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

BACKGROUND: Patient-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. METHODS: Concept 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. RESULTS: During 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. CONCLUSION: Development of a new PRO measure to support a label claim requires significant investment and early planning, as demonstrated by the omecamtiv mecarbil program.

Patient-Reported Outcomes in Chronic Heart Failure: Applicability for Regulatory Approval.

OBJECTIVES: The study sought to review the characteristics of existing patient-reported outcome (PRO) instruments used with chronic heart failure (HF) patients and evaluate their potential to support an approved U.S. Food and Drug Administration (FDA) product label claim. BACKGROUND: PROs, including symptoms and their associated functional limitations, contribute substantially to HF patient morbidity. PRO measurements capture the patient perspective and can be systematically assessed with structured questionnaires, however rigorous recommendations have been set by the FDA regarding the acceptability of PRO measures as a basis for product label claims. METHODS: Extensive searches of databases and specialty guidelines identified PRO instruments used in patients with chronic HF. Information on critical properties recommended by the FDA guidance were systematically extracted and used to evaluate the selected PRO instruments. RESULTS: Nineteen PRO instruments used with chronic HF patients were identified. The Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire were the most extensively evaluated and validated in studies of this population. However, judged by criteria listed in the FDA PRO guidance, no existing PRO measure met all of the criteria to support a product label claim in the United States. CONCLUSIONS: Currently available chronic HF PRO measures do not fulfill all the recommendations provided in the FDA PRO guidance and therefore may not support an FDA-approved product label claim. Future investigations are merited to develop a PRO measure for use in patients with chronic HF in accordance with the FDA guidance.

Improvement in Psoriasis Signs and Symptoms Assessed by the Psoriasis Symptom Inventory with Brodalumab Treatment in Patients with Psoriatic Arthritis.

OBJECTIVE: To evaluate the effect of brodalumab on psoriasis signs and symptoms assessed by the Psoriasis Symptom Inventory (PSI) in patients with psoriatic arthritis (PsA). METHODS: This prespecified analysis of a phase II study (NCT01516957) evaluated patients with active PsA and psoriasis-affected body surface area ≥ 3%, randomized to brodalumab (140 or 280 mg) or placebo every 2 weeks (Q2W) for 12 weeks with loading dose at Week 1. At Week 12, patients entering an open-label extension received brodalumab 280 mg Q2W. The PSI measures 8 psoriasis signs and symptoms: itch, redness, scaling, burning, stinging, cracking, flaking, and pain. PSI response is defined as total PSI ≤ 8 (range 0-32), each item ≤ 1 (range 0-4). PSI scores were assessed at weeks 12 and 24. RESULTS: There were 107 eligible patients. At Week 12, mean improvement in PSI scores was 7.8, 11.2, and 1.5 in brodalumab 140 mg, 280 mg, and placebo groups, respectively; by Week 24, improvement was 10.2, 12.4, and 11.7. At Week 12, 75.0%, 81.8%, and 16.7% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI response; improvement was sustained through Week 24, when 83.9% of prior placebo recipients achieved response. At Week 12, 25.0%, 36.4%, and 2.8% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI 0. Percentages improved through Week 24: 40.0% brodalumab 140 mg, 42.9% brodalumab 280 mg, and 48.4% placebo. CONCLUSION: Significantly more brodalumab-treated patients with PsA achieved patient-reported improvements in psoriasis signs and symptoms than did those receiving placebo. Improvements were comparable between brodalumab groups.

The experience of pain and redness in patients with moderate to severe plaque psoriasis.

INTRODUCTION: The Psoriasis Symptom Inventory is a patient-reported outcome instrument that assesses severity of psoriasis signs and symptoms. In early qualitative research, patients reported pain related to psoriasis skin lesions and redness of affected areas of skin as key symptoms. METHODS: Individual concept elicitation interviews and cognitive interviews were conducted in adults with moderate to severe plaque psoriasis. Interviews were audio-recorded and transcribed. Concepts were identified, coded and grouped by similar content using Atlas.ti software. Results were evaluated using qualitative research methods. RESULTS: Of 30 patients recruited, 20 patients participated in concept elicitation interviews and 10 participated in cognitive interviews. Concept codes for skin pain and descriptions of color comprised 11% and 15%, respectively, of all symptom-related expressions. Of 90 pain-related expressions, 22 were about pain related to unconscious scratching and 68 were about pain from the psoriasis lesions. Of 199 color-related expressions, 72 were about red or reddish lesion color. Patients with darker skin tones were found to interpret redness consistently. DISCUSSION: These results provide further support to content validity of pain and redness concepts in the Psoriasis Symptom Inventory. CONCLUSIONS: Symptoms of skin pain and redness are highly relevant to patients with psoriasis.

