What is the value of ‘me-too' drugs?

The objective of this article is to estimate the value of ‘follow-on' or ‘me-too' drugs from the payer, industry and societal perspectives. Since me-too drugs do not bring additional clinical benefits, they are only valuable to payers if they save costs. An empirical model was constructed to identify the factors affecting whether a me-too drug results in cost savings to the pharmaceutical budgets of payers. These factors included the intensity of promotional spending, price discount and time to entry. Twenty-seven second-entrant products with limited differentiation were identified; their launch dates ranged from 1988 to 2009. On average, me-too drugs launch 2.5years after the first entrant, with 20% more promotional investment, and capture 38% of market share within 4years. Peak market share is significantly affected by share of voice (p < 0.001) but not price discount (p = 0.77). Launch delay was significant in terms of reducing both market share (p < 0.001) and price (p < 0.05). With a launch price 15% below the incumbent, cumulative savings from use of a me-too drug peak at over $1000 million, but decrease rapidly after the first entrant becomes generic and only amount to$450 million over the me-too drug's lifecycle. With a price discount less than 10%, cumulative savings are negative over the life of the me-too drug. Therefore, me-too drugs may be cost saving in the short term, but can represent a cost in the longer term. From a societal perspective, me-too drugs always decrease the economic surplus if they do not grow the market. If me-too drugs grow the market by 20%, they augment, on average, the economic surplus only if the variable costs (including promotional investment) do not increase by more than $300 million per yea

Variable gain haptic coupling for molecular simulation

Molecularinteractionstypicallyhaveahighdynamicrange(HDR), combining short-range stiff repulsive effects with long-range, soft attractive and repulsive terms. As a result, faithful haptic renderingofsuchmolecularinteractionsisbothimportantanddifficult,in particularinapplicationswherethepreciseperceptionofmolecular forces is necessary (e.g. in molecular docking simulations). Traditionally,teleoperationcouplingusingconstantgaincontrolschemes have limited applications since they are unable to transmit to users low attractive forces without truncating repulsive ones. Furthermore, constant scaling displacement induces either instability or time-consuming experiments (displacements are slow), which deteriorates the ease of manipulation. In this paper, we describe a variable gain haptic coupling method specifically designed to render high dynamic range (molecular) forces. The proposed method is evaluated by user tests on an experiment involving two water molecules. We observe that variable force amplification is widely appreciated, whereas variable displacement scaling is appropriated only for users familiar with haptic manipulation. A complex experiment on a HIV molecule is carried out using this variable gain system. Advantages and limitations of thisapproach arediscussed.

Variable gain haptic coupling for molecular simulation

International audienceMolecular interactions typically have a high dynamic range (HDR), combining short-range stiff repulsive effects with long-range, soft attractive and repulsive terms. As a result, faithful haptic rendering of such molecular interactions is both important and difficult, in particular in applications where the precise perception of molecular forces is necessary (e.g. in molecular docking simulations). Traditionally, teleoperation coupling using constant gain control schemes have limited applications since they are unable to transmit to users low attractive forces without truncating repulsive ones. Furthermore, constant scaling displacement induces either instability or time-consuming experiments (displacements are slow), which deteriorates the ease of manipulation. In this paper, we describe a variable gain haptic coupling method specifically designed to render high dynamic range (molecular) forces. The proposed method is evaluated by user tests on an experiment involving two water molecules. We observe that variable force amplification is widely appreciated, whereas variable displacement scaling is appropriated only for users familiar with haptic manipulation. A complex experiment on a HIV molecule is carried out using this variable gain system. Advantages and limitations of this approach are discussed

Haptic molecular simulation based on force control

International audienceIn this paper, force control is proposed to connect a molecular simulator to a haptic device. Most of the works dealing with this kind of simulators use position control to manipulate the molecules, with major stability concerns. These two control modes are compared in terms of adequacy with the molecular simulator. Stability with respect to the scaling coefficients introduced to connect the macro and the nanoworlds is also considered. The theoretical results and the experiments carried out confirm that position control is sensitive to the gain tuning. Force control enables to get stable force feedback for varying gains, and is thus a promising coupling to perform manipulations on complex molecular systems

