Qualitative Development of the Allergan Satisfaction with Treatment Experience Questionnaire (ASTEQ) Instrument, a Patient-Reported Outcome Measure in Glaucoma and Ocular Hypertension.

INTRODUCTION: Sustained-release intraocular implants provide a therapeutic option for open-angle glaucoma (OAG) and ocular hypertension (OHT) patients who are non-compliant with eyedrops. Currently, there are no published patient-reported outcome (PRO) measures that assess treatment satisfaction with intraocular implants. To address this gap, a new PRO instrument, the Allergan Satisfaction with Treatment Experience Questionnaire (ASTEQ), has been developed in accordance with Food and Drug Administration guidance. METHODS: Qualitative research interviews were conducted among patients with OAG/OHT who had received three intraocular injections of a sustained-release bimatoprost (10 or 15 µg) implant within the clinical trial setting. A preliminary conceptual framework capturing treatment satisfaction concepts in glaucoma, as identified from the literature, was used to develop a semi-structured interview guide. A concept elicitation (CE) interview to identify aspects of the glaucoma treatment experience pertinent to intraocular implants provided content for a draft instrument. A cognitive debriefing (CD) interview to test the instrument's interpretability, relevance, and validity informed its subsequent refinement. Interview analysis followed a grounded theory approach to identify data patterns and relationships. RESULTS: CE interviews (n = 19) indicated that participants' main considerations in rating satisfaction with implant treatment were physical comfort during preparation for the implant and implant administration, anxiety about the procedure, frequency of implant administration, possible side effects, convenience and accessibility of the implant, relationship with the clinician, and lifestyle fit. Draft ASTEQ revision based on CD interviews (n = 20) and readability tests yielded a nine-item ASTEQ instrument comprising satisfaction with overall implant experience and frequency of administration, occurrence/bother of immediate and long-term side effects, worry about implant administration and possible risks/side effects, and physical discomfort during preparation for the implant and implant administration. CONCLUSION: The ASTEQ instrument has demonstrated content validity in patients with OAG/OHT treated with a sustained-release bimatoprost implant. Further research is necessary to evaluate its psychometric properties.

Patient-reported outcomes and quality of life in advanced ALK+ non-small-cell lung cancer trial of brigatinib (ALTA).

Aim: Patient-reported outcomes (PRO) can support clinically relevant primary end points. Materials & methods: The ALTA trial, an open-label, Phase II, randomized dose-comparison study, evaluated the safety and efficacy of brigatinib in ALK+ non-small-cell lung cancer. PRO data collection included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30). A linear mixed model for repeated measures was used to analyze change from baseline in the Global Health Status/Quality of Life subscale (GHS/QOL), with a change of greater than or equal to ten points deemed meaningful. Results: Improvement in mean GHS/QOL scores was statistically significant in the majority of treatment cycles; <10% of patients experienced a meaningful worsening of their GHS/QOL and symptom scores. Conclusion: PRO-measured benefits are consistent with objective response benefits associated with brigatinib.

Converting EORTC QLQ-C30 scores to utility scores in the brigatinib ALTA study.

Aims: Health utilities summarize a patient's overall health status. This study estimated utilities based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30), a widely used measure of health-related quality-of-life (HRQoL) in oncology, using published mapping algorithms. Materials and methods: Data were from the Anaplastic Lymphoma Kinase (ALK) in Lung Cancer Trial of brigatinib (ALTA; NCT02094573), an open-label, international, phase 2 study. ALTA evaluated the efficacy and safety of two randomized dosing regimens of brigatinib in patients with locally advanced or metastatic ALK + non-small cell lung cancer (NSCLC) that had progressed on prior therapy with crizotinib. QLQ-C30 scores were mapped to European Quality-of-Life-5 Dimensions (EQ-5D) utility scores using two published algorithms (Khan et al. for EQ-5D-5L; Longworth et al. for EQ-5D-3L). The impact of brigatinib treatment on health utilities over time was assessed. Results: The analysis included 208 subjects. Mean baseline utility scores for both algorithms ranged between 0.60 - 0.71 and increased to 0.78 by cycle 5. Utility improvements were sustained during most of the treatment, before disease progression. Minor variations were observed between utility scores; Khan et al. estimates were approximately 0.01 or 0.02 points lower than Longworth et al. estimates. Limitations: Algorithms considered were limited to those available in the published literature at the time of the study. This utility analysis was exploratory, and the ALTA trial did not include an internal control group (i.e. standard of care) and was not powered to detect differences in QoL/utility outcomes between treatment arms. Conclusions: Converting QLQ-C30 scores into utilities in trials using established mapping algorithms can improve evaluation of medicines from the patient perspective. Both algorithms suggested that brigatinib improved health utility in crizotinib-refractory ALK + NSCLC patients, and improvements were maintained during most of the treatment. Clinicaltrials.gov identifier: NCT02094573.

Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer.

OBJECTIVE: Brigatinib, ceritinib, and alectinib are approved to treat crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), but no trial has compared them head-to-head. A matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting. METHODS: MAIC is a propensity score-type method that adjusts for differences in baseline characteristics between trials to estimate relative efficacy. Analyses were based on patient-level data from the ALTA trial for brigatinib and published summary-level trial data from ASCEND-1 and ASCEND-2 for ceritinib and NP28761 and NP28673 for alectinib. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: After matching, all key baseline characteristics were balanced between trials. Compared with ceritinib, brigatinib was associated with longer PFS (ASCEND-1: median 15.7 vs 6.9 months, hazard ratio (HR) [95% confidence interval] = 0.38 [0.26-0.57]; ASCEND-2: median = 18.3 vs 7.2 months, HR = 0.33 [0.20-0.56]) and OS (ASCEND-1: not available; ASCEND-2: median 27.6 vs 14.9 months, HR = 0.33 [0.17-0.63]). Versus alectinib, brigatinib was associated with longer PFS (NP28761: median = 17.6 vs 8.2 months, HR = 0.56 [0.36-0.86]; NP28673: median = 17.6 vs 8.9 months, HR = 0.61 [0.40-0.93]); results for OS were inconclusive (NP28761: median = 27.6 vs 22.7 months, HR = 0.70 [0.42-1.16]; NP28673: median = 27.6 vs 26.0 months, HR = 0.66 [0.39-1.09]). ORR was similar. CONCLUSION: In crizotinib-refractory ALK + NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.

The budget impact of cervical cancer screening using HPV primary screening.

OBJECTIVES: This study assessed the clinical and budgetary impacts of human papillomavirus (HPV) primary screening with HPV16/18 genotyping, in contrast to current cervical cancer screening strategies. STUDY DESIGN: A decision-tree framework and Markov model were used to model clinical and cost implications of screening and diagnosis of disease. METHODS: A model was developed to compare the annual clinical and budgetary impact of HPV screening with genotyping versus cytology, and co-testing with and without genotyping. Epidemiology and test performance inputs are from the literature and the Addressing THE Need for Advanced HPV Diagnostics (ATHENA) trial. Costs are from a US payer perspective. Clinical impact was measured as the resulting incidence of cervical cancer, and budget impact is reported as annual cost per screened woman. The model considered the impact of patient noncompliance (loss to follow-up) at both the initial screen and re-test. RESULTS: Cytology was found to be inferior to both co-testing and HPV primary screening. Co-testing was inferior to co-testing with genotyping. Co-testing with genotyping every 3 years (incidence = 5.5 per 100,000 women; annual investment = $61) or 5 years (incidence = 7.4 per 100,000 women; annual investment = $37) was slightly more effective, but more costly than HPV primary screening every 3 years (incidence = 6.2 per 100,000 women; annual investment = $48) or 5 years (incidence = 8.1 per 100,000 women; annual investment = $30). Genotyping strategies were relatively stable to the effects of patient noncompliance. CONCLUSIONS: Primary HPV screening with genotyping represents a sensible combination of clinical effectiveness and costs, while reducing the risks associated with patient noncompliance.

Cost effectiveness of human papillomavirus-16/18 genotyping in cervical cancer screening.

