Incrementalism in Pharmaceutical Research: Incentives and Policy Implications

The tremendous commercial success of drugs which scientific data suggest are of no benefit to most patients relative to pre-existing drugs is illustrative of a phenomenon in pharmaceutical markets whereby products can become commercially successful even though their social costs vastly outweigh their social benefits. This suggests that a confluence of market failures, patent laws and FDA regulation of pharmaceuticals is creating perverse incentives that both encourage inefficient allocation of resources and decrease consumer access. In this paper, I explore this phenomenon by addressing two related questions. First, how can incremental improvements in medications be characterized so as to identify which incremental research should be encouraged or discouraged by patent and regulatory law? And second, which doctrinal or policy levers should Congress and the courts use to reduce incentives for undesirable incrementalism? Part I of this paper describes the economic and legal context that must inform pharmaceutical policy. Part II attempts to characterize pharmaceutical innovations in terms of their social value and degree of innovation, and thereby to identify the types of innovations that patent law and FDA regulations should promote. Part III presents possible policy solutions for tailoring incentives to discourage undesirable forms of incrementalism and encourage valuable forms of innovation. In particular, mandatory and voluntary comparative testing of drugs, increasing the standard of nonobviousness for patentability, improvements to the patent application process, and penalties for holders of invalid patents in paragraph IV challenges are explored as means to enhance the correlation between the social benefits and royalties derived from pharmaceutical patents

Effects of statins on metabolic adaptations to aerobic exercise training : preliminary findings [abstract]

Emerging evidence suggests statins, unlike exercise, may cause deleterious effects on skeletal muscle oxidative capacity and insulin sensitivity. The purpose of this study was to determine if daily statin therapy altered the ability of exercise to lower fasting plasma insulin and glucose and improve cardiorespiratory fitness

A Tunable, Three-Dimensional \u3ci\u3eIn Vitro\u3c/i\u3e Culture Model of Growth Plate Cartilage Using Alginate Hydrogel Scaffolds

Defining the final size and geometry of engineered tissues through precise control of the scalar and vector components of tissue growth is a necessary benchmark for regenerative medicine, but it has proved to be a significant challenge for tissue engineers. The growth plate cartilage that promotes elongation of the long bones is a good model system for studying morphogenetic mechanisms because cartilage is composed of a single cell type, the chondrocyte; chondrocytes are readily maintained in culture; and growth trajectory is predominately in a single vector. In this cartilage, growth is generated via a differentiation program that is spatially and temporally regulated by an interconnected network composed of long- and short-range signaling mechanisms that together result in the formation of functionally distinct cellular zones. To facilitate investigation of the mechanisms underlying anisotropic growth, we developed an in vitro model of the growth plate cartilage by using neonatal mouse growth plate chondrocytes encapsulated in alginate hydrogel beads. In bead cultures, encapsulated chondrocytes showed high viability, cartilage matrix deposition, low levels of chondrocyte hypertrophy, and a progressive increase in cell proliferation over 7 days in culture. Exogenous factors were used to test functionality of the parathyroid-related protein–Indian hedgehog (PTHrP-IHH) signaling interaction, which is a crucial feedback loop for regulation of growth. Consistent with in vivo observations, exogenous PTHrP stimulated cell proliferation and inhibited hypertrophy, whereas IHH signaling stimulated chondrocyte hypertrophy. Importantly, the treatment of alginate bead cultures with IHH or thyroxine resulted in formation of a discrete domain of hypertrophic cells that mimics tissue architecture of native growth plate cartilage. Together, these studies are the first demonstration of a tunable in vitro system to model the signaling network interactions that are required to induce zonal architecture in growth plate chondrocytes, which could also potentially be used to grow cartilage cultures of specific geometries to meet personalized patient needs

Order from Disorder: Non Magnetic Impurities in the Spin-gap Phase of the Cuprates

We solve the problem of $N$ non magnetic impurities in the staggered flux phase of the Heisenberg model which we assume to be a good mean-field approximation for the spin-gap phase of the cuprates. The density of states is evaluated exactly in the unitary limit and is porportional to 1/\left (\omega \ln^2(|\omega|/D)), in analogy with the 1D case of doped spin-Peierls and two-leg ladders compounds. We argue that the system exhibits a quasi long-range order at T=0 with instantaneous spin-spin correlations decreasing as n_i/ \ln^2\left (n_i R_{ij}) for large distances $R_{ij}$ and we predict enhanced low energy fluctuations in Neutron Scattering.Comment: 4 pages, corrected typos, references adde

Simplification of soil biota communities impairs nutrient recycling and enhances above- and belowground nitrogen losses

Agriculture is a major source of nutrient pollution, posing a threat to the earth system functioning. Factors determining the nutrient use efficiency of plant-soil systems need to be identified to develop strategies to reduce nutrient losses while ensuring crop productivity. The potential of soil biota to tighten nutrient cycles by improving plant nutrition and reducing soil nutrient losses is still poorly understood. We manipulated soil biota communities in outdoor lysimeters, planted maize, continuously collected leachates, and measured N$_{2}$ O- and N$_{2}$ -gas emissions after a fertilization pulse to test whether differences in soil biota communities affected nutrient recycling and N losses. Lysimeters with strongly simplified soil biota communities showed reduced crop N (-20%) and P (-58%) uptake, strongly increased N leaching losses (+65%), and gaseous emissions (+97%) of N$_{2}$ O and N$_{2}$ . Soil metagenomic analyses revealed differences in the abundance of genes responsible for nutrient uptake, nitrate reduction, and denitrification that helped explain the observed nutrient losses. Soil biota are major drivers of nutrient cycling and reductions in the diversity or abundance of certain groups (e.g. through land-use intensification) can disrupt nutrient cycling, reduce agricultural productivity and nutrient use efficiency, and exacerbate environmental pollution and global warming

Planet Formation Imager (PFI): Science vision and key requirements

The Planet Formation Imager (PFI) project aims to provide a strong scientific vision for ground-based optical astronomy beyond the upcoming generation of Extremely Large Telescopes. We make the case that a breakthrough in angular resolution imaging capabilities is required in order to unravel the processes involved in planet formation. PFI will be optimised to provide a complete census of the protoplanet population at all stellocentric radii and over the age range from 0.1 to ∼100 Myr. Within this age period, planetary systems undergo dramatic changes and the final architecture of planetary systems is determined. Our goal is to study the planetary birth on the natural spatial scale where the material is assembled, which is the Hill Sphere of the forming planet, and to characterise the protoplanetary cores by measuring their masses and physical properties. Our science working group has investigated the observational characteristics of these young protoplanets as well as the migration mechanisms that might alter the system architecture. We simulated the imprints that the planets leave in the disk and study how PFI could revolutionise areas ranging from exoplanet to extragalactic science. In this contribution we outline the key science drivers of PFI and discuss the requirements that will guide the technology choices, the site selection, and potential science/technology tradeoffs

Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology

Background: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. Methods: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. Results: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1–10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. Conclusion: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue