Manufacturing Barriers to Biologics Competition and Innovation

As finding breakthrough small-molecule drugs gets harder, drug companies are increasingly turning to “large molecule” biologics. Although biologics represent many of the most promising new therapies for previously intractable diseases, they are extremely expensive. Moreover, the pathway for generic-type competition set up by Congress in 2010 is unlikely to yield significant cost savings. In this Article, we provide a fresh diagnosis of, and prescription for, this major public policy problem. We argue that the key cause is pervasive trade secrecy in the complex area of biologics manufacturing. Under the current regime, this trade secrecy, combined with certain features of FDA regulation, not only creates high barriers to entry of indefinite duration but also undermines efforts to advance fundamental knowledge. In sharp contrast, offering incentives for information disclosure to originator manufacturers would leverage the existing interaction of trade secrecy and the regulatory state in a positive direction. Although trade secrecy, particularly in complex areas like biologics manufacturing, often involves tacit knowledge that is difficult to codify and thus transfer, in this case regulatory requirements that originator manufacturers submit manufacturing details have already codified the relevant tacit knowledge. Incentivizing disclosure of these regulatory submissions would not only spur competition but it would provide a rich source of information upon which additional research, including fundamental research into the science of manufacturing, could build. In addition to provide fresh diagnosis and prescription in the specific area of biologics, the Article contributes to more general scholarship on trade secrecy and tacit knowledge. Prior scholarship has neglected the extent to which regulation can turn tacit knowledge not only into codified knowledge but into precisely the type of codified knowledge that is most likely to be useful and accurate. The Article also draws a link to the literature on adaptive regulation, arguing that greater regulatory flexibility is necessary and that more fundamental knowledge should spur flexibility. A vastly shortened version of the central argument that manufacturing trade secrecy hampers biosimilar development was published at 348 Science 188 (2015), available online

Malathion Resistance in Larvae of Some Southern Minnesota Populations of the Indianmeal Moth,\u3ci\u3e Plodia Interpunctella\u3c/i\u3e (Lepidoptera: Pyralidae), Infesting Bulk-Stored Shelled Corn

Larvae of 21 field collected populations of the Indianmeal moth, Plodia interpunctella, infesting stored shelled corn in southern Minnesota were tested for their susceptibility to malathion in the laboratory. A population that was a composite of the 21 populations and a malathion susceptible population were also tested for their susceptibility to malathion, pirimiphos-methyl and chlorpyrifos-methyl. Comparison of the LDso values of the field populations with the malathion susceptible population indicated that the field populations were ca. 33- to 625-fold resistant to malathion. The composite field population was ca. 243-fold resistant to malathion, and this population was 3.2-fold cross-resistant to pirimiphos-methyl, but was highly susceptible to chlorpyrifos-methyl

Calculation of inviscid flow over shuttle-like vehicles at high angles of attack and comparisons with experimental data

A computer code HALIS, designed to compute the three dimensional flow about shuttle like configurations at angles of attack greater than 25 deg, is described. Results from HALIS are compared where possible with an existing flow field code; such comparisons show excellent agreement. Also, HALIS results are compared with experimental pressure distributions on shuttle models over a wide range of angle of attack. These comparisons are excellent. It is demonstrated that the HALIS code can incorporate equilibrium air chemistry in flow field computations

The Introduction of the Reserve Clause in Major League Baseball: Evidence of its Impact on Select Player Salaries During the 1880s

This paper investigates the introduction of the reserve clause in Major League Baseball during the 1880s. Taking advantage of a unique data set describing the salaries for twenty nine high-quality players throughout the decade of the 1880s, we investigate the impact of the reserve clause as it evolved from a "gentleman's agreement" to a formal contract stipulation. We test three specific hypotheses concerning the reserve clause: its effect on average salaries, on the remuneration to marginal product, and the premium paid to a player for changing teams. The evidence suggests that introducing the reserve clause reduced average salaries and the premium for changing teams; detectable monopsony power was transferred to team owners almost immediately. However, there was no statistically significant impact of the reserve clause on how much players were paid for their marginal product. The empirical results indicate that reserve clause shifted considerable monopsony power to team owners immediately after it was instituted.Sports economics, monopsony, free agency, negotiation

The use of checks and other noncash payment instruments in the United States

Statistical estimates indicate that the use of checks in the United States has been declining since the mid-1990s, even as the population and the level of economic activity have been increasing. In contrast, the use of electronic payments has been growing at high and accelerating rates. Nonetheless, the paper check remains the predominant means of making retail payments and will likely continue to play a significant role in the U.S. payment system for the foreseeable future. The number and value of checks paid varies across depository institutions according to type, size, and location, in part a result of differences in the use of checks and electronic payments by households, businesses, and governments. Overall, household's share of total checks written has increased relative to that of businesses and governments.Payment systems ; Electronic funds transfers

Orientation Dependence of a Dislocation Etch for Zinc

The dislocation etch for (101-[bar]0] surfaces of zinc reported by Brandt, Adams, and Vreeland have been further explored. Additional surface orientations have been found where dislocation etching takes place. These orientations cover an area located between 3 degrees and 12.2 degrees to the [0001], and the area is symmetric about that axis. Attempts to produce dislocation etching on within 2 degrees of (0001) were generally unsuccessful. This is in contrast to etching of many crystals which takes place only within a few degrees of a low index plane

