DIBSS-C abdominal score can be considered highly responsive to change. Triangulation across 3 sets of anchor-based analyses indicated that a threshold of −2.0 points on the abdominal score is an appropriate threshold for identifying meaningful change. Conclusions Overall, this study provides evidence that the DIBSS-C abdominal score is valid, reliable, responsive to change, and interpretable for assessing treatment benefit in patients with IBS-C.

Supplemental Digital Content is available in the text., Goals: This study aimed to characterize the impact of stool consistency on patient-reported bowel movement (BM) satisfaction in patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation, with a focus on linaclotide. Background: As new medications for constipation become available, understanding patients’ perceptions of treatment effects may help clinicians manage patient expectations and inform clinical decision-making. Materials and Methods: Data were derived from the Chronic Constipation and IBS-C Treatment and Outcomes Real-world Research Platform (CONTOR) study from 2 patient-reported 7-day daily BM diaries to create a dataset of 2922 diaries representing 26,524 BMs for 1806 participants. Binary variables were created for: medication(s) used in the past 24 hours and categorization of BMs as loose or watery stools (LoWS), hard or lumpy stools (HoLS), or intermediate (neither LoWS nor HoLS). The relationship between stool consistency, medication use, and BM satisfaction was analyzed using logistic regression with SEs corrected for repeated observations. Results: BMs characterized as intermediate stools and LoWS were satisfactory more often (61.2% and 51.2%, respectively) than HoLS (19.4%). Participants who reported taking linaclotide rated a similar proportion of BMs as satisfactory when described as LoWS (65.6%) or intermediate (64.1%). Linaclotide use was associated with higher odds of BMs being reported as satisfactory compared with nonlinaclotide use (odds ratio: 1.23, P

A review of new drug approvals (NDAs) by the US Food and Drug Administration (FDA) for 2006 to 2015 showed that approximately 20% of new drugs had labeling based on patient-reported outcomes (PROs). The purpose of this study was to review labeling text based on PRO endpoints for NDAs from 2016 to 2020, with a special focus on the comprehensibility of such statements when included.We reviewed drug approval reports on the Drugs@FDA web page of the FDA website to determine the number of NDAs from 2016 to 2020. For all identified NDAs, drug approval package and product labels were reviewed. NDAs from 2016 to 2020 were grouped by disease category as per International Classification of Diseases 10th Revision. Data were summarized for diseases that traditionally rely on PROs for evaluating treatment benefit (PRO dependent) and for diseases that traditionally do not rely on PROs (non-PRO dependent). Results were compared with NDAs from 2006 to 2010.NDAs amounting to 228 were identified from 2016 to 2020, 26.3% of which had labeling statements based on PRO endpoints. From 2006 to 2015 and from 2016 to 2020, PRO labeling statements were included in 46.5% (46 of 99) and 50.0% (47 of 94), respectively, of NDAs for PRO-dependent new molecular entities and in 6.0% (12 of 199) and 9.7% (13 of 199), respectively, of NDAs for non-PRO-dependent new molecular entities. Comprehensibility of labeling statements based on PRO endpoints was judged to be complex in 56.7% of product labels.The increase in labeling text based on PRO endpoints in product labels is encouraging. However, there is room for improvement on the comprehensibility of labeling statements based on PRO endpoints.

Background Diabetic gastroparesis (DG) is defined as delayed gastric emptying with associated gastrointestinal symptoms, without mechanical obstruction. Patient-reported symptoms are critical for diagnosis and evaluation of treatment benefit in DG. The Diabetic Gastroparesis Symptom Severity Diary (DGSSD), a new patient-reported outcome measure, was developed for use in clinical trials to support product approval and labeling claims for DG treatments. Materials and methods Initial DGSSD development was based on a review of the existing instruments and qualitative research (focus groups and cognitive debriefing interviews) in 41 patients with DG. Psychometric evaluations (individual items and composite scores) were conducted using data from Phase IIa and IIb relamorelin clinical trials. Results Qualitative research in patients with DG resulted in a six-item DGSSD, included in the Phase IIa trial, addressing symptom severity for nausea, vomiting, abdominal pain, early satiety, and bloating, as well as vomiting frequency. An item addressing severity of postprandial fullness (PPF) was subsequently added based on regulatory advice and included in the Phase IIb trial. Measurement properties were generally strong for weekly averages of daily item and composite scores. Item-level intraclass correlation coefficients ranged from 0.79 to 0.97 and correlations with other measures matched hypothesized patterns; the discriminating ability and responsiveness of the DGSSD were also supported. Multiple methods supported the computation of a composite score based on items addressing nausea, abdominal pain, bloating, and PPF severity. Conclusion Qualitative and quantitative evidence support use of the DGSSD as a reliable and valid measure from which to derive endpoints to evaluate treatment benefit in future DG interventional trials.

