Overview of Differences and Similarities of Published Mixed Treatment Comparisons on Pharmaceutical Interventions for Multiple Sclerosis.

INTRODUCTION: Mixed treatment comparisons (MTCs) are increasingly important in the assessment of the benefit-risk profile of pharmaceutical treatments for relapsing-remitting multiple sclerosis (RRMS). Interpretation of MTCs requires a clear understanding of the methods of analysis and population studied. The objectives of this work were to compare MTCs of pharmaceutical treatments for RRMS, including a detailed description of differences in populations, treatments assessed, methods used and findings; and to discuss key considerations when conducting an MTC. METHODS: Fourteen databases were searched until July 2019 to identify MTCs (published during or after 2010) in adults (at least 18 years of age) with RRMS or rapidly evolving severe RRMS treated with any form of pharmaceutical treatment. No language restriction was imposed. RESULTS: Twenty-seven MTCs assessing 21 treatments were identified. Comparison highlighted many differences in conduct and reporting between MTCs relating to the patient populations or treatments included, duration of follow-up and outcomes of interest measured. The lack of similarity between the MTCs leads to questions about variability in the robustness of analyses and makes comparisons between studies challenging. CONCLUSION: Given the importance of MTCs for healthcare decision-making, it is imperative that reporting of methods, results and assumptions is clear and transparent to allow accurate interpretation of findings. For MTCs to be relevant, the choice of outcome measures should reflect clinical practice. Combination of treatments or of outcomes measured at different points of time should be avoided, as should imputation without justification. Furthermore, all approved treatment options should be included and updates of MTCs should be conducted when data for new treatments are published.

A Systematic Review and Mixed Treatment Comparison of Pharmaceutical Interventions for Multiple Sclerosis.

BACKGROUND: Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued evolution in the field of MTCs. Additionally, limitations in methodological approach and reporting transparency, even in the most recent publications, makes interpretation and comparison of existing studies difficult. OBJECTIVES: The objectives of this study are twofold: (1) to estimate the efficacy and safety of DMTs at European Commission-approved doses compared with placebo in adults with relapsing-remitting multiple sclerosis (RRMS) using MTC, and (2) to identify and address methodological challenges when performing MTC in RRMS, thereby creating a baseline for comparisons with future treatments. METHODS: Searches were completed in 14 databases, including MEDLINE, Embase, CENTRAL, CDSR and DARE, from inception to June 2018 to identify published or unpublished prospective, randomised controlled trials of all European Union-approved DMTs or DMTs expected to be approved in the near future in RRMS or rapidly-evolving severe RRMS. No language or date restrictions were applied. Studies were included in the MTC if they were judged to have sufficiently similar characteristics, based on the following: patient age; proportion of male participants; Expanded Disability Status Scale (EDSS) score; duration of disease; number of relapses prior to enrolment and proportion of previously treated patients. Background information from the included studies, as well as effect size and confidence intervals (where relevant) of defined outcomes were extracted. Reporting of the MTC was consistent with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) network meta-analysis guidelines. RESULTS: In total, 33 studies were included in the MTC. Annualised relapse rate (ARR 28 trials) was significantly reduced in all treatments compared with placebo. Alemtuzumab had the highest probability (63%) of being the most effective treatment in terms of ARR compared with placebo (rate ratio [RR] 0.28, 95% credible interval [CrI] 0.21-0.38), followed by natalizumab (30% probability; RR 0.32, 95% CrI 0.23-0.43). The risk of 3- and 6-month confirmed disability progression (CDP3M, 13 trials; CDP6M, 14 trials) were similar; CDP6M was significantly reduced for alemtuzumab (hazard ratio [HR] 0.365; 95% CrI 0.165-0.725), ocrelizumab (HR 0.405, 95% CrI 0.188-0.853) and natalizumab (HR 0.459, 95% CrI 0.252-0.840) relative to placebo. There were no significant differences in the odds of serious adverse events (SAEs, 6 trials) between any treatment and placebo. The results of the MTC were limited by the lack of studies reporting direct comparisons between the included treatments and by heterogeneous reporting of key outcome data. CONCLUSIONS: Meta-analyses confirmed the benefit of all DMTs in terms of relapse rate compared with placebo with a comparable rate of SAEs for the DMTs that could be included in the network. The rigor and transparency of reporting in this study provide a benchmark for comparisons with future new agents.

Patient and physician preferences for multiple sclerosis treatments in Germany: A discrete-choice experiment study.

OBJECTIVE: To assess heterogeneity in patient and physician preferences for multiple sclerosis treatment features and outcomes via a discrete-choice experiment. METHOD: Patients with self-reported multiple sclerosis and treating physicians participated in an online discrete-choice experiment. Patients, each considering a better or worse reference condition, and physicians, each considering two patient profiles, chose between hypothetical treatment profiles defined by seven attributes with varying levels: years until disability progression, number of relapses in the decade, mode of administration, dosing frequency, and risks of mild, moderate, and severe side effects. Latent class analysis was used to measure respondent preferences and identify potential subgroups with distinct preferences. RESULTS: Distinct treatment preferences emerged among subgroups of patients (n = 301) and physicians (n = 308). Patients in class 1 (43% of sample) were most concerned about side effects; chief concerns of class 2 patients (57%) were delaying disability progression and avoiding severe side-effect risks. The most important attributes for physicians (by class) were delaying disability (class 1, 45%), avoiding severe side-effect risks and (class 2, 33%), and avoiding all side-effect risks (class 3, 22%). CONCLUSION: Patients and physicians have diverse preferences for multiple sclerosis treatments, reflecting heterogeneity in the disease course and available therapies and the need for shared decision making.

PREFERENCES OF PATIENTS WITH MULTIPLE SCLEROSIS FOR ATTRIBUTES OF INJECTABLE MULTIPLE SCLEROSIS TREATMENTS IN THE UNITED KINGDOM AND FRANCE.

OBJECTIVES: Adherence to injectable disease-modifying treatments in patients with multiple sclerosis (MS) impacts outcomes and can be influenced by perceptions of treatment efficacy, side effects, injection frequency, and the duration of injection. This study aimed to quantify preferences for selected attributes of injectable treatments among individuals with MS in the United Kingdom and France. METHODS: Respondents with a self-reported diagnosis of MS completed an online discrete-choice-experiment survey, consisting of a series of treatment-choice questions. Each choice question presented two hypothetical treatments, each with six attributes (years until disability progression, relapses in the next 4 years, injection time, injection frequency, flu-like symptoms (FLS), and injection-site reactions), each with various levels. Mixed-logit regression analysis was used to estimate preference weights for attribute levels and to calculate the relative importance of changes in treatment attributes (vertical distance between preference weights). Minimum acceptable efficacy estimates indicate improvement in efficacy that respondents would require in exchange for worsening injection frequency and FLS. RESULTS: In both countries, 100 respondents completed the survey. In the United Kingdom and France, respectively, improving the time until disability progression from 2 to 4 years, reducing injection frequency from "daily" to "every 2 weeks", and reducing FLS from 3 days after every injection to none had a relative importance of 2.9 and 2.6, 3.0 and 3.5, and 2.5 and 3.1. Given the ranges included in the study, changes in these attributes were more important than most changes in other attributes assessed. CONCLUSIONS: Reductions in the injection frequency of MS treatments and FLS can be as important to patients as improvements in treatment efficacy.

Measuring the impact of multiple sclerosis: Enhancing the measurement performance of the Multiple Sclerosis Impact Scale (MSIS-29) using Rasch Measurement Theory (RMT).

BACKGROUND: Study objectives were to evaluate the Multiple Sclerosis Impact Scale (MSIS-29) and explore an optimized scoring structure based on empirical post-hoc analyses of data from the Phase III ADVANCE clinical trial. METHODS: ADVANCE MSIS-29 data from six time-points were analyzed in a sample of patients with relapsing-remitting multiple sclerosis (RRMS). Rasch Measurement Theory (RMT) analysis was undertaken to examine three broad areas: sample-to-scale targeting, measurement scale properties, and sample measurement validity. Interpretation of results led to an alternative MSIS-29 scoring structure, further evaluated alongside responsiveness of the original and revised scales at Week 48. RESULTS: RMT analysis provided mixed evidence for Physical and Psychological Impact scales that were sub-optimally targeted at the lower functioning end of the scales. Their conceptual basis could also stand to improve based on item fit results. The revised MSIS-29 rescored scales improved but did not resolve the measurement scale properties and targeting of the MSIS-29. In two out of three revised scales, responsiveness analysis indicated strengthened ability to detect change. CONCLUSION: The revised MSIS-29 provides an initial evidence-based improved patient-reported outcome (PRO) instrument for evaluating the impact of MS. Revised scoring improves conceptual clarity and interpretation of scores by refining scale structure to include Symptoms, Psychological Impact, and General Limitations. CLINICAL TRIAL: ADVANCE (ClinicalTrials.gov identifier NCT00906399).

Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

BACKGROUND: In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL). METHODS: In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ⩾1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ⩾ 1.0, or ⩾1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset. RESULTS: Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by ⩾1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks. CONCLUSIONS: Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing-remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [ClinicalTrials.gov identifier: NCT00906399].

Identification of Key Cost Generating Events for Idiopathic Pulmonary Fibrosis: A Systematic Review.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable, debilitating disease which impairs lung function and eventually leads to death. Currently, there is a lack of effective modifying therapies and treatments for IPF as the underlying epidemiological mechanism is not clearly understood. This leads to difficulty in diagnosing and managing IPF, which results in a high incurment of disease-associated cost. Even though IPF poses a substantial economic burden, there is a lack of research available on cost triggers and healthcare utilization, which can be a barrier to future economic evaluations of new medicines for IPF. OBJECTIVES: We aimed to conduct a systematic literature review (SLR) to identify the key cost-generating events of IPF and to gather any related costing information. RESULTS: The data showed that the main events triggering high resource use in patients were the symptoms of IPF progression along with comorbidities and lung transplantations. These events result in a high economic impact through the use of medications, health care professionals, and hospital stays. CONCLUSION: More research is needed to identify the direct, and indirect, relationships between IPF events and the costs they generate. This would help to further evaluate the area of need for future health technologies and to understand what events should be targeted to reduce the global economic burden of IPF.

Cost-effectiveness analysis of peginterferon beta-1a compared with interferon beta-1a and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis in the United States.

Objective Peginterferon beta-1a 125 mcg, administered subcutaneously (SC) every 2 weeks, a new disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS), was approved by the US Food and Drug Administration in 2014. This study assesses the cost-effectiveness of peginterferon beta-1a vs interferon beta-1a (44 mcg SC 3 times per week) and glatiramer acetate (20 mg SC once-daily) in the treatment of RRMS from the perspective of a US payer over 10 years. Methods A Markov cohort economic model was developed for this analysis. The model predicts disability progression, occurrence of relapses and other adverse events and translates them into quality-adjusted life years (QALYs) and costs. Natural history data were obtained from the placebo arm of the ADVANCE trial of peginterferon beta-1a, the London Ontario (Canada) database and a large population-based MS survey. Comparative efficacy of each DMT vs placebo was obtained from a network meta-analysis. Costs (in 2014 US dollars) were sourced from public databases and literature. Clinical and economic outcomes were discounted at 3% per year. Results Over 10 years, peginterferon beta-1a was dominant (i.e., more effective and less costly), with cost-savings of $22,070 and additional 0.06 QALYs when compared with interferon beta-1a 44 mcg and with cost-savings of $19,163 and 0.07 QALYs gained when compared with glatiramer acetate 20 mg. Results were most sensitive to variations in the treatment effect of each DMT, treatment acquisition costs of each DMT and the time horizon. Probabilistic sensitivity analyses indicated that peginterferon beta-1a remains dominant in >90% of 5,000 replications compared with either DMTs. Conclusion This analysis suggests that long-term treatment with peginterferon beta-1a improves clinical outcomes at reduced costs compared with interferon beta-1a 44 mcg and glatiramer acetate 20 mg and should be a valuable addition to managed care formularies for treating patients with RRMS.

