Drotrecogin alfa (activated) ... a sad final fizzle to a roller-coaster party

Following the failure of PROWESS-SHOCK to demonstrate efficacy, Eli Lilly and Company withdrew drotrecogin alfa (activated) from the worldwide market. Drotrecogin was initially approved after the original trial, PROWESS, was stopped early for overwhelming efficacy. These events prompt consideration of both the initial approval decision and the later decision to withdraw. It is regrettable that the initial decision was made largely on a single trial that was stopped early. However, the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world. Furthermore, the overall withdrawal rate of approved drugs remains very low. The decision to withdraw was a voluntary decision by Eli Lilly and Company and likely reflected key business considerations. Drotrecogin does have important biologic effects, and it is probable that we do not know how best to select patients who would benefit. Overall, there may still be a small advantage to drotrecogin alfa, even used non-selectively, but the costs of determining such an effect with adequate certainty are likely prohibitive, and the point is now moot. In the future, we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval. At the same time, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response. © 2012 BioMed Central Ltd

Probabilistic analysis and comparison of stress-dependent rock physics models

A rock physics model attempts to account for the nonlinear stress dependence of seismic velocity by relating changes in stress and strain to changes in seismic velocity and anisotropy. Understanding and being able to model this relationship is crucial for any time-lapse geophysical or geohazard modelling scenario. In this study, we take a number of commonly used rock physics models and assess their behaviour and stability when applied to stress versus velocity measurements of a large (dry) core data set of different lithologies. We invert and calibrate each model and present a database of models for over 400 core samples. The results of which provide a useful tool for setting a priori parameter constraints for future model inversions. We observe that some models assume an increase in VP/VS ratio (hence Poisson’s ratio) with stress. A trait not seen for every sample in our data set. We demonstrate that most model parameters are well constrained. However, third-order elasticity models become ill-posed when their equations are simplified for an isotropic rock. We also find that third-order elasticity models are limited by their approximation of an exponential relationship via functions that lack an exponential term. We also argue that all models are difficult to parametrize without the availability of core data. Therefore, we derive simple relationships between model parameters, core porosity and clay content. We observe that these relationship are suitable for estimating seismic velocities of rock but poor when comes to predicting changes related to effective stress. The findings of this study emphasize the need for improvement to models if quantitatively accurate predictions of time-lapse velocity and anisotropy are to be made. Certain models appear to better fit velocity depth log data than velocity–stress core data. Thus, there is evidence to suggest a limitation in core data as a representation of the stress dependence of the subsurface. The differences in the stress dependence of the subsurface compared to that measured under laboratory conditions could potentially be significant. Although potentially difficult to investigate, its importance is of great significance if we wish to accurately interpret the stress dependence of subsurface seismic velocities