Laser microprobe study of cosmic dust (IDPs) and potential source materials

The study of cosmic dust or interplanetary dust particles (IDP) can provide vital information about primitive materials derived primarily from comets and asteroids along with a small unknown fraction from the nearby interstellar medium. The study of these particles can enhance our understanding of comets along with the decoding of the history of the early solar system. In addition the study of the cosmic dust for IDP particles can assist in the elucidation of the cosmic history of the organogenic elements which are vital to life processes. Studies to date on these particles have shown that they are complex, heterogeneous assemblages of both amorphous and crystalline components. In order to understand the nature of these particles, any analytical measurements must be able to distinguish between the possible sources of these particles. A study was undertaken using a laser microprobe interfaced to a quadrupole mass spectrometer for the analysis of the volatile components present in cosmic dust particles, terrestrial contaminants present in the upper atmosphere, and primitive carbonaceous chondrites. From the study of the volatiles released from the carbonaceous materials it is hoped that one could distinguish between components and sources in the IDP particles analyzed. The technique is briefly described and results for the CI, CM, and CV chondrites and cosmic dust particle W7027B8 are presented

Outcomes of ab interno trabeculectomy with the trabectome by degree of angle opening.

AimTo analyse ab interno trabeculectomy (AIT) with the trabectome and combined phacoemulsification with AIT (phaco-AIT) by Shaffer angle grade (SG).MethodsProspective study of AIT and phaco-AIT with narrow angles of SG≤2 versus open angles ≥3. Outcomes included intraocular pressure (IOP), medications, complications, secondary surgery and success (IOP <21 mm Hg and >20% reduction without further surgery). Exclusion criteria were missing preoperative data and <1 year follow-up.ResultsOf 671 included cases, at 1 year AIT SG≤2 (n=43) had an IOP reduction of 42% from 27.3±7.4 to 15.7±3.0 mm Hg (p<0.01) versus AIT SG≥3 (n=271) with an IOP reduction of 37% from 26.1±7.8 to 16.4±3.9 mm Hg (p<0.01). In phaco-AIT with SG≤2 (n=48), IOP was reduced 24% from 20.7±7.0 to 15.7±3.6 mm Hg (p<0.01) versus phaco-AIT with SG≥3 (n=309) with an IOP reduction of 25% from 22.6±6.4 to 17.0±3.4 mm Hg (p<0.01). There was no difference between SG≤2 and SG≥3 in reduction of IOP or medications, complications, secondary surgery and success rates (p>0.05).ConclusionsSG≤2 is not associated with worse outcomes in AIT or phaco-AIT

Effect of Pressure on the Activity Coefficients of Au and Other Siderophile Elements in Liquid Fe-Si Alloys

Light elements can alloy into the iron cores of terrestrial planetary bodies. It is estimated that the Earths core contains ~10% of a light element, most likely a combination of S, C, Si, and O with Si probably being the most abundant. Si dissolved into Fe metal liquids can have a significant influence on the activity coefficients of siderophile elements, and thus the partitioning behavior of those elements between the core and mantle. Many of these elements have been investigated extensively at ambient pressure, and studies up to 1 GPa are becoming more common, but few have been studied at pressures above this. The formation of the Earths core has been estimated to have formed at pressures between 40-60 GPa, so investigating the effect pressure has on Sis influence on siderophile element partitioning is important for modeling core formation in the Earth and smaller planets. Pressure is well known to influence volumetric properties of metallic and silicate liquids, and oxygen fugacity (e.g., [10,11]), but less is known about its effect on activity coefficients (e.g., [12]). Some activity coefficients depend strongly upon the Si content of Fe liquids, and the concentration of siderophile elements such as P, Sb, and As in the terrestrial mantle is easily influenced by dissolved Si in the core. Thus, isolating the effect of pressure on activity coefficients in general is critical in quantitative analysis of core formation models. In this work, we investigate the effect variable Si content has on the partitioning of Au between Fe metal and silicate melt at 10 GPa and 2373 K, with the intention of comparing the behavior to that already investigated at lower pressures. In addition, P, V, Mn, Ga, Zn, Cd, Sn, W, Pb, and Nb were also measured and could thus be included in the assessment of potential pressure effects

On the Complexity of Limit Sets of Cellular Automata Associated with Probability Measures

We study the notion of limit sets of cellular automata associated with probability measures (mu-limit sets). This notion was introduced by P. Kurka and A. Maass. It is a refinement of the classical notion of omega-limit sets dealing with the typical long term behavior of cellular automata. It focuses on the words whose probability of appearance does not tend to 0 as time tends to infinity (the persistent words). In this paper, we give a characterisation of the persistent language for non sensible cellular automata associated with Bernouilli measures. We also study the computational complexity of these languages. We show that the persistent language can be non-recursive. But our main result is that the set of quasi-nilpotent cellular automata (those with a single configuration in their mu-limit set) is neither recursively enumerable nor co-recursively enumerable