A discrete-choice experiment to determine patient preferences for injectable multiple sclerosis treatments in Germany.

OBJECTIVES: The aim of this study was to assess the relative importance of features of a hypothetical injectable disease-modifying treatment for patients with multiple sclerosis using a discrete-choice experiment. METHODS: German residents at least 18 years of age with a self-reported physician diagnosis of multiple sclerosis completed a 25-30 minute online discrete-choice experiment. Patients were asked to choose one of two hypothetical injectable treatments for multiple sclerosis, defined by different levels of six attributes (disability progression, the number of relapses in the next 4 years, injection time, frequency of injections, presence of flu-like symptoms, and presence of injection-site reactions). The data were analyzed using a random-parameters logit model. RESULTS: Of 202 adults who completed the survey, results from 189 were used in the analysis. Approximately 50% of all patients reported a diagnosis of relapsing-remitting multiple sclerosis, and 31% reported secondary progressive multiple sclerosis. Approximately 71% of patients had current or prior experience with injectable multiple sclerosis medication. Approximately 53% had experienced flu-like symptoms caused by their medication, and 47% had experienced mild injection-site reactions. At least one significant difference was seen between levels in all attributes, except injection time. The greatest change in relative importance between levels of an attribute was years until symptoms get worse from 1 to 4 years. The magnitude of this difference was about twice that of relapses in the next 4 years, frequency of injections, and flu-like symptoms. CONCLUSIONS: Most attributes examined in this experiment had an influence on patient preference. Patients placed a significant value on improvements in the frequency of dosing and disability progression. Results suggest that changes in injection frequency can be as important as changes in efficacy and safety attributes. Understanding which attributes of injectable therapies influence patient preference could potentially improve outcomes and adherence in patients with multiple sclerosis.

Patient Preferences for Injectable Treatments for Multiple Sclerosis in the United States: A Discrete-Choice Experiment.

BACKGROUND AND OBJECTIVE: Patients' perceptions and experiences of medication efficacy, medication adverse events, dosing frequency, and dosing complexity have been found to influence adherence to injectable disease-modifying treatments (DMTs) in patients with multiple sclerosis (MS). The aim of this study was to quantify patient preferences for features of injectable DMTs for MS. METHODS: Adult patients in the United States (US) with a self-reported diagnosis of MS completed an online discrete-choice experiment survey to assess preference for a number of features of a hypothetical injectable DMT. Patients chose hypothetical treatments in paired comparisons, where each treatment was described by features or attributes, including the number of years until disability progression, the number of relapses in the next 4 years, injection time, the frequency of injections, the occurrence of flu-like symptoms (FLS), and severity of injection-site reactions. Random-parameters logit regression parameters were used to calculate preference weights of attribute levels and the relative importance of changes in treatment features. RESULTS: Of the 205 patients who completed the survey, 192 provided sufficient data for analysis. The results indicated a broad range of tradeoffs that patients would be willing to make. With regard to this, the relative importance of an improvement in the number of years until disability progression from 1 to 2 (i.e., vertical distance between preference weights for these attribute levels) was 0.9 [95% confidence interval (CI) 0.5-1.2], the relative importance of this change was approximately equivalent to that of an improvement from 12 injections per month to two (mean 0.8, 95% CI 0.4-1.2), or approximately equivalent to a decrease from four to one relapses in the next 4 years (mean 0.8, 95% CI 0.5-1.2), or FLS 3 days after every injection to 3 days after some injections (mean 1.0, 95% CI 0.6-1.4). CONCLUSIONS: These results suggest that an improvement in treatment efficacy may be as important as a reduction in injection frequency or a reduction in some adverse events for patients who self-administer injectable DMTs for MS. Understanding the preferences of patients who use injectable treatments will inform the development of such treatments, which may in turn improve patient medication adherence and well-being.