BACKGROUND: There is limited understanding of the health economic implications of cervical screening with human papillomavirus (HPV)-16/18 genotyping. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of cervical cancer primary screening with a HPV-16/18 genotyping test which simultaneously detects 12 other high-risk HPV types. METHODS: A Markov cohort model compared four strategies: (1) cytology with reflex HPV testing for atypical squamous cells of undetermined significance (ASC-US); (2) co-testing with cytology and HPV testing; (3) HPV with reflex to cytology; and (4) HPV with 16/18 genotyping and reflex cytology (ASC-US threshold). Screening began at age 30 and was performed triennially over 40 years. Screening sensitivity and specificity values for cervical intraepithelial neoplasia (CIN) 3 were obtained from the Addressing THE Need for Advanced HPV Diagnostics (ATHENA) trial. Outcomes for a 1-year follow-up scenario wherein persistent disease was detected were estimated. Screening and cancer treatment costs were calculated from a US payer's perspective in 2013. Costs and quality-adjusted life-years (QALYs) were discounted at 3 % annually. RESULTS: Applying a US$50,000/QALY threshold, strategy (4) dominated strategies (2) and (3) by reducing costs and cancer incidence and improving QALYs, and was cost effective versus strategy (1). Accounting for persistent ≥CIN 3 at 1 year, strategy (4) was cost effective versus all other strategies. Detecting HPV-16/18 resulted in earlier diagnosis of clinically relevant ≥CIN 3 at initial screening and efficient use of follow-up resources. Outcomes were most influenced by strategy performance. CONCLUSIONS: Incorporating HPV-16/18 genotyping is cost effective and may improve detection of CIN, thereby preventing cervical cancer.

Influence of patient perceptions and preferences for osteoporosis medication on adherence behavior in the Denosumab Adherence Preference Satisfaction study.

OBJECTIVE: This study aims to evaluate patient perceptions of subcutaneous denosumab or oral alendronate in postmenopausal women with or at risk for osteoporosis and how these perceptions influence adherence. METHODS: Postmenopausal women with low bone mass were randomized to denosumab 60 mg every 6 months for 1 year (treatment period 1 [TP1]) followed by alendronate 70 mg once weekly for 1 year (treatment period 2 [TP2]), or vice versa. Beliefs about Medicines Questionnaire data were collected at baseline and at 6, 12, 18, and 24 months; a necessity-concerns differential (NCD) was calculated for each time point. Logistic regression analyses were performed to evaluate the influences of baseline characteristics on nonadherence. RESULTS: Participants included 250 women (alendronate/denosumab, n = 124; denosumab/alendronate, n = 126). During TP1, the NCD at month 6 was higher with denosumab than with alendronate (P = 0.0076). In TP2, the NCD was higher for women switched to denosumab than for women switched to alendronate at 6 months (P = 0.0126) and 12 months (P = 0.4605). Denosumab was preferred to alendronate regardless of treatment sequence (P < 0.0001). Covariate analysis revealed that higher TP2 baseline necessity scores were associated with lower odds of nonadherence (P = 0.0055), whereas higher concerns about medication scores were associated with higher odds of nonadherence (P = 0.0247). Higher NCD scores were also associated with lower odds of nonadherence (P = 0.0015). CONCLUSIONS: Participants preferred denosumab to alendronate while on treatment and had more positive perceptions of denosumab than alendronate. These perceptions were associated with better adherence.

Cost effectiveness of denosumab versus oral bisphosphonates for postmenopausal osteoporosis in the US.