Total skin clearance results in improvements in health-related quality of life and reduced symptom severity among patients with moderate to severe psoriasis.

BACKGROUND: Newer therapies provide high levels of skin clearance in patients with moderate to severe psoriasis. However, insufficient evidence exists on the impact of total skin clearance from the patient's perspective. OBJECTIVES: To examine effects of total skin clearance on health-related quality of life (HRQoL) and psoriasis symptom severity in subjects with moderate to severe psoriasis. METHODS: Pooled data from a phase 2 dose-ranging trial in psoriasis using brodalumab (antibody to interleukin-17 receptor A) were used to compare subjects with static physician global assessment (sPGA) 1 versus sPGA 0 and subjects with Psoriasis Area and Severity Index (PASI) 75 to <100 versus PASI 100 at week 12 based on no impairment in Dermatology Life Quality Index (DLQI = 0) and no psoriasis symptoms (Psoriasis Symptom Inventory = 0). RESULTS: Of subjects with sPGA 0 (clear) and 1 (almost clear), 61.4% and 45.7% had a DLQI = 0 (p = 0.15), and 65.5% and 32.6% had a Psoriasis Symptom Inventory = 0 (p = 0.001), respectively. Significantly more subjects with sPGA 1 continued to report itching, redness, scaling, and flaking compared to subjects with sPGA 0. Similar results were observed based on PASI score. CONCLUSIONS: A higher proportion of subjects with total skin clearance reported no impairment in HRQoL and no psoriasis symptoms than those who were almost clear.

Treatment patterns and therapy effectiveness in psoriasis patients initiating biologic therapy in England.

OBJECTIVE: To describe biologic treatment patterns and effectiveness among patients with psoriasis who initiated biologic therapy. METHODS: A chart review was conducted for 169 patients with psoriasis initiating biologic treatment between 1 July 2005 and 30 June 2009 from six dermatology clinics. Severity was measured by the Psoriasis Area and Severity Index (PASI) at baseline and time of treatment change. Biologic treatment patterns in the 12 months following initiation (discontinuation, switching, dose increase, and persistence) were collected. RESULTS: Mean (SD) PASI score at initiation was 18.4 (7.8). Eighteen percent of patients discontinued biologic use, 12% switched, and 7% increased biologic dose within the first 12 months. Patients persistent on initial biologic therapy (64%) achieved a mean PASI score of 3.8 at 12 months; 69% achieved PASI ≥75. For patients who discontinued due to lack of effectiveness, mean PASI score was 22.6; no patient reached PASI ≥75. Among patients who switched, mean PASI was 15.7 (0% PASI ≥75) at the time of switch. In those who increased their dose, mean PASI score was 9.1 (43% reached PASI ≥75) at the time of dose increase. CONCLUSIONS: A large proportion (36%) of patients changed or discontinued biologic therapy within the first year. These patients experienced limited PASI response, if any, suggesting an unmet need for this population.

Reliability and validity of the psoriasis symptom inventory in patients with moderate-to-severe psoriasis.