A Network Meta-Analysis of Efficacy and Evaluation of Safety of Subcutaneous Pegylated Interferon Beta-1a versus Other Injectable Therapies for the Treatment of Relapsing-Remitting Multiple Sclerosis.

Subcutaneous pegylated interferon beta-1a (peginterferon beta-1a [PEG-IFN]) 125 µg every two or four weeks has been studied in relapsing-remitting multiple sclerosis (RRMS) patients in the pivotal Phase 3 ADVANCE trial. In the absence of direct comparative evidence, a network meta-analysis (NMA) was conducted to provide an indirect assessment of the relative efficacy, safety, and tolerability of PEG-IFN versus other injectable RRMS therapies. Systematic searches were conducted in MEDLINE, Embase, and the Cochrane Library, and conference proceedings from relevant annual symposia were hand-searched. Included studies were randomized controlled trials evaluating ≥1 first-line treatments including interferon beta-1a 30, 44, and 22 µg, interferon beta-1b, and glatiramer acetate in patients with RRMS. Studies were included based on a pre-specified protocol and extracted by a team of independent reviewers and information scientists, utilizing criteria from NICE and IQWiG. In line with ADVANCE findings, NMA results support that PEG-IFN every 2 weeks significantly reduced annualized relapse rate, and 3- and 6-month confirmed disability progression (CDP) versus placebo. There was numerical trend favoring PEG-IFN every 2 weeks versus other IFNs assessed for annualized relapse rate, and versus all other injectables for 3- and 6-month CDP (6-month CDP was significantly reduced versus IFN beta-1a 30 µg). The safety and tolerability profile of PEG-IFN beta-1a 125 µg every 2 weeks was consistent with that of other evaluated treatments. Study limitations for the NMA include variant definitions of relapse and other systematic differences across trials, assumptions that populations were sufficiently similar, and inability to perform NMA of adverse events. With similar efficacy compared to other RRMS treatments in terms of annualized relapse rate and 3- and 6-month CDP, a promising safety profile, and up to 93% reduction in number of injections (which may improve adherence), PEG-IFN every 2 weeks offers a valuable alternative treatment option for patients with RRMS.

A comparison of two experimental design approaches in applying conjoint analysis in patient-centered outcomes research: a randomized trial.