BACKGROUND: In the US, 26 % of women aged ≥65 years, and over 50 % of women aged ≥85 years are affected with postmenopausal osteoporosis (PMO). Each year, the total direct health care costs are estimated to be $US12-18 billion. OBJECTIVE: The cost effectiveness of denosumab versus oral bisphosphonates in postmenopausal osteoporotic women from a US third-party payer perspective was evaluated. METHODS: A lifetime cohort Markov model was developed with seven health states: 'well', hip fracture, vertebral fracture, 'other' osteoporotic fracture, post-hip fracture, post-vertebral fracture, and dead. During each cycle, patients could have a fracture, remain healthy, remain in a post-fracture state or die. Relative fracture risk reductions, background fracture risks, mortality rates, treatment-specific persistence rate, utilities, and medical and drug costs were derived using published sources. Expected costs and quality-adjusted life years (QALYs) were estimated for generic alendronate, denosumab, branded risedronate, and branded ibandronate in the overall PMO population and high-risk subgroups: (a) ≥2 of the following risks: >70 years of age, bone mineral density (BMD) T score less than or equal to -3.0, and prevalent vertebral fracture; and (b) ≥75 years of age. Costs and QALYs were discounted at 3 % annually, and all costs were inflated to 2012 US dollars. Sensitivity analyses were conducted by varying parameters e.g., efficacies of interventions, costs, utilities, and the medication persistence ratio. RESULTS: In the overall PMO population, total lifetime costs for alendronate, denosumab, risedronate, and ibandronate were $US64,400, $US67,400, $US67,600 and $US69,200, respectively. Total QALYs were 8.2804, 8.3155, 8.2735 and 8.2691, respectively. The incremental cost-effectiveness ratio (ICER) for denosumab versus generic alendronate was $US85,100/QALY. Risedronate and ibandronate were dominated by denosumab. In the high-risk subgroup (a), total costs for alendronate, denosumab, risedronate and ibandronate were $US70,400, $US70,800, $US74,000 and $US76,900, respectively. Total QALYs were 7.2006, 7.2497, 7.1969 and 7.1841, respectively. Denosumab had an ICER of $US7,900/QALY versus generic alendronate and dominated all other strategies. Denosumab dominated all strategies in women aged ≥75 years. Base-case results between denosumab and generic alendronate were most sensitive to the relative risk of hip fracture for both drugs and the cost of denosumab. CONCLUSION: In each PMO population examined, denosumab represented good value for money compared with branded bisphosphonates. Furthermore, denosumab was either cost effective or dominant compared with generic alendronate in the high-risk subgroups.

Prostate cancer screening trends in a large, integrated health care system.

BACKGROUND: As the debate over the effectiveness of prostate-specific antigen (PSA) screening for prostate cancer continues, it is increasingly important to understand how PSA screening occurs in general-practice settings. METHODS: We conducted a retrospective cohort study within Kaiser Permanente Southern California, a large integrated health care system. Men aged 35 years and older at baseline, in 1998, were eligible. The proportion of men who underwent PSA screening was estimated and compared across groups defined by patient and physician characteristics. We also evaluated trends in screening across time and serum PSA levels for all subgroups. RESULTS: Of 2,061,047 men, 572,306 (28%) underwent PSA screening from 1998 through 2007. Patterns of PSA screening varied modestly by age, race, and physician. The lowest frequencies of screening occurred among men younger than age 45 years (19%) and men ages 85 years and older (13%). PSA screening was most common among white men (33.5%) and in men seen by physicians of the same race/ethnicity (32%), compared with men with physicians of disparate race/ethnicity (26%, p < 0.001). PSA screening increased over time for all racial/ethnic groups and among men age 75 years and older but decreased over time for men younger than age 75 years old. CONCLUSIONS: Nearly 1 in 4 eligible men underwent PSA screening from 1998 through 2007, and screening varied only modestly by patient and physician characteristics. Estimates of the frequency of PSA screening in general-practice settings can inform the debate and provide useful insight as to how changes in cancer screening guidelines would alter practice patterns in an increasingly integrated health care environment.

Cost-effectiveness of Prostate Health Index for prostate cancer detection.

OBJECTIVE: • To evaluate the cost-effectiveness of early prostate cancer detection with the Beckman Coulter Prostate Health Index (phi) (not currently available in the USA) adding to the serum prostate-specific antigen (PSA) test compared with the PSA test alone from the US societal perspective. PATIENTS AND METHODS: • Phi was developed as a combination of PSA, free PSA, and a PSA precursor form [-2]proPSA to calculate the probability of prostate cancer and was used as an aid in distinguishing prostate cancer from benign prostatic conditions for men with a borderline PSA test (e.g. PSA 2-10 ng/mL or 4-10 ng/mL) and non-suspicious digital rectal examination. • We constructed a Markov model with probabilistic sensitivity analysis to estimate expected costs and utilities of prostate cancer detection and consequent treatment for the annual prostate cancer screening in the male population aged 50-75 years old. • The transition probabilities, health state utilities and prostate cancer treatment costs were derived from the published literature. The diagnostic performance of phi was obtained from a multi-centre study. Diagnostic related costs were obtained from the 2009 Medicare Fee Schedule. • Cost-effectiveness was compared between the strategies of PSA test alone and PSA plus phi under two PSA thresholds (≥2 ng/mL and ≥4 ng/mL) to recommend a prostate biopsy. RESULTS: • Over 25 annual screening cycles, the strategy of PSA plus phi dominated the PSA-only strategy using both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL, and was estimated to save $1199 or $443, with an expected gain of 0.08 or 0.03 quality adjusted life years, respectively. • The probabilities of PSA plus phi being cost effective were approximately 77-70% or 78-71% at a range of $0-$200,000 willingness to pay using PSA thresholds ≥2 ng/mL and ≥4 ng/mL, respectively. CONCLUSION: • The strategy PSA plus phi may be an important strategy for prostate cancer detection at both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL to recommend a prostate biopsy compared with using PSA alone.

