Indirect Comparison of Ropinirole and Pramipexole as Levodopa Adjunctive Therapy in Advanced Parkinson's Disease: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: To evaluate the comparative efficacy and safety of ropinirole and pramipexole as adjunctive therapies to levodopa (L-dopa) for the management of advanced Parkinson's disease (PD), via a systematic review and network meta-analysis. METHODS: Twenty-one double-blind randomised controlled trials of patients with advanced PD with motor fluctuations receiving L-dopa comparing ropinirole or pramipexole with comparators were identified from 2550 publications. Bayesian indirect comparison methods were applied to independently review efficacy outcomes including off-time reduction, Unified Parkinson's Disease Rating Scale-Activity of Daily Living (UPDRS-ADL) and UPDRS-motor scores, and safety outcomes including adverse events (AE) and patient withdrawals, to determine indirect treatment comparison mean differences (MD) or hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: The indirect efficacy comparison resulted in a statistically nonsignificant off-time reduction difference (hours) of ropinirole-sustained release (SR) versus pramipexole-immediate release (MD - 0.25; 95% CI - 0.71, 0.21) and ropinirole-SR versus pramipexole-extended release (ER) (MD 0.18; 95% CI - 0.40, 0.76). Ropinirole-SR adjunctive treatment showed a tendency towards more improvement in UPDRS-ADL score (MD 1.24; 95% CI 0.23, 2.24) than adjunctive treatment of pramipexole-ER. Pramipexole-ER may be less likely to induce somnolence as an AE compared with ropinirole-SR (HR 0.46; 95% CI 0.23, 0.89). However, there were no statistically significant differences in UPDRS-motor score reduction, incidence of dyskinesia, hallucination, hypotension, insomnia and nausea, or withdrawals due to AE, for any reason. CONCLUSION: Adjunctive therapy with ropinirole-SR or pramipexole appears to offer similar efficacy and tolerability in patients with advanced PD on the basis of this indirect comparison. FUNDING: GSK.

Cost-Effectiveness and Dynamic Efficiency: Does the Solution Lie Within?

The majority of the current systems spread across the world require the value of pharmaceuticals to be demonstrated with an acceptable degree of certainty before a technology is funded. Often involving the notion of cost-effectiveness, one of the key characteristics of such assessments tends to be the consideration of efficiency as a static outcome; with a strong emphasis on current health gains but a disregard for the impact of decision making on the potential health value over time. In this article, we argue that current systems using cost-effectiveness thresholds may provide an incomplete indicator of value. We defend the idea that funding decisions should also be informed by dynamic efficiency considerations and reflect both the current and the future value of achieving a certain level of effectiveness in a specific disease area. We further lay down the foundations for the implementation of such a value assessment framework.

Cost-Effectiveness of Dolutegravir in HIV-1 Treatment-Naive and Treatment-Experienced Patients in Canada.

INTRODUCTION: The Antiretroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model was adapted to evaluate the cost-effectiveness of dolutegravir (DTG) in Canada in treatment-naive (TN) and treatment-experienced (TE) human immunodeficiency virus (HIV)-1 patients. METHODS: The ARAMIS-DTG model is a microsimulation model with a lifetime analytic time horizon and a monthly cycle length. Markov health states were defined by HIV health state (with or without opportunistic infection). DTG was compared to efavirenz (EFV), raltegravir (RAL), darunavir/ritonavir, rilpivirine (RPV), elvitegravir/cobicistat, atazanavir/ritonavir and lopinavir/ritonavir in TN patients and to RAL in TE patients. The initial cohort, the main efficacy data and safety data were derived from phase III clinical trials. Treatment algorithms were based on expert opinion. Costs normalized to the year 2013 included antiretroviral treatment cost, testing, adverse event, HIV and cardiovascular disease care and were derived from the literature. RESULTS: Dolutegravir was estimated to be the dominant strategy compared with all comparators in both TN and TE patients. Treatment with DTG was associated with additional quality-adjusted life-years that ranged from 0.17 (vs. RAL) to 0.47 (vs. EFV) in TN patients and was 0.60 in TE patients over a lifetime. Cost savings ranged from Can$1393 (vs. RPV) to Can$28,572 (vs. RAL) in TN patients and amounted to Can$3745 in TE patients. Sensitivity analyses demonstrated the robustness of the model. CONCLUSIONS: Dolutegravir is a dominant strategy in the management of TN and TE patients when compared to recommended comparators. This is mainly related to the high efficacy and high barrier to resistance. FUNDING: ViiV Healthcare.