BACKGROUND: While the application of conjoint analysis and discrete-choice experiments in health are now widely accepted, a healthy debate exists around competing approaches to experimental design. There remains, however, a paucity of experimental evidence comparing competing design approaches and their impact on the application of these methods in patient-centered outcomes research. OBJECTIVES: Our objectives were to directly compare the choice-model parameters and predictions of an orthogonal and a D-efficient experimental design using a randomized trial (i.e., an experiment on experiments) within an application of conjoint analysis studying patient-centered outcomes among outpatients diagnosed with schizophrenia in Germany. METHODS: Outpatients diagnosed with schizophrenia were surveyed and randomized to receive choice tasks developed using either an orthogonal or a D-efficient experimental design. The choice tasks elicited judgments from the respondents as to which of two patient profiles (varying across seven outcomes and process attributes) was preferable from their own perspective. The results from the two survey designs were analyzed using the multinomial logit model, and the resulting parameter estimates and their robust standard errors were compared across the two arms of the study (i.e., the orthogonal and D-efficient designs). The predictive performances of the two resulting models were also compared by computing their percentage of survey responses classified correctly, and the potential for variation in scale between the two designs of the experiments was tested statistically and explored graphically. RESULTS: The results of the two models were statistically identical. No difference was found using an overall chi-squared test of equality for the seven parameters (p = 0.69) or via uncorrected pairwise comparisons of the parameter estimates (p-values ranged from 0.30 to 0.98). The D-efficient design resulted in directionally smaller standard errors for six of the seven parameters, of which only two were statistically significant, and no differences were found in the observed D-efficiencies of their standard errors (p = 0.62). The D-efficient design resulted in poorer predictive performance, but this was not significant (p = 0.73); there was some evidence that the parameters of the D-efficient design were biased marginally towards the null. While no statistical difference in scale was detected between the two designs (p = 0.74), the D-efficient design had a higher relative scale (1.06). This could be observed when the parameters were explored graphically, as the D-efficient parameters were lower. CONCLUSIONS: Our results indicate that orthogonal and D-efficient experimental designs have produced results that are statistically equivalent. This said, we have identified several qualitative findings that speak to the potential differences in these results that may have been statistically identified in a larger sample. While more comparative studies focused on the statistical efficiency of competing design strategies are needed, a more pressing research problem is to document the impact the experimental design has on respondent efficiency.

Decision-making criteria among national policymakers in five countries: a discrete choice experiment eliciting relative preferences for equity and efficiency.

BACKGROUND: Worldwide, there is a need for formalization of the priority setting processes in health. Recent research has used the term multicriteria decision analysis for methods that systematically include preferences for both equity and efficiency. The present study compares decision-makers' preferences at the country level for a set of equity and efficiency criteria according to a multicriteria decision analysis framework. METHODS: Discrete choice experiments were conducted for Brazil, Cuba, Nepal, Norway, and Uganda. By using standardized methods, we elicited preferences for intervention attributes using a individual choice questionnaire. A multinomial logistic regression was applied to estimate the coefficients for all single-policy criteria, per country. Attributes were assigned to an equity group or to an efficiency group. After testing for scale variance, predicted probabilities for interventions with both types of attributes were compared across countries. RESULTS: The Norway and Nepal groups showed considerable preferences for efficiency criteria over equity criteria with percent change in respective predicted sum probabilities of [10%, -84%] and [6%, -79%]. Brazil and Uganda also showed preference for the efficiency criteria though less convincingly ([-34%, -93%], [-18%, -63%], respectively). The Cuban group showed the strongest preferences with equity attributes dominating efficiency ([-52%, 213%]). CONCLUSIONS: Group preferences of policymakers show explicit but varying trade-offs of efficiency and equity in these diverse settings. This multicriteria decision analysis approach, using discrete choice experiments, indicates that systematic setting of health priorities is possible across a variety of countries. It may be a valuable tool to guide health reform initiatives.

Can patients diagnosed with schizophrenia complete choice-based conjoint analysis tasks?

BACKGROUND: Schizophrenia is a severe mental illness associated with hallucinations, delusions, apathy, poor social functioning, and impaired cognition. Researchers and funders have been hesitant to focus efforts on treatment preferences of patients with schizophrenia because of the perceived cognitive burden that research methods, such as conjoint analysis, place on them. OBJECTIVE: The objective of this study was to test if patients diagnosed with schizophrenia were able to complete a choice-based conjoint analysis (often referred to as discrete-choice experiments) and to test if meaningful trade-offs were being made. METHODS: German outpatients diagnosed with schizophrenia were eligible to participate in this study if they were aged 18-65 years, had received treatment for at least 1 year and were not experiencing acute symptoms. Conjoint analysis tasks were based on six attributes, each with two levels, which were identified via a literature review and focus groups. A psychologist in a professional interview facility presented each respondent with the eight tasks with little explanation. All interviews were recorded, transcribed, and analyzed to verify that respondents understood the tasks. Preferences were assessed using logistic regression, with a correction for clustering. RESULTS: We found evidence that the 21 patients diagnosed with schizophrenia participating in the study could complete conjoint analysis tasks in a meaningful way. Patients not only related to the scenarios presented in conjoint tasks, but explicitly stated that they used their own preferences to judge which scenarios were better. Statistical analysis confirmed all hypotheses about the attributes (i.e. all attributes had the expected sign). Having a supportive physician, not feeling slowed, and improvements in stressful situations (p < 0.01) were the most important attributes. CONCLUSIONS: We found that patients diagnosed with schizophrenia can complete conjoint analysis tasks, that they base their decisions on their own preferences, and that patients make trade-offs between attributes.

