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.

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).

Reconsidering the economic value of multiple sclerosis therapies.

OBJECTIVES: To illustrate a more comprehensive view of value associated with medicines treating a highly severe illness and to apply these insights to estimate the costs and benefits of 3 treatments for multiple sclerosis (MS): Avonex, Tysabri, and Tecfidera. STUDY DESIGN: Retrospective study spanning 2002 to 2013. We used economic theory to derive the value of therapy to patients with MS and to individuals who face the risk of contracting MS in the future, under the alternative assumptions that therapies were fully insured or paid for out of pocket. METHODS: Models were parameterized through secondary data analysis and targeted literature review. Estimates of individual value were aggregated to the societal level using therapy-specific treatment prevalence rates. Aggregate consumer value was compared with manufacturer revenue. RESULTS: In the baseline model, Avonex, Tysabri, and Tecfidera generated $46.2 billion of total value to consumers, almost one-third of which accrued to those without MS. The total value to consumers was double manufacturer revenue. Results were qualitatively robust to the use of alternate epidemiological and economic parameters. We found that value to the healthy is positively related to disease severity, and that value to both the sick and the healthy are larger when costs are shared via health insurance. CONCLUSIONS: Theory predicts that treatments for severe disease provide "peace of mind" value to the healthy. Avonex, Tysabri, and Tecfidera have generated significant social value, a large majority of which accrues to consumers. Future economic valuations of medical technology should consider both the potential value to the healthy and the effects of insurance.

Pain relief and improved physical function in knee osteoarthritis patients receiving ongoing hylan G-F 20, a high-molecular-weight hyaluronan, versus other treatment options: data from a large real-world longitudinal cohort in Canada.

From the Southwestern Ontario database, one of the largest primary-care datasets in Canada, 1,263 patients with osteoarthritis (OA) of one or both knees were identified who received two consecutive series of intra-articular (IA) injections of hylan G-F 20 preparation and no other prescribed OA medications, and were evaluated fully between 2006 and 2012. A cohort of 3,318 demographically matched OA patients who had not been treated with IA injection therapy was identified from the same database for comparison. Responses to therapy were assessed by means of a 10-point visual analog scale (VAS) for pain at rest and after completion of a 6-minute walk test (6 MWT), while physical capacity was measured by performance in the 6 MWT itself. After two cycles of hylan G-F 20 therapy, the average VAS score for pain at rest declined from 7.82 ± 1.27 at baseline to 4.16 ± 1.51 (average change 3.66 ± 1.78, significantly more than the reduction of 3.12 ± 2.03 seen in the reference group [P < 0.012]) and the average VAS score for pain after the 6 MWT decreased by 5.56 ± 1.74 points (from 9.58 ± 0.4 at baseline to 4.02 ± 1.67 at the final assessment), a significantly larger change than that seen in the reference group (Δ2.99 ± 1.85; P<0.001 for intergroup comparison). Distance walked in the 6 MWT increased on average by 115 m, significantly more than that seen in the reference group (Δ91 m; P < 0.001 for intergroup comparison). These findings from a primary-care database suggest sustained benefits in terms of pain and physical function from repeat cycles of IA injections of hylan G-F 20 and no other prescribed OA medications in adults with OA of the knee.