Haptic feedback for molecular simulation

International audienceIn this paper, a new tool dedicated to the analysis and the conception of molecules is presented. It is composed of an adaptive simulation software and a haptic device used to interact with molecules while feeling either the forces applied by the environment or the internal forces. The adaptive articulated body algorithm allows fast simulations of complex flexible molecules. To handle the coupling with the force feedback device, two different control schemes designed for nanoscale applications and providing high transparency rendering are proposed and compared. The system we propose is highly flexible since either a single rigid body or the entire molecule can be manipulated via the haptic device. The user can choose between setting a desired position/orientation of the molecule, or apply forces/torques to manipulate it. It allows the operator to control each stage of the design process of new molecular structures. The validity of this tool is demonstrated through examples of haptic interaction between the HIV protease and its inhibitors, and unfolding one of these drugs

Comparing position and force control for interactive molecular simulators with haptic feedback

International audienceThis paper presents a novel tool for the analysis of new molecular structures which enables a wide variety of manipulations. It is composed of a molecular simulator and a haptic device. The simulation software deals with systems of hundreds or thousands of degrees of freedom and computes the reconfiguration of the molecules in a few tenths of a second. For the ease of manipulation and to help the operator understand nanoscale phenomena, a haptic device is connected to the simulator. To handle a wide variety of applications, both position and force control are implemented. To our knowledge, this is the first time the applications of force control are detailed for molecular simulation. These two control modes are compared in terms of adequacy with molecular dynamics, transparency and stability sensitivity with respect to environmental conditions. Based on their specificity the operations they can realize are detailed. Experiments highlight the usability of our tool for the different steps of the analysis of molecular structures. It includes the global reconfiguration of a molecular system, the measurement of molecular properties and the comprehension of nanoscale interactions. Compared to most existing systems, the one developed in this paper offers a wide range of possible experiments. The detailed analysis of the properties of the control modes can be easily used to implement haptic feedback on other molecular simulators

Efficacy of Anti-VEGF and Laser Photocoagulation in the Treatment of Visual Impairment due to Diabetic Macular Edema: A Systematic Review and Network Meta-Analysis

<div><p>Objective</p><p>Compare the efficacy of ranibizumab, aflibercept, laser, and sham in the first-line treatment of diabetic macular edema (DME) to inform technology assessments such as those conducted by the UK National Institute for Health and Care Excellence (NICE).</p><p>Data sources</p><p>MEDLINE, Embase, Cochrane Library, congress abstracts, ClinicalTrials.gov registry and Novartis data on file.</p><p>Inclusion criteria</p><p>Studies reporting 6- or 12-month results of randomized controlled trials (RCTs) evaluating at least two of ranibizumab 0.5 mg <i>pro re nata</i>, aflibercept 2.0 mg bi-monthly, laser photocoagulation or sham. Study quality was assessed based on likelihood of bias in selection, attrition, detection and performance.</p><p>Outcome measure</p><p>Improvement in best-corrected visual acuity (BCVA) measured as the proportion of patients gaining ≥10 letters on the Early Treatment Diabetic Retinopathy Study scale. The outcome was chosen following acceptance by NICE of a Markov model with 10-letter health states in the assessment of ranibizumab for DME.</p><p>Meta-analysis</p><p>Bayesian network meta-analyses with fixed and random effects adjusted for differences in baseline BCVA or central retinal thickness.</p><p>Results</p><p>The analysis included 1,978 patients from eight RCTs. The random effects model adjusting for baseline BCVA was the best model based on total residual. The efficacy of ranibizumab was numerically, but not statistically, superior to aflibercept (odds ratio [OR] 1.59; 95% credible interval [CrI], 0.61–5.37). Ranibizumab and aflibercept were statistically superior to laser monotherapy with ORs of 5.50 (2.73–13.16) and 3.45 (1.62–6.84) respectively. The probability that ranibizumab is the most efficacious treatment was 73% compared with 14% for aflibercept, 12% for ranibizumab plus laser, and 0% for laser.</p><p>Limitations</p><p>Three of the eight RCTs included are not yet published. The models did not adjust for all potential effect modifiers.</p><p>Conclusion</p><p>Ranibizumab was non-significantly superior to aflibercept and both anti-VEGF therapies had statistically superior efficacy to laser.</p></div