Distribution of health-related social surplus in pharmaceuticals: an estimation of consumer and producer surplus in the management of high blood lipids and COPD.

BACKGROUND: Following suggestions that developers should be allowed to capture a defined share of the total value generated by their technologies, the amount of surplus accruing to the pharmaceutical industry has become an important concept when discussing policies to encourage innovation in healthcare. METHODS: Observational clinical and market data spanning over a period of 20 years were applied in order to estimate the social surplus generated by pharmaceuticals used in the management of high cholesterol and chronic obstructive pulmonary disease (COPD). The distribution of social surplus between consumers and producers was also computed and the dynamics of rent extraction examined. RESULTS: Health-related social surplus increased consistently over time for both disease areas, mostly due to the launch of more effective technologies and a greater number of patients being treated for the conditions. However, the growth rate of social surplus differed for each disease and dissimilar patterns of distribution between consumer and producer surplus emerged across the years. For lipid-lowering therapies, yearly consumer surplus reaches 85 % of total health-related social surplus after the loss of exclusivity of major molecules, whilst for COPD it ranges from 54 to 69 %. Average producer surplus is approximately 25 % of total health-related social surplus in the lipid-lowering market between 1990 and 2010, and 37 % for COPD between 2001 and 2010. The share of surplus captured by non-innovative generic producers also varies differently across periods for both markets, reaching 11.12 % in the case of lipid-lowering therapies but just 1.55 % in the case of COPD. CONCLUSION: A considerable amount of the value may be recouped by consumers only towards the end of the lifecycle. Elements affecting the distribution of social surplus vary across disease areas and include the market pricing structure and the pattern of clinical effectiveness observed over time. The application of a longer-term disease specific perspective may be required when assessing the cost-effectiveness of health technologies at launch.

The determinants of cost-effectiveness potential: an historical perspective on lipid-lowering therapies.

BACKGROUND: The concept of cost effectiveness emerged in an attempt to link the prices of new healthcare technologies to the immediate value they provide, with payers defining the acceptable cost per unit of incremental effect over the alternatives available. It has been suggested that such measures allow developers to assess potential market profitability in an early stage of development, but may result in discouraging investment in efficient research if not used appropriately. OBJECTIVE: The objective of this study is to identify the pattern of the factors determining cost effectiveness and assess the evolution of cost-effectiveness potential for drugs in development using lipid-lowering therapy as a case study. METHODS: The study is based on observational clinical and market data covering a 20-year period (from 1990 to 2010) in the UK. Real-life clinical data including total cholesterol laboratory test results were extracted from the Clinical Practice Research Datalink (CPRD) and are used to illustrate how the clinical effectiveness of existing standard care changed over time in patients managed in clinical practice. Prescription Cost Analysis (PCA) data were extracted and the average price of the drug mix used was computed throughout the study period. Using this information, the maximum clinical benefit and cost savings to be had were estimated for each year of the analysis using a cost-effectiveness model. Subsequently, the highest price a new technology providing the maximum clinical effectiveness possible (i.e. eliminating cardiovascular risk from high cholesterol levels) could achieve under current cost-effectiveness rules was calculated and used as a measure of the potential cost effectiveness of drugs in development. RESULTS: The results in this study show that the total cholesterol values of patients managed in clinical practice moved steadily towards recommended clinical targets. Overall, the absolute potential for incremental health-related quality of life decreased by approximately 78 %, contracting from 0.36 QALYs to 0.08 QALYs, which resulted in a saving of approximately 15 % of the costs related to cardiovascular events. The price of the drug mix used in the management of high blood cholesterol varied considerably across the years: the weighted average monthly price (in year 2007 values) started at approximately £14, peaked around £26 and progressively decreased to its minimum at £6.85 in 2010. As a consequence, the maximum price allowed by current cost-effectiveness rules for a new technology achieving the clinical target was found to decrease by a minimum of 80 % between 1990 and 2010. CONCLUSION: The analysis supports the hypothesis that the potential for cost effectiveness of new therapies is dependent on factors specific to each disease area and furthermore to sub-populations within disease areas. Despite a clinical need still existing, the results suggest that no more technologies are likely to be developed in certain disease areas based on their low perceived cost-effectiveness potential. This occurs without considering the immediate and future value of the effectiveness lost, which may depend on the technical difficulty of materializing future advancements, and ignores the permanent character of such a decision. The analysis suggests that a single, static and arbitrary cost-effectiveness threshold may not be sufficient to capture the drug-development dynamics occurring at the disease level and successfully direct research to the disease areas that are most valued by society.