Objectives: The Functional Dyspepsia Symptom Diary (FDSD) was developed to address the lack of symptom-focused, patient-reported outcome (PRO) measures designed for use in functional dyspepsia (FD) patients and meeting Food and Drug Administration recommendations for PRO instrument development. Methods: Concept elicitation interviews were conducted with FD participants to identify symptoms important and relevant to FD patients. A preliminary version of the FDSD was constructed, then completed by FD participants on an electronic device in cognitive interviews to evaluate the readability, comprehensibility, relevance, and comprehensiveness of the FDSD, and to preliminarily evaluate its measurement properties. Results: During concept elicitation interviews, 45 participants spontaneously reported 19 symptom concepts. Of those, seven symptoms were selected for assessment by the eight-item FDSD. Cognitive interviews with 57 participants confirmed that participants were able to comprehend and provide meaningful responses to the FDSD, and that the handheld electronic FDSD format was suitable for use in the target population. Scores of the FDSD were well-distributed among response options, item discrimination indices suggested that the FDSD items differentiate among patients with varying degrees of FD severity, and inter-item correlations suggested that no items of the FDSD were capturing redundant information. Internal consistency estimates (0.87) and construct-related validity estimates using known-groups methods were within acceptable ranges. Conclusions: The FDSD is a content-valid PRO measure, with preliminary psychometric evidence providing support for the FDSD’s items and total score. Further psychometric evaluations are recommended to more fully test the FDSD’s score performance and other measurement properties in the target patient population.

Background Diabetic gastroparesis (DG) is defined as delayed gastric emptying with associated gastrointestinal symptoms, without mechanical obstruction. Patient-reported symptoms are critical for diagnosis and evaluation of treatment benefit in DG. The Diabetic Gastroparesis Symptom Severity Diary (DGSSD), a new patient-reported outcome measure, was developed for use in clinical trials to support product approval and labeling claims for DG treatments. Materials and methods Initial DGSSD development was based on a review of the existing instruments and qualitative research (focus groups and cognitive debriefing interviews) in 41 patients with DG. Psychometric evaluations (individual items and composite scores) were conducted using data from Phase IIa and IIb relamorelin clinical trials. Results Qualitative research in patients with DG resulted in a six-item DGSSD, included in the Phase IIa trial, addressing symptom severity for nausea, vomiting, abdominal pain, early satiety, and bloating, as well as vomiting frequency. An item addressing severity of postprandial fullness (PPF) was subsequently added based on regulatory advice and included in the Phase IIb trial. Measurement properties were generally strong for weekly averages of daily item and composite scores. Item-level intraclass correlation coefficients ranged from 0.79 to 0.97 and correlations with other measures matched hypothesized patterns; the discriminating ability and responsiveness of the DGSSD were also supported. Multiple methods supported the computation of a composite score based on items addressing nausea, abdominal pain, bloating, and PPF severity. Conclusion Qualitative and quantitative evidence support use of the DGSSD as a reliable and valid measure from which to derive endpoints to evaluate treatment benefit in future DG interventional trials., Video abstract

Objectives The aim was to document, from the perspective of the empirical literature, the primary symptoms of functional dyspepsia (FD), evaluate the extent to which existing questionnaires target those symptoms, and, finally, identify any missing evidence that would impact the questionnaires’ use in regulated clinical trials to assess treatment efficacy claims intended for product labeling. Methods A literature review was conducted to identify the primary symptoms of FD and existing symptom-based FD patient-reported outcome (PRO) instruments. Following a database search, abstracts were screened and articles were retrieved for review. The primary symptoms of FD were organized into a conceptual model and the PRO instruments were evaluated for conceptual coverage as well as compared against evidentiary requirements presented in the FDA’s PRO Guidance for Industry. Results Fifty-six articles and 16 instruments assessing FD symptoms were reviewed. Concepts listed in the Rome III criteria for FD (n = 7), those assessed by existing FD instruments (n = 34), and symptoms reported by patients in published qualitative research (n = 6) were summarized in the FD conceptual model. Except for vomiting, all of the identified symptoms from the published qualitative research reports were also specified in the Rome III criteria. Only three of the 16 instruments, the Dyspepsia Symptom Severity Index (DSSI), Nepean Dyspepsia Index (NDI), and Short-Form Nepean Dyspepsia Index (SF-NDI), measure all seven FD symptoms defined by the Rome III criteria. Among these three, each utilizes a 2-week recall period and 5-point Likert-type scale, and had evidence of patient involvement in development. Despite their coverage, when these instruments were evaluated in light of regulatory expectations, several issues jeopardized their potential qualification for substantiation of a labeling claim. Conclusions No existing PRO instruments that measured all seven symptoms adhered to the regulatory principles necessary to support product labeling. As such, the development of a new FD symptom PRO instrument is supported.

