A Critical Examination of the FDA’s Efforts to Preempt Failure-to-Warn Claims

This article explores the legality and wisdom of the FDA’s effort to persuade courts to find most failure-to-warn claims preempted. The article first analyzes the FDA’s justifications for reversing its long-held views to the contrary and explains why the FDA’s position cannot be reconciled with its governing statute. The article then examines why the FDA’s position, if ultimately adopted by the courts, would undermine the incentives drug manufacturers have to change labeling to respond to newly-discovered risks. The background possibility of failure-to-warn litigation provides important incentives for drug companies to ensure that drug labels reflect accurate and up-to-date safety information. The article next explains why the agency’s view that it is capable of singlehandedly regulating the safety of drugs is unrealistic. The agency does not have the resources to perform the Herculean task of monitoring the performance of every drug on the market. Both the Institute of Medicine and the Government Accountability Office have explained the shortcomings in the FDA’s recent performance, and they express doubt that the FDA is in capable of facing an increasingly challenging future. The article then explains how state damages litigation helps uncover and assess risks that are not apparent to the agency during a drug’s approval process, and why this “feedback loop” enables the agency to better do its job. FDA approval of drugs is based on clinical trials that involve, at most, a few thousand patients and last a year or so. These trials cannot detect risks that are relatively rare, affect vulnerable sub-populations, or have long latency periods. For this reason, most serious adverse effects do not become evident until a drug is used in larger population groups for periods in excess of one year. Time and again, failure-to-warn litigation has brought to light information that would not otherwise be available to the FDA, to doctors, to other health care providers, and to consumers. And failure-to-warn litigation often has preceded and clearly influenced FDA decisions to modify labeling, and, at times, to withdraw drugs from the market

Fiscal federalism: US history for architects of Europe's fiscal union

Ever since first the blueprints for monetary union in Europe were drawn up, the United States, considered as a collection of individual states or regions, has served as a benchmark for assessing its feasibility and evaluating alternative policy options. Starting with Robert Mundellâ??s seminal 1961 article on optimal currency areas, countless papers have explored the inner workings of US labour, product and capital markets, and of its public finances, in the hope of learning lessons for Europe. It could be argued that this US inspiration is mistaken. After all, it is not the only economic and monetary federation in the world. Other federations work on different principles â?? especially when it comes to public finances â?? and there is no guarantee that US arrangements are optimal â?? especially, again, regarding public finances. But we know the US better and we think we understand it better, so success or failure relative to the US test carries much more weight than with the Australian, Canadian, Indian or Swiss tests. For better or worse, the US remains our ultimate policy laboratory. This essay on US fiscal federalism by Randall Henning and Martin Kessler builds on the established tradition. But unlike many papers that take current US features as a given, they tell us what present arrangements governing responsibility over public debt gradually emerged from, and why. By bringing in the historical dimension and the trial-and-error process that took place over more than two centuries, they help us understand the logic behind alternative arrangements and why the current one has in the end prevailed. Their careful historical account yields several important lessons. It first recalls that the US system as we know it, with its combination of a large federal budget responsible for the bulk of public debt and limited thrifty state budgets subject to balanced budget rules, emerged gradually from a sequence of events; in fact the initial set-up, as designed and enforced by Alexander Hamilton, was almost exactly the opposite. Second, it makes clear that beyond economic principles, attitudes towards what was in the aftermath of independence called the â??assumptionâ?? of state debt were shaped by broader political considerations â?? not least the aim of building a genuine federal government. Third, it explains how after the US was firmly established as a federation, changing political conditions led to a reversal of the federal governmentâ??s stance and to the enforcement of a â??no bail-outâ?? principle. An intriguing feature of US history is therefore that the competences and features of federal government grew out of its assumption of state debt, and that the centre imposed a de-facto no bail-out regime only after having assumed essential powers. Another interesting observation by Henning and Kessler is that balanced budget rules were adopted spontaneously by states in response to financial stress and defaults, rather than as a disciplinary device mandated by the centre. Thus, there is still significant variability between states regarding the modus operandi and strictness of budget rules. The question remains if what matters is the strictness of the rule, or deeper political preferences at state level, of which the rule is only an expression. Finally, Henning and Kessler emphasise, a no less important lesson for Europe is that policy principles and institutions should be looked at as a system rather than in isolation. As the authors point out, it may seem obvious to recall that states in the US can abide by strict budget balance rules to the extent the federal government is responsible for stabilisation and the bail-out of insolvent banks, but this simple lesson is sometimes overlooked in European discussion. Jean Pisani-Ferry Director of Bruegel