A discrete-event simulation of smoking-cessation strategies based on varenicline pivotal trial data.

BACKGROUND: Smoking is the leading cause of preventable death in the US. While one in five individuals smoke, and 70% of these indicate a desire to quit, <5% of unaided quit attempts succeed. Cessation aids can double or triple the odds of successfully quitting. Models of smoking-cessation behaviour can elucidate the implications of individual abstinence patterns to allow better tailoring of quit attempts to an individual's characteristics. OBJECTIVE: The objectives of this study were to develop and validate a discrete-event simulation (DES) to evaluate the benefits of smoking abstinence using data from the pooled pivotal clinical trials of varenicline versus bupropion or placebo for smoking cessation and to provide a foundation for the development of a lifetime smoking-cessation model. METHODS: The DES model simulated the outcome of a single smoking-cessation attempt over 1 year, in accordance with the clinical trial timeframes. Pharmaceutical costs were assessed from the perspective of a healthcare payer. The model randomly sampled patient profiles from the pooled varenicline clinical trials. All patients were physically and mentally healthy adult smokers who were motivated to quit abruptly. The model allowed for comparisons of up to five distinct treatment approaches for smoking cessation. In the current analyses, three interventions corresponding to the clinical trials were evaluated, which included brief counselling plus varenicline 1.0 mg twice daily (bid) or bupropion SR 150 mg bid versus placebo (i.e. brief counselling only). The treatment periods in the clinical trials were 12 weeks (target quit date: day 8), with a 40-week non-treatment follow-up, and counselling continuing over the entire 52-week period in all treatment groups. The main outcome modelled was the continuous abstinence rate (CAR; defined as complete abstinence from smoking and confirmed by exhaled carbon monoxide ≤ 10 ppm) at end of treatment (weeks 9-12) and long-term follow-up (weeks 9-52), and total time abstinent from smoking over the course of 52 weeks. The model also evaluated costs and cost-effectiveness outcomes. RESULTS: For the varenicline, bupropion and placebo cohorts, respectively, the model predicted CARs for weeks 9-12 of 44.3%, 30.4% and 18.6% compared with observed rates of 44.0%, 29.7% and 17.7%; over weeks 9-52, predicted CARs in the model compared with observed rates in the pooled clinical studies were 22.9%, 16.4% and 9.4% versus 22.4%, 15.4% and 9.3%, respectively. Total mean abstinence times accrued in the model varenicline, bupropion and placebo groups, respectively, were 3.6, 2.6 and 1.5 months and total pharmaceutical treatment costs were $US261, $US442 and $US0 (year 2008 values) over the 1-year model period. Using cost per abstinent-month achieved as a measure of cost effectiveness, varenicline dominated bupropion and yielded an incremental cost-effectiveness ratio of $US124 compared with placebo. CONCLUSION: The model accurately replicated abstinence patterns observed in the clinical trial data using individualized predictions and indicated that varenicline was more effective and may be less costly than bupropion. This simulation incorporated individual predictions of abstinence and relapse, and provides a framework for lifetime modelling that considers multiple quit attempts over time in diverse patient populations using a variety of quit attempt strategies.

Identifying patient-relevant endpoints among individuals with schizophrenia: an application of patient-centered health technology assessment.