Economic burden of atopic manifestations in patients with atopic dermatitis--analysis of administrative claims.

BACKGROUND: Atopic dermatitis (AD) has been associated with atopic manifestations (AMs), such as food allergies, asthma, allergic rhinitis, and allergic conjunctivitis. OBJECTIVES: To (1) compare the risk of developing AMs in patients with AD versus those without AD, (2) estimate the incremental costs attributable to AMs in patients with AD, and (3) examine the factors associated with incremental costs. METHODS: In this retrospective cohort study, the authors used MarketScan research databases containing medical and pharmacy claims with dates of service from January 1, 1999, to December 31, 2004. Patients were considered to have AD if they had at least 1 medical claim with a primary or secondary diagnosis of AD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 691.8x) or contact dermatitis or other eczema of unspecified cause (ICD-9-CM codes 692.9x). To create comparable study cohorts, patients with AD were matched with non-AD patients using propensity scores that represented the likelihood of developing AD as predicted by logistic regression. After propensity score matching, the AD and non-AD cohorts did not statistically differ with respect to age, gender, geographic region, type of health insurance, Charlson Comorbidity Index, or baseline measures of medical and prescription drug utilization. The relative risks of developing AMs in the AD and non-AD cohorts were estimated using competing risk-survival analysis. AM was defined by ICD-9-CM codes for asthma (493.xx), allergic rhinitis (477.xx), allergic conjunctivitis (372.05 or 372.14), and food allergy (693.1x, 692.5x, 995.60). The annual incremental cost attributable to AMs in these AD patients was calculated from medical claims with AM and AD diagnosis codes and from pharmacy claims for prescription drugs used to treat asthma, allergic rhinitis, allergic conjunctivitis, or food allergy, and 95% confidence intervals (CIs) were calculated using the bootstrap method. RESULTS: Patients with AD were significantly more likely to develop AMs than patients without AD (21.8% versus 16.9%, adjusted relative risk [RR] = 1.33, 95% CI, 1.28-1.38). Among AD patients who developed AMs, allergic rhinitis was the most frequent manifestation (66.3%), followed by asthma (24.8%), allergic conjunctivitis (7.6%), and food allergy (1.8%). The incidence and adjusted RRs of developing AM for AD patients versus comparison patients were 5.3% versus 4.5% for asthma (RR = 1.20, 95% CI, 1.12-1.29), 14.6% versus 11.2% for allergic rhinitis (RR = 1.35, 95% CI, 1.29-1.41), 1.6% versus 1.1% for allergic conjunctivitis (RR = 1.50, 95% CI, 1.31-1.72), and 0.3% versus 0.1% for food allergy (RR = 2.35, 95% CI, 1.66-3.32). The annual AD + AM treatment costs for patients with AD increased substantially after they developed AMs. The additional financial burden attributable to AMs was estimated to be $482 per year, an almost 1.5-fold increase compared with AD cost alone (from $338 before AM development to $820 afterward, P < 0.001), with approximately equal distribution of costs between medical services ($243) and prescription drugs ($239). The largest incremental costs were observed in asthma ($973), followed by allergic rhinitis ($341). CONCLUSIONS: Patients with AD are significantly more likely to develop AM compared with patients without AD. The total treatment costs for AD patients who developed AMs were nearly 2.5 times the total treatment costs for patients with AD alone.