Antihypertensive drugs: a perspective on pharmaceutical price erosion and its impact on cost-effectiveness.

OBJECTIVE: When comparators' prices decrease due to market competition and loss of exclusivity, the incremental clinical effectiveness required for a new technology to be cost-effective is expected to increase; and/or the minimum price at which it will be funded will tend to decrease. This may be, however, either unattainable physiologically or financially unviable for drug development. The objective of this study is to provide an empirical basis for this discussion by estimating the potential for price decreases to impact on the cost-effectiveness of new therapies in hypertension. METHODS: Cost-effectiveness at launch was estimated for all antihypertensive drugs launched between 1998 and 2008 in the United Kingdom using hypothetical degrees of incremental clinical effectiveness within the methodologic framework applied by the UK National Institute for Health and Clinical Excellence. Incremental cost-effectiveness ratios were computed and compared with funding thresholds. In addition, the levels of incremental clinical effectiveness required to achieve specific cost-effectiveness thresholds at given prices were estimated. RESULTS: Significant price decreases were observed for existing drugs. This was shown to markedly affect cost-effectiveness of technologies entering the market. The required incremental clinical effectiveness was in many cases greater than physiologically possible so, as a consequence, a number of products might not be available today if current methods of economic appraisal had been applied. CONCLUSIONS: We conclude that the definition of cost-effectiveness thresholds is fundamental in promoting efficient innovation. Our findings demonstrate that comparator price attrition has the potential to put pressure in the pharmaceutical research model and presents a challenge to new therapies being accepted for funding.

A dynamic perspective on pharmaceutical competition, drug development and cost effectiveness.

Limited healthcare budgets result in payers adopting policies at national, regional or local level to achieve allocative efficiency in drug spending. Some of these aim at creating a link between pharmaceutical prices and the value they provide by setting a cost effectiveness (CE) threshold as the maximum acceptable ratio between incremental costs and effects of new drugs. The clinical effectiveness of the comparator used in those CE analyses tends to be greater over time, whilst, due to market competition and loss of exclusivity, their price is expected to be lower. At the same time, research and development (R&D) costs increase with inflation and with efforts to address regulation towards increased safety concerns. As effective patent times decrease, a minimum price constraint raises for the new entrant. These features occur at different rates across disease areas and are expected to result in differently shaped innovation curves. In this scenario, we demonstrate that a general arbitrary threshold may prevent further efficient R&D. Investment may be withdrawn before the optimum innovation point is reached and affordable clinical effectiveness may be lost. We conclude that disease-specific characteristics are an additional consideration in CE decision rules to accommodate the particularities of innovation across disease areas.