OBJECTIVES: The psoriasis symptom inventory (PSI) is a patient-reported outcome measure for assessing symptom severity in patients with moderate-to-severe psoriasis. The primary objective of this study was to evaluate the measurement properties of the PSI. MATERIALS AND METHODS: Analyses of psychometric characteristics (reliability, convergent and known-groups validity,responsiveness, item performance, and dimensionality) were conducted using data from a Phase II trail to evaluate efficacy of brodalumab in subjects with moderate-to-severe psoriasis. RESULTS: The PSI had excellent internal consistency (α = 0.93-0.98) and good test-retest reliability (ICCs = 0.77-0.87). Convergent and discriminant validity was indicated by moderate-to-strong correlations between the PSI and Dermatology Life Quality Index scores, and small correlations between PSI total scores and ShortfFrm-36 Health Survey mental health, role emotional, and role physical scales. Known groups validity was shown as mean PSI total scores varied by Psoriasis Area and Severity Index (PASI) and Static Physician's Global Assessment (sPGA) defined groups (p < 0.001). PSI total scores were responsive to changes in clinical status as assessed by PASI (p < 0.001) and sPGA (p < 0.001). Unidimensionality of the PSI was supported. CONCLUSIONS: The PSI is a short and valid unidimensional measure of psoriasis symptom severity that is well suited for use in clinical trials.

Equivalence and measurement properties of an electronic version of the Psoriasis Symptom Inventory.

PURPOSE: To evaluate the equivalence of electronic and paper versions of the Psoriasis Symptom Inventory and to examine measurement properties of the electronic version. METHODS: In a prospective, randomized, crossover, non-interventional study in adult subjects (age ≥18 years) with plaque psoriasis conducted over a period of 15 days, subjects were randomized to two groups, completing either the paper or electronic Psoriasis Symptom Inventory daily for 7 consecutive days followed by the alternate version. Equivalence was assessed by the intraclass correlation coefficient (ICC) between both administration modes. Differences in scores were also tested using paired Student's t test. Measurement properties included internal consistency reliability, test-retest reliability, and convergent and discriminant validity between the Psoriasis Symptom Inventory and (1) disease-specific (Dermatology Life Quality Index) and (2) general health (SF-36v2) status. RESULTS: Eighty subjects [74 % (59/80) moderate-to-severe psoriasis; 26 % (21/80) mild psoriasis receiving systemic treatment] were enrolled from 8 sites in the USA. The two modes were highly concordant for both total (ICC = 0.97) and individual item scores (ICC range = 0.93-0.97). Response bias testing showed no differences based on completion order with all ICC values >0.91. All mean score differences, except for one item ("flaking"), were non-significant (P > 0.05). Minimum values for reliability (>0.70) and validity (convergent, r ≥ 0.40) were exceeded for the electronic Psoriasis Symptom Inventory. CONCLUSIONS: Equivalence between paper and electronic versions of the Psoriasis Symptom Inventory and strong measurement properties of the electronic mode indicated a successful migration from paper to electronic format of the Psoriasis Symptom Inventory.

Treatment and referral patterns for psoriasis in United Kingdom primary care: a retrospective cohort study.

BACKGROUND: In the UK, referrals to specialists are initiated by general practitioners (GPs). Study objectives were to estimate the incidence of diagnosed psoriasis in the UK and identify factors associated with GP referrals to dermatologists. METHODS: Newly diagnosed patients with psoriasis were identified in The Health Improvement Network (THIN) database between 01 July 2007-31 Oct 2009. Incidence of diagnosed psoriasis was calculated using the number of new psoriasis patients in 2008 and the mid-year total patient count for THIN in 2008. A nested case-control design and conditional logistic regression were used to identify factors associated with referral. RESULTS: Incidence rate of diagnosed adult psoriasis in 2008 was 28/10,000 person-years. Referral rate to dermatologists was 18.1 (17.3-18.9) per 100 person-years. In the referred cohort (N=1,950), 61% were referred within 30 days of diagnosis and their median time to referral was 0 days from diagnosis. For those referred after 30 days (39%, median time to referral: 5.6 months), an increase in the number of GP visits prior to referral increased the likelihood of referral (OR=1.87 95% CI:1.73-2.01). A prescription of topical agents such as vitamin D3 analogues 30 days before referral increased the likelihood of being referred (OR=4.67 95% CI: 2.78-7.84), as did corticosteroids (OR=2.45 95% CI: 1.45-4.07) and tar products (OR=1.95 95% CI: 1.02-3.75). CONCLUSIONS: Estimates of the incidence of diagnosed adult psoriasis, referral rates to dermatologists, and characteristics of referred patients may assist in understanding the burden on the UK healthcare system and managing this population in primary and secondary care.