Purpose Irritable bowel syndrome with diarrhea (IBS-D) significantly impacts health-related quality of life (HRQOL). This post hoc analysis of two phase III trials evaluated the effects of eluxadoline treatment on disease-specific HRQOL among patients with IBS-D. Methods Adult patients meeting Rome III criteria for IBS-D were randomized to oral eluxadoline (75 mg or 100 mg) or placebo twice daily in two phase III clinical trials for 52 weeks (IBS-3001) and 26 weeks (IBS-3002). The Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire assessed disease-specific HRQOL throughout the study. Changes from baseline to Week 26 in IBS-QOL total and subscale scores were analyzed using an analysis of covariance model. Percentages of IBS-QOL responders with ≥ 14- and 20-point changes were evaluated for IBS-QOL total and subscale scores. A longitudinal mixed-effects model was fitted to evaluate mean IBS-QOL total scores. A cumulative distribution function for change from baseline to Week 26 in IBS-QOL total score was plotted. Results Mean changes from baseline to Week 26 for the IBS-QOL total and all subscale scores were significantly higher for patients treated with eluxadoline (both doses) compared to placebo. A significantly greater proportion of eluxadoline-treated patients were responders compared to placebo. Mean and mixed-effects model estimated mean IBS-QOL total scores were consistently higher for eluxadoline versus placebo over 52 weeks. Conclusions Compared to placebo, twice-daily eluxadoline treatment significantly improved HRQOL among patients with IBS-D in two phase III trials.

Patient-reported outcomes (PROs), which provide a direct measure of a patient's health status or treatment preferences, represent a key component of the shift toward patient-centered health care. PROs can measure the state of a patient's disease-specific and overall health throughout the care continuum, enabling them to have a variety of uses for key health care stakeholders. Currently, PROs are used in drug development, aligning patient and clinician goals in care, quality-of-care measures, and coverage and reimbursement decisions. While there have been significant strides by key health care stakeholders to further the development and use of PROs, there are a number of challenges limiting more widespread use. In light of these current challenges and the potential for PROs to improve health care quality and value, on October 19, 2017, the Academy of Managed Care Pharmacy convened a forum of key stakeholders representing patients, payers, providers, government, and pharmaceutical companies to discuss and identify solutions to the current challenges and barriers to further use of PROs. These discussions informed the development of participants' ideal future state in which PROs maximize the goals of all health care stakeholders and the actionable steps required to make the future state a reality. While stakeholders shared unique perspectives throughout the forum, they had consensus on 2 overarching issues: the importance of PROs in defining value, improving patient care, and implementing value-based payment models and the need for strong organizational and operational systems to achieve optimal adoption and use. Participants identified several key challenges in PRO use and adoption: achieving a representative patient population, inclusion of PRO data in medication labels, the necessity for both standardized and customizable PROs, and operational and organizational barriers to collecting and analyzing PROs. To overcome these challenges, participants recommended that manufacturers should engage key stakeholders early and throughout the drug development process to ensure the most valid and representative PROs and patient populations will be included. To streamline the PRO collection process, participants suggested engaging pharmacists and other providers who may have more frequent interaction with patients. Participants also recommended that PRO collection and analysis should use common technology platforms, streamline components of clinician care to reduce workflow, and be integrated with claims data to provider payers a better understanding of patient health in real time. Finally, additional work should be done to develop patient-reported outcome measures that contain relevant measures for all healthcare stakeholders. While significant challenges remain in PRO development and adoption, participants agreed that greater use can only be achieved through collaboration and patient-centered care.The AMCP Partnership Forum titled "Improving Quality, Value, and Outcomes with Patient-Reported Outcomes" and the development of this proceedings report were supported by Amgen, Boehringer Ingelheim Pharmaceuticals, Genentech, GlaxoSmithKline, Novartis Pharmaceuticals, Novo Nordisk, Precision for Value, Premier, Sanofi, Takeda Pharmaceuticals USA, and Xcenda.

As expected, pharmacy costs increased with the introduction of this new treatment in a market dominated by over-the-counter and generic treatments. On the other hand, outpatient GI-related and irritable bowel disease health care resource use and costs substantially decreased among commercial and Medicare patients following linaclotide treatment initiation.

Background Irritable bowel syndrome (IBS) affects 10–15% of adults in the US, and is associated with significant impairment in health-related quality of life (HRQoL); however, information specific to the diarrhea subtype (IBS-D) is lacking. We assessed the impact of IBS-D on HRQoL, work productivity, and daily activities, and the associated indirect costs, among a sample of the US population. Methods Respondents (≥18 years) from the 2012 US National Health and Wellness Survey who reported an IBS-D diagnosis by a physician or symptoms consistent with Rome II criteria for IBS-D were identified as having IBS-D. Controls included respondents without IBS-D or inflammatory bowel disease. HRQoL was assessed via the Short Form 36 Health Survey version 2 questionnaire and summarized into Mental and Physical Component Summary (MCS; PCS) scores and a Short Form-6 dimension (SF-6D) utility score. Work and activity impairment were assessed via the Work Productivity and Activity Impairment Questionnaire: General Health version (WPAI:GH), which measures absenteeism, presenteeism, overall work productivity loss, and daily activity impairment. Indirect costs were calculated using unit cost data from the Bureau of Labor Statistics and variables from the WPAI:GH. Generalized linear models were used to examine differences in health outcomes between respondents with IBS-D and controls, controlling for demographic and health characteristics. Results In total, 66,491 respondents (1102 IBS-D; 65,389 controls) were analyzed. Mean age was 48.7 years; 50% were female. Compared with controls, the IBS-D cohort reported significantly lower HRQoL (mean MCS: 45.16 vs. 49.48; p