New Aspects of Thromboangiitis obliterans (von Winiwarter-Buerger's Disease)

The existence of thromboangiitis obliterans as a clinical entity has been a matter of debate for many years. In contrast to other immunovasculitides there is no organ involvement while peripheral vessels are affected. Heavy smokers under 40 years of age have a high predisposition for the disease. The cerebral form shows relapsing brain infarctions which can be visualized in CCT while panarteriography remains negative. Apart from unspecific inflammatory signs in blood and CSF there are distinctive laboratory findings proving the autoimmunological character of von Winiwarter-Buerger's disease. In the serum anti-elastin antibodies, IgE and anticollagen antibody activity are detectable. In 3 patients the authors detected specific immunohistochemical findings in a biopsy specimen of the temporal artery. In addition to platelet-inhibiting substances corticoids in acute and azathioprine in chronic treatment becomes necessary

Equation-free Dynamic Renormalization of a KPZ-type Equation

In the context of equation-free computation, we devise and implement a procedure for using short-time direct simulations of a KPZ type equation to calculate the self-similar solution for its ensemble averaged correlation function. The method involves "lifting" from candidate pair-correlation functions to consistent realization ensembles, short bursts of KPZ-type evolution, and appropriate rescaling of the resulting averaged pair correlation functions. Both the self-similar shapes and their similarity exponents are obtained at a computational cost significantly reduced to that required to reach saturation in such systems

The fixation probability of rare mutators in finite asexual populations

A mutator is an allele that increases the mutation rate throughout the genome by disrupting some aspect of DNA replication or repair. Mutators that increase the mutation rate by the order of 100 fold have been observed to spontaneously emerge and achieve high frequencies in natural populations and in long-term laboratory evolution experiments with \textit{E. coli}. In principle, the fixation of mutator alleles is limited by (i) competition with mutations in wild-type backgrounds, (ii) additional deleterious mutational load, and (iii) random genetic drift. Using a multiple locus model and employing both simulation and analytic methods, we investigate the effects of these three factors on the fixation probability $P_{fix}$ of an initially rare mutator as a function of population size $N$, beneficial and deleterious mutation rates, and the strength of mutations $s$. Our diffusion based approximation for $P_{fix}$ successfully captures effects (ii) and (iii) when selection is fast compared to mutation ($\mu/s \ll 1$). This enables us to predict the conditions under which mutators will be evolutionarily favored. Surprisingly, our simulations show that effect (i) is typically small for strong-effect mutators. Our results agree semi-quantitatively with existing laboratory evolution experiments and suggest future experimental directions.Comment: 46 pages, 8 figure

Fluctuation Induced Instabilities in Front Propagation up a Co-Moving Reaction Gradient in Two Dimensions

We study 2D fronts propagating up a co-moving reaction rate gradient in finite number reaction-diffusion systems. We show that in a 2D rectangular channel, planar solutions to the deterministic mean-field equation are stable with respect to deviations from planarity. We argue that planar fronts in the corresponding stochastic system, on the other hand, are unstable if the channel width exceeds a critical value. Furthermore, the velocity of the stochastic fronts is shown to depend on the channel width in a simple and interesting way, in contrast to fronts in the deterministic MFE. Thus, fluctuations alter the behavior of these fronts in an essential way. These affects are shown to be partially captured by introducing a density cutoff in the reaction rate. Some of the predictions of the cutoff mean-field approach are shown to be in quantitative accord with the stochastic results

The Impact of MD5 File Hash Collisions On Digital Forensic Imaging

The Message Digest 5 (MD5) hash is commonly used as for integrity verification in the forensic imaging process. The ability to force MD5 hash collisions has been a reality for more than a decade, although there is a general consensus that hash collisions are of minimal impact to the practice of computer forensics. This paper describes an experiment to determine the results of imaging two disks that are identical except for one file, the two versions of which have different content but otherwise occupy the same byte positions on the disk, are the same size, and have the same hash value