Early development and qualitative evidence of content validity for the Psoriasis Symptom Inventory (PSI), a patient-reported outcome measure of psoriasis symptom severity.

OBJECTIVE: To develop and assess content validity of the Psoriasis Symptom Inventory (PSI), a patient-reported outcome (PRO) measure of psoriasis symptoms. METHODS: Following initial literature exploration and input from experts, concept elicitation was conducted in two rounds (focus groups and individual interviews) with 59 subjects with mild to severe psoriasis. Transcripts were coded to identify symptom concepts and develop a conceptual framework using ATLAS.ti software. Qualitative content analysis and clinical expert input supported item generation and development of a draft measure. Two rounds of face-to-face cognitive interviews with 40 subjects with moderate to severe psoriasis were conducted to test subject comprehension and content coverage. RESULTS: Concepts of itching, scaling, flaking, tearing/cracking, burning, stinging, pain, bleeding and color of appearance were the most common symptom-related expressions. Saturation of concept was demonstrated. Severity was identified as the most meaningful attribute of psoriasis symptoms. A final 8-item measure was developed to assess patient-perceived symptom severity for itch, pain, burning, stinging, cracking, scaling, flaking and redness. Twenty-four-hour recall and 7-day recall versions were prepared for future quantitative assessment of measurement properties. CONCLUSIONS: The PSI is a short, low burden, patient-reported measure of psoriasis symptom severity with documented evidence of content validity.

Work productivity and healthcare resource utilization outcomes for patients on etanercept for moderate-to-severe plaque psoriasis: results from a 1-year, multicentre, open-label, single-arm study in a clinical setting.

BACKGROUND: Data investigating the effect of etanercept on work productivity and healthcare resource utilization in Canadian patients in a clinical setting is limited. OBJECTIVE: The aim of the study was to describe work productivity and healthcare resource utilization in patients with psoriasis prescribed etanercept. METHODS: A 12-month, phase IV, non-randomized, multicentre, open-label, single-arm prospective trial of patients with moderate-to-severe plaque psoriasis was conducted between March 2006 and July 2009 in 37 community dermatology practice sites across Canada. A total of 246 patients were enrolled. Major eligibility criteria: ≥18 years of age; diagnosis of moderate-to-severe plaque psoriasis at baseline (Physician Global Assessment [PGA] ≥3, scale 0-5); able to start etanercept therapy as per product monograph. Patients received etanercept (Enbrel(®)) 50 mg subcutaneously twice weekly for 3 months, then 50 mg once weekly for 9 months. Outcomes were measured by average change and average percent change from baseline at months 3, 6, 9 and 12 on the Work Productivity and Activity Impairment (WPAI) and Healthcare Resource Utilization (HRU) questionnaires. RESULTS: The mean degree of impairment while working ± standard deviation (SD) in the total population decreased from 22.7% ± 23.2 at baseline to 6.6% ± 14 after 3 months of treatment (p < 0.0001). From baseline to 3 months, overall work impairment ± SD decreased from 23.7% ± 23.7 to 8.3% ± 16.5 (p < 0.0001) and mean activity impairment outside the workplace decreased from 31.4% ± 26.4 to 12.9% ± 22.4 (p < 0.0001). All these improvements were sustained to month 12. Other variables that decreased on average from baseline to month 3, sustained to month 12, included physician office visits (2.3/month ± 3.5 at baseline to 0.6/month ± 1.0 at month 3; p < 0.0002), hours of assistance required of family and friends to assist with psoriasis (1.1 hours/week ± 2.6 at baseline to 0.3 hours/week ± 1.5 at month 3; p = 0.0002) and amount of time spent on activities to manage psoriasis (5.5 hours/week ± 6.2 at baseline to 1.9 hours/week ± 3.7 at month 3; p < 0.0001). Also, the amount of out-of-pocket expenses to manage psoriasis decreased from $Can94.9/month ± 331.6 at baseline to $Can35.7 ± 69.1 at month 12 (p = 0.0153). CONCLUSIONS: Use of etanercept in Canadian patients in a clinical practice setting correlated with improvement in work productivity and reduced HRU after 3 months of treatment, and improvement was sustained up to 12 months.