Symptom measurement in pediatric chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) trials requires appropriately developed clinical outcome assessments (COAs).Literature was reviewed to identify symptom COAs meeting regulatory standards. Searches were conducted in Pubmed/Medline, EMBASE, and PsychINFO. Title/abstracts were reviewed to identify qualitative studies and those using COAs to measure pediatric CIC/IBS symptoms. Pediatric functional gastrointestinal experts provided input on relevant symptom-concepts to measure.Review of 1,105 abstracts identified 1 relevant qualitative article and 113 articles including COAs. Symptoms most frequently measured in CIC studies were frequency of bowel movements, fecal incontinence/encopresis, abdominal pain, stool consistency, and painful defecation. Symptoms most frequently measured in IBS were abdominal pain, abdominal distention/bloating, stool consistency, frequency of bowel movements, and gas. Evidence of development/validity of COAs was limited. Expert feedback was broadly consistent with the literature.Findings demonstrate consistency in the literature on key CIC/IBS symptoms to measure in pediatric trials, but existing COAs do not meet regulatory standards.

The prevalence of irritable bowel syndrome with constipation (IBS-C) is estimated to be between 4.3% and 5.2% among adults in the United States. Little is known about the health care resource utilization and costs associated with IBS-C.To (a) evaluate the annual total all-cause, gastrointestinal (GI)-related, and IBS-C-related health care costs among IBS-C patients seeking medical care in a commercially insured population and (b) estimate the incremental all-cause health care costs among IBS-C patients relative to matched controls.Patients aged ≥ 18 years with continuous medical and pharmacy benefit eligibility in 2010 were identified from the HealthCore Integrated Research Database, which consists of administrative claims from 14 geographically dispersed U.S. health plans representing 45 million lives. IBS-C patients were defined as those with ≥ 1 medical claim with an ICD-9-CM diagnosis code in any position for IBS (ICD-9-CM 564.1x) and either ≥ 2 medical claims for constipation (ICD-9-CM 564.0x) on different service dates or ≥ 1 medical claim for constipation plus ≥ 1 pharmacy claim for a constipation-related prescription on different dates of service during the study period. Controls were defined as patients without any medical claims for IBS, constipation, abdominal pain, or bloating or pharmacy claims for constipation-related prescriptions. Controls were randomly selected and matched with IBS-C patients in a 1:1 ratio based on age (± 4 years), gender, health plan region, and health plan type. Patients with diagnoses or prescriptions suggesting mixed IBS, IBS with diarrhea, chronic diarrhea, or drug-induced constipation were excluded. Total health care costs in 2010 U.S. dollars were defined as the sum of health plan and patient paid costs for prescriptions and medical services, including inpatient visits, emergency room (ER) visits, physician office visits, and other outpatient services. The total cost approach was used to assess total all-cause or disease-specific health care costs for patients with IBS-C, while the incremental cost approach was used to examine the excess all-cause costs of IBS-C by comparing IBS-C patients with matched controls. Generalized linear models with bootstrapping were used to assess the incremental all-cause costs attributable solely to IBS-C after adjusting for demographics, Elixhauser Comorbidity Index (ECI) score, and other general and GI-related comorbidities not included in the ECI score.A total of 7,652 patients (n = 3,826 each in the IBS-C and control cohorts) were included in the analysis. The mean (± SD) age was 48 (± 17) years, and 83.6% were female. The mean annual all-cause health care costs for IBS-C patients were $11,182, with over half (53.7%) of the costs attributable to outpatient services, including physician office visits and other outpatient services (13.1% and 40.6%, respectively). Remaining total all-cause costs were attributable to hospitalizations (21.8%), prescriptions (19.1%), and ER visits (5.4%). GI-related costs ($4,456) comprised 39.8% of total all-cause costs, while IBS-C-related costs ($1,335) accounted for 11.9% and were primarily driven by costs of other outpatient services (50.3%). After adjusting for demographics and comorbidities, the incremental annual all-cause health care costs associated with IBS-C were $3,856 ($8,621 for IBS-C patients vs. $4,765 for controls, P less than 0.01) per patient per year, of which 78.1% of the incremental costs were due to medical services, and 21.9% were due to prescription fills.IBS-C imposes a substantial economic burden in terms of direct health care costs in a commercially insured population. Compared with matched controls, IBS-C patients incurred significantly higher total annual all-cause health care costs even after controlling for general and GI-related comorbidities. Incremental all-cause costs associated with IBS-C were mainly driven by costs related to more frequent use of medical services as opposed to prescriptions.