OBJECTIVES: Schizophrenia imposes a great burden on society, and while evaluation should play an important role in informing society's efforts to alleviate these burdens, it is unclear what "endpoints" should be chosen as the objective of such analyses. The objectives of the study were to elicit endpoints directly from patients with schizophrenia, to ascertain whether patients are sufficiently cognoscente to express what endpoints are and are not important to them and to rank the relevant endpoints. METHODS: We applied principles of patient-centered health technology assessment to identify and value endpoints from the patient's perspective. Focus groups were conducted to elicit endpoints, using interpretive phenomalogical analysis (IPA) to guide the collection, analysis and interpretation of data. Patient interviews were subsequently used to elicit patient preference over endpoints. Respondents were presented with cards outlining the endpoints and asked to remove irrelevant cards. They where then asked to identify and rank their five most relevant endpoints in order of importance. Interviews were recorded for the purposed of triangulation, and data was analyzed using descriptive statistics. Patients were recruited from five geographically diverse cities in Germany. Eligibility required a diagnosis of schizophrenia by a physician and treatment with an antipsychotic medication for at least one year. Respondents were excluded if they were experiencing an acute episode. RESULTS: Thirteen endpoints emerged as important from the focus groups spanning side-effects, functional status, processes of care and clinical outcomes. Respondents could clearly identify relevant and irrelevant endpoints, and rank which factors were important to them. Triangulation between field notes of the ranking exercise and recordings confirmed that rankings were not arbitrary, but justified from the respondents' point of view. CONCLUSIONS: Patients with schizophrenia can express preferences over endpoints. Our results show that qualitative methods such as IPA can be used to identify factors, but ranking exercises provide a more robust method for ranking the importance of endpoints. Future research involving patients with schizophrenia ranking outcomes is needed to identify variations across patients and methods such as conjoint analysis could prove beneficial in identifying acceptable tradeoffs across endpoints.

Things are Looking up Since We Started Listening to Patients: Trends in the Application of Conjoint Analysis in Health 1982-2007.

Clinical and healthcare decision makers have repeatedly endorsed patient-centered care as a goal of the health system. However, traditional methods of evaluation reinforce societal views, and research focusing on views of patients is often referred to as 'soft science.' Conjoint analysis presents a scientifically rigorous research tool that can be used to understand patient preferences and inform decision making. This paper documents applications of conjoint analysis in medicine and systematically reviews this literature in order to identify publication trends and the range of topics to which conjoint analysis has been applied. In addition, we document important methodological aspects such as sample size, experimental design, and method of analysis.Publications were identified through a MEDLINE search using multiple search terms for identification. We classified each article into one of three categories: clinical applications (n = 122); methodological contributions (n = 56); and health system applications (n = 47). Articles that did not use or adequately discuss conjoint analysis methods (n = 164) were discarded. We identified a near exponential increase in the application of conjoint analyses over the last 10 years of the study period (1997-2007). Over this period, the proportion of applications on clinical topics increased from 40% of articles published in MEDLINE from 1998 to 2002, to 64% of articles published from 2003 to 2007 (p = 0.002).The average sample size among articles focusing on health system applications (n = 556) was significantly higher than clinical applications (n = 277) [p = 0.001], although this 2-fold difference was primarily due to a number of outliers reporting sample sizes in the thousands. The vast majority of papers claimed to use orthogonal factorial designs, although over a quarter of papers did not report their design properties. In terms of types of analysis, logistic regression was favored among clinical applications (28%), while probit was most commonly used among health systems applications (38%). However, 25% of clinical applications and 33% of health systems articles failed to report what regression methods were used. We used the International Classification of Diseases - version 9 (ICD-9) coding system to categorize clinical applications, with approximately 26% of publications focusing on neoplasm. Program planning and evaluation applications accounted for 22% of the health system articles.While interest in conjoint analysis in health is likely to continue, better guidelines for conducting and reporting conjoint analyses are needed.