To evaluate total annual all-cause, gastrointestinal-related, and symptom-related healthcare costs among chronic constipation (CC) patients and estimate incremental all-cause healthcare costs of CC patients relative to matched controls.Patients aged ≥18 years with continuous medical and pharmacy benefit eligibility in 2010 were identified from the HealthCore Integrated Research Database. CC patients had ≥2 medical claims for constipation (ICD-9-CM code 564.0x) ≥90 days apart or ≥1 medical claim for constipation plus ≥1 constipation-related pharmacy claim ≥90 days apart, and no medical claims for irritable bowel syndrome (IBS). Sub-groups with and without abdominal symptoms were classified according to the presence/absence of abdominal pain (ICD-9-CM code 789.0x) and bloating (ICD-9-CM code 787.3x). Controls without claims for constipation, abdominal pain, bloating, or IBS or constipation-related prescriptions were randomly selected and matched 1:1 with CC patients on age, gender, health plan region, and plan type. Generalized linear models with bootstrapping evaluated incremental all-cause costs attributable to CC, adjusting for demographics and comorbidities.Overall, 14,854 patients (n = 7427 each in CC and control groups) were identified (mean age = 59 years; 75.4% female). Mean annual all-cause costs for CC patients were $11,991 (2010 USD), with nearly half (44.8%) attributable to outpatient services, including physician office visits and other outpatient services (10.0% and 34.8%, respectively). GI-related costs comprised 33.7% of total all-cause costs. Symptom-related costs accounted for 10.5%, primarily driven by costs of other outpatient services (50.6%). Adjusted incremental all-cause costs associated with CC were $3508 per patient per year ($4446 for CC with abdominal symptoms; $2783 for CC without abdominal symptoms), of which 81.0% were from medical services. Incremental cost estimates may be over- or under-estimated due to classification based on claims.CC imposes a substantial burden in direct healthcare costs in a commercially insured population, mainly attributable to greater use of medical services.

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

To evaluate the effectiveness and costs of linaclotide (Linzess) versus lubiprostone (Amitiza) in the treatment of adult patients with chronic idiopathic constipation (CIC).A decision-tree model using model inputs derived from published literature, linaclotide phase 3 trial data, and a physician survey.Measures of treatment efficacy were selected based on comparability between trial data, with posthoc analyses of linaclotide required to ensure comparability with available lubiprostone data. Response to therapy was defined as (1) having one of the best two satisfaction answers of a 5-point global treatment satisfaction scale at Week 4 or (2) having a weekly spontaneous bowel movement (SBM) frequency 4 at Week 4. Patients who do not respond to therapy are assumed to accrue costs associated with a treatment failure. Model time horizon is aligned with the lubiprostone clinical trial duration of 4 weeks. Model outputs include response rates, quality-adjusted life-years (QALYs) and direct costs.Linaclotide was associated with lower per-patient costs vs lubiprostone for both definitions of response ($946 vs $1,015 for global assessment and $727 vs $737 for SBM frequency). When treatment response was based on a global assessment of treatment satisfaction, linaclotide was associated with higher effectiveness (response: 39.3% vs 35.0%). For SBM frequency, linaclotide was slightly less effective compared to lubiprostone (response: 58.6% vs 59.6%), but also less costly. Base-case results were robust in sensitivity analysis.Linaclotide is less expensive with similar effectiveness when compared to lubiprostone for the treatment of CIC in adult patients.

The incidence of skin and skin structure infections (SSSIs) due to Staphylococcus aureus (SA) is increasing. The objective of this study was to assess the costs of a treatment episode for SA-SSSIs.This retrospective analysis used a managed-care claims database to assess the duration and costs of incident SA-SSSI episodes treated with selected antibiotics (i.v. vancomycin, oral linezolid, and daptomycin, termed 'study antibiotics'). Patients were included if they had an ICD-9-CM diagnosis of an SSSI and SA between January 1, 2002 and December 31, 2005. Treatment episodes began on the date of the first antibiotic and ended when the patient had fourteen consecutive days without a study antibiotic or SSSI hospitalization. Costs, represented by health plan payments for SSSIs and overall, were updated to 2005 US dollars. A generalized linear model (GLM) assessed predictors of costs.A total of 1997 patients met the selection criteria. Mean (+/- SD) age was 46.3 (+/- 12.6) years and 55.9% of patients were male. Average episode length was 24 days, and over 95% of patients received i.v. vancomycin or oral linezolid as their initial study antibiotic. Patients remained on study antibiotics for an average of 16.4 days, and only 5% of patients were switched to another study antibiotic. Mean (+/- SD) overall episode costs were $8865 (+/- $20,003), primarily composed of inpatient and outpatient medical services. Treatment failure (i.e., study antibiotic switching or hospitalization), younger age, a diagnosis of bacteremia, osteomyelitis, or multiple complications during the episode, treatment with daptomycin, and greater Charlson co-morbidity score were significant positive predictors of overall costs. Alternatively, treatment with oral linezolid and hospitalization before the start of the outpatient treatment episode were significant negative predictors of overall costs. Mean (+/- SD) SSSI-related costs were $4551 (+/- $11,058).Medical charts and laboratory test results were not available to confirm SSSI and SA diagnoses, and no information was available regarding antibiotics received in the inpatient setting.The costs of treating SA-SSSIs are substantial and vary by failure rates, co-morbidities, and type of antibiotic therapy.

Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain.The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms.Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed.Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48-0.54, 0.32-0.39, and 0.61-0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%-76% and 71%-82% of weeks with agreement, respectively).AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

To use techniques of decision-analytic modeling to evaluate the effectiveness and costs of linaclotide vs lubiprostone in the treatment of adult patients with irritable bowel syndrome with constipation (IBS-C).Using model inputs derived from published literature, linaclotide Phase III trial data and a physician survey, a decision-tree model was constructed. Response to therapy was defined as (1) a ≥ 14-point increase from baseline in IBS-Quality-of-Life (IBS-QoL) questionnaire overall score at week 12 or (2) one of the top two responses (moderately/significantly relieved) on a 7-point IBS symptom relief question in ≥ 2 of 3 months. Patients who do not respond to therapy are assumed to fail therapy and accrue costs associated with a treatment failure. Model time horizon is aligned with clinical trial duration of 12 weeks. Model outputs include number of responders, quality-adjusted life-years (QALYs), and total costs (including direct and indirect). Both one-way and probabilistic sensitivity analyses were conducted.Treatment for IBS-C with linaclotide produced more responders than lubiprostone for both response definitions (19.3% vs 13.0% and 61.8% vs 57.2% for IBS-QoL and symptom relief, respectively), lower per-patient costs ($803 vs $911 and $977 vs $1056), and higher QALYs (0.1921 vs 0.1917 and 0.1909 vs 0.1894) over the 12-week time horizon. Results were similar for most one-way sensitivity analyses. In probabilistic sensitivity analyses, the majority of simulations resulted in linaclotide having higher treatment response rates and lower per-patient costs.There are no available head-to-head trials that compare linaclotide with lubiprostone; therefore, placebo-adjusted estimates of relative efficacy were derived for model inputs. The time horizon for this model is relatively short, as it was limited to the duration of available clinical trial data.Linaclotide was found to be a less costly option vs lubiprostone for the treatment of adult patients with IBS-C.

Lauren M Nelson,1 Valerie SL Williams,1 Sheri E Fehnel,1 Robyn T Carson,2 James MacDougall,3 Mollie J Baird,3 Stavros Tourkodimitris,2 Caroline B Kurtz,3 Jeffrey M Johnston31RTI Health Solutions, Durham, NC, USA; 2Forest Research Institute, Jersey City, NJ, USA; 3Ironwood Pharmaceuticals, Cambridge, MA, USABackground: Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes.Aim: Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures.Study methods: Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed.Results: The CC Symptom Severity Measures demonstrated satisfactory test–retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change.Conclusion: In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.Keywords: psychometric evaluation, patient-reported outcomes, linaclotide

Claire M Ervin,1 Sheri E Fehnel,1 Mollie J Baird,2 Robyn T Carson,3 Jeffrey M Johnston,2 Steven J Shiff,3 Caroline B Kurtz,2 Allen W Mangel11RTI Health Solutions, Research Triangle Park, NC, USA; 2Ironwood Pharmaceuticals, Inc., Cambridge, MA, USA; 3Forest Research Institute, Jersey City, NJ, USABackground: While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptoms directly related to bowel movements), abdominal symptoms are also prevalent among patients. The United States Food and Drug Administration’s (FDA’s) guidance on the use of patient-reported outcome measures to support product approvals or labeling claims recommends that endpoints be developed with direct patient input and include all symptoms important to patients.Aim: To identify a comprehensive set of CC symptoms that are important to patients for measurement in clinical trials.Methods: Following a targeted literature review to identify CC symptoms previously reported by patients, 28 patient interviews were conducted consistent with the FDA’s guidance on patient-reported outcomes. Subsequent to open-ended questions eliciting descriptions of all symptoms, rating and ranking methods were used to identify those of greatest importance to patients.Results: All 67 studies reviewed included bowel symptoms; more than half also addressed at least one abdominal symptom. Interview participants reported 62 potentially distinct concepts: 12 bowel symptoms; 21 abdominal symptoms; and 29 additional symptoms/impacts. Patients’ descriptions revealed that many symptom terms were highly related and/or could be considered secondary to CC. The rating and ranking task results suggest that both bowel (for example, stool frequency and consistency) and abdominal symptoms (for example, bloating, abdominal pain) comprise patients’ most important symptoms. Further, improvements in both bowel and abdominal symptoms would constitute an improvement in patients’ CC overall.Conclusion: Abdominal symptoms in CC patients are equal in relevance to bowel symptoms and should also be addressed in clinical trials to fully evaluate treatment benefit.Keywords: abdominal symptoms, straining, infrequent bowel movements, incomplete bowel movements, patient-reported outcomes

To compare healthcare resource utilization (HRU) and costs between patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC) with and without evidence of treatment failure.Claims data from the Missouri Medicaid program were used to identify adults with IBS-C or CC treated for constipation. IBS-C patients were required to have ≥2 constipation therapy claims, and the index date was defined as the date of the first constipation therapy claim within 12 months after an IBS diagnosis. For CC, the index date was defined as the date of the first constipation treatment claim followed by a second claim for constipation treatment or diagnosis between 60 days and 12 months later. Indicators of treatment failure were: switch/addition of constipation therapy, IBS- or constipation-related inpatient/emergency admission, megacolon/fecal impaction, constipation-related surgery/procedure, or aggressive prescription treatments. Annual incremental HRU and costs (public payer perspective) were compared between patients with and without treatment failure. Incidence rate ratios (IRRs) and cost differences are reported.In total, 2830 patients with IBS-C and 8745 with CC were selected. Approximately 50% of patients had ≥1 indicator of treatment failure. After adjusting for confounding factors, patients with treatment failure experienced higher HRU, particularly in inpatient days (IRR = 1.75 for IBS-C; IRR = 1.54 for CC) and higher total healthcare costs of $4353 in IBS-C patients and $2978 in CC patients. Medical service costs were the primary driver of the incremental costs associated with treatment failure, making up 71.3% and 67.0% of the total incremental healthcare costs of the IBS-C and CC samples, respectively.Sample was limited to Medicaid patients in Missouri. Claims data were used to infer treatment failure.Treatment failure is frequent among IBS-C and CC patients, and sub-optimal treatment response with available IBS-C and CC therapies may lead to substantial HRU and healthcare costs.

Irritable bowel syndrome with constipation (IBS-C), a chronic functional gastrointestinal disorder, has been shown to negatively affect work productivity and impair daily activity, resulting in a substantial burden for patients and employers. Linaclotide is a first-in-class guanylate cyclase-C agonist approved for the treatment of adults with IBS-C and chronic idiopathic constipation in the United States.To analyze the impact of treatment with linaclotide on work productivity and daily activity impairment in adults with IBS-C and estimate the indirect costs associated with this condition.This was a post-hoc analysis of data on IBS-C-related work time missed and work and activity impairment from 2 phase 3 clinical trials that assessed the efficacy and safety of linaclotide therapy in adults with IBS-C. The Work Productivity and Activity Impairment Questionnaire for IBS-C (WPAI:IBS-C) was self-administered at baseline and at weeks 4, 8, and 12 during the 12-week treatment periods in Trials 1 and 2 and at weeks 16, 20, and 26 during the extended treatment period in Trial 2. An analysis of covariance was conducted to assess changes from baseline to all study weeks for each WPAI:IBS-C measure. Indirect costs were calculated by converting overall work productivity losses into monetary values using the human capital cost approach.Of the 1602 patients with IBS-C who were randomized in the 2 clinical trials, 1555 (97.1%) completed a baseline and at least 1 postbaseline WPAI:IBS-C assessment and were included in the analysis cohort; 1148 (71.7%) of these patients were employed. Once-daily treatment with linaclotide significantly reduced overall work productivity loss and daily activity impairment among patients with IBS-C at all study weeks. From baseline to week 12, compared with placebo, linaclotide significantly reduced presenteeism by 5.2%, overall work productivity loss by 6.1%, and daily activity impairment by 4.7% (all P.01) and led to a numerically greater decrease in absenteeism. From baseline to week 26, compared with placebo, reductions with linaclotide were 5.9% for presenteeism, 7.5% for overall work productivity loss, and 6.7% for daily activity impairment (all P.05). Reductions in overall work productivity loss from baseline to week 26 translate to 103 hours to 156 hours annually and correspond to an avoided overall work loss of $3209 to $4861 annually for an employee with IBS-C.The results of this analysis indicate that appropriate treatment of IBS-C with medications such as linaclotide can reduce work-related impairment associated with IBS-C. In addition, IBS-C therapies that effectively manage this chronic condition and improve employees' quality of life and work productivity may represent significant cost-savings for employers in the form of avoided work productivity losses.

SummaryBackground Historically, measures of symptom severity of irritable bowel syndrome with constipation (IBS-C) in clinical trials have not met the evidence requirements described in the FDA guidance on patient-reported outcomes (PROs), which describes the evidentiary requirements and review criteria for patient-reported outcome measures intended to support product approval or labelling claims. Aim Data from two phase 3 trials (N = 1608) of linaclotide for the treatment of IBS-C were analysed to evaluate the psychometric properties of patient-reported outcome measures assessing changes in the severity of abdominal and bowel symptoms. Methods A set of patient-reported outcome assessments addressing abdominal and bowel symptoms, the IBS-C Symptom Severity Measures, were administered daily using interactive voice response system technology. Intraclass correlation coefficients (ICCs), Pearson correlations, factor analyses, F-tests and effect sizes were computed to evaluate the reliability, construct validity, discriminating ability and responsiveness of the IBS-C Symptom Severity Measures in a clinical trial context. Results The IBS-C Symptom Severity Measures showed highly satisfactory test–retest reliability (ICCs ranging from 0.79 to 0.95) and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests comparing subgroups based on various responder definitions were statistically significant and in the expected direction, substantiating the discriminating ability of the IBS-C Symptom Severity Measures. Responsiveness statistics (ranging from 0.6 to 2.1) demonstrated these measures are also capable of detecting change. Conclusions The psychometric analysis results strongly support the reliability, construct validity, discriminating ability and responsiveness of the IBS-C Symptom Severity Measures and substantiate the conclusion of linaclotide treatment benefit.

Irritable bowel syndrome (IBS) and chronic constipation (CC) are common functional gastrointestinal disorders affecting 14% and 20% of the U.S. population, respectively. Reviews of the evidence on the burden of illness associated with IBS and CC have not been comprehensive in scope and have not provided an assessment of the distribution of health care costs across categories of resource use.To (a) identify studies from any geographic region or country perspective that measure the economic burden of the disease; (b) analyze the direct (medical, drug, and other components) and indirect costs of illness; and (c) assess published evidence of the humanistic burden as measured by quality of life (QOL).An electronic literature search was conducted using journal databases, including MEDLINE, The Cochrane Library, EconLit, CINAHL, and Digestive Disease Week meeting abstracts. Specific search terms used were "irritable bowel syndrome" and "chronic constipation." In databases that accommodated Boolean searches, terms related to economic and quality of life outcomes were incorporated. Studies were included if they evaluated patients with an IBS or CC diagnosis and quantitatively measured the economic or humanistic burden of disease. Results were descriptively analyzed.The search identified a total of 882 unique publications. Thirty-five articles and abstracts met the inclusion criteria. Studies included 1,706 IBS-C, 2,264 IBS-D, 2,892 IBS-A, 15,830 IBS unclassified, and 1,278 CC patients. Nineteen of 35 studies assessed cost-of-illness endpoints, and from the U.S. perspective, the direct cost per-patient for IBS ranged from $1,562 to $7,547 per year, while direct costs of CC ranged from $1,912 to $7,522 per year. From the U.S. perspective, the indirect costs of IBS ranged from $791 to $7,737 per year, and no study assessed the indirect costs of CC. For IBS, data on the distribution of costs attributable to categories of resource use varied widely, particularly outpatient costs (12.7% to50% of total costs), inpatient costs (6.2% to 40.8%), and pharmacy or drug costs (5.9% to 46.6%). Comparable data on CC were not identified. Nineteen studies of IBS patients measured the humanistic burden of disease; 14 studies utilized SF-36; and within-study domain scores were significantly lower in IBS patients compared with non-IBS controls. Only 1 study of CC patients reported humanistic burden of disease.The studies identified in the systematic review varied in the method used to identify patients with IBS and CC. Results were not typically reported by IBS subtype. We observed a large variation in attributable direct and indirect costs and drivers of these costs. Future research should refine burden of illness estimates to subtypes so that estimates associated with IBS-C and CC are differentiated.

Background Staphylococcus aureus (SA) is a common bacterial pathogen in skin and skin structure infections (SSSIs). Limited data exist on hospital treatment patterns and costs for SA-SSSIs. Methods This retrospective analysis examined the lengths of stay, treatment patterns, and costs of hospitalized patients with an SA-SSSI diagnosis using a nationally representative inpatient database. Patients were selected if they had an ICD-9-CM diagnosis of an SSSI with SA noted between January 2005 and June 2006, received a study antibiotic (ie, intravenous [IV] vancomycin, IV or oral linezolid, and IV daptomycin), and were not in the intensive care unit before receiving a study antibiotic. Generalized linear models assessed predictors of length of stay and costs. Costs are expressed in 2005 US dollars. Results Thirteen thousand four hundred thirty-three patients met the selection criteria and mean (±SD) age was 48.2 (±18.3) years. Forty percent of patients received a nonstudy antibiotic before receiving their first study antibiotic. Ninety-five percent were prescribed vancomycin as their first study antibiotic. Study antibiotics were administered for an average of 4.3 days, and 8% of patients switched study antibiotics. Nineteen percent of patients receiving IV linezolid stepped down to oral linezolid. Mean (±SD) lengths of hospital stay and costs were 6.1 (±6.0) days and $6830 (±$7100). In-hospital mortality, switching antibiotics, and diagnoses of selected complications or comorbidities were associated with increased lengths of stay and costs. Younger age, location outside the Northeast, and use of oral linezolid were associated with lower lengths of stay and costs. Conclusion The costs of treating inpatient SA-SSSIs are substantial and vary by patient demographics and treatment characteristics.