Inference and Decision Making for 21st-Century Drug Development and Approval

ABSTRACT

The cost and time of pharmaceutical drug development continue to grow at rates that many say are unsustainable. These trends have enormous impact on what treatments get to patients, when they get them and how they are used. The statistical framework for supporting decisions in regulated clinical development of new medicines has followed a traditional path of frequentist methodology. Trials using hypothesis tests of “no treatment effect” are done routinely, and the p-value < 0.05 is often the determinant of what constitutes a “successful” trial. Many drugs fail in clinical development, adding to the cost of new medicines, and some evidence points blame at the deficiencies of the frequentist paradigm. An unknown number effective medicines may have been abandoned because trials were declared “unsuccessful” due to a p-value exceeding 0.05. Recently, the Bayesian paradigm has shown utility in the clinical drug development process for its probability-based inference. We argue for a Bayesian approach that employs data from other trials as a “prior” for Phase 3 trials so that synthesized evidence across trials can be utilized to compute probability statements that are valuable for understanding the magnitude of treatment effect. Such a Bayesian paradigm provides a promising framework for improving statistical inference and regulatory decision making.     

EXAMINING THE WAGE DIFFERENTIAL FOR MARRIED AND COHABITING MEN

Wage analyses indicate that married and cohabiting men earn more than do single, noncohabiting men. This article examines the nature of these wage differentials using data from the National Survey of Families and Households. Results indicate that the marital and cohabitation differentials are quite distinct. The higher wage observed for cohabiting men is driven primarily by selection and is eliminated by first differencing, but the higher wage observed for married men (and perhaps long-term cohabiters) arises largely because of differential wage growth. Wages appear to rise more rapidly following marriage.     

TOOLS OR TOYS? THE IMPACT OF HIGH TECHNOLOGY ON SCHOLARLY PRODUCTIVITY

We examine the impact of communication technology on scholarly productivity by considering patterns of coauthored economics articles. Using articles in three major economics journals from 1970–79 and 1992–96, we find (1) sharp growth from distant coauthorships (authors not in the same metropolitan area prior to publication), as the theory predicts, and, contrary to theory, (2) lower productivity of distant than close-coauthored works and no decline in their relative disadvantage. These findings are reconciled by noting that high technology has aspects of a consumer good. The relative productivity of solo-authored articles has decreased, perhaps explaining the secular increase in coauthorship.     

The University: An Agent of Social Change?

Can universities be agents of progressive social change? How would we know if a university was acting as an agent of social change? Drawing on four case studies, I raise a number of questions to problematize our understanding of the university as an agent of social change. I outline a number of contributing factors that appear to explain successful cases. I conclude by arguing the relevancy of these cases for larger, and more traditional, sociological projects.     

Design optimization using ANOVA

This paper describes the design optimization of a robot sensor used for locating 3-D objects employing the Taguchi method in a computer simulation scenario. The location information from the sensor is to be utilized to control the movements of an industrial robot in a 'pick-and-place' or assembly operation. The Taguchi method, which is based on the Analysis-of-Variance (ANOVA) approach, is utilized to improve the performance of the sensor over a wider operating range. A review of the Taguchi method is presented along with step-by-step implementation details to identify and optimize the design parameters of the sensor. The method allows us to gauge the impact of various interactions present in the sensor system exclusively and permits us to single out those factors that have a dominant influence on the overall performance of the sensor. The investigation suggests that the Taguchi method is a more structured and efficient approach for achieving a robust design compared with the classical full factorial design approach.     

Still-births among the offspring of male radiation workers at the Sellafield nuclear reprocessing plant: detailed results and statistical aspects

Summary. This study investigates whether there was evidence of increasing risk of still-birth with increasing paternal exposure to ionizing radiation received during employment at the Sellafield nuclear installation before the child was conceived. A significant positive association is found between the total paternal preconceptional exposure to external ionizing radiation and the risk of still-birth (after adjustment for year of birth, social class, birth order and paternal age, odds ratio at 100 mSv 1.24 (95% confidence interval 1.04–1.45)). A summary of the principal scientific findings of this study has been published in the Lancet . This paper describes in detail the statistical methods that were used in the investigation and presents the results in full.     

Measuring agreement between two statistics with applications to age standardization

Summary.  We detail a general method for measuring agreement between two statistics. An application is two ratios of directly standardized rates which differ only by the choice of the standard. If the statistics have a high value for the coefficient of agreement then the expected squared difference between the statistics is small relative to the variance of the average of the two statistics, and inferences vary little by changing statistics. The estimation of a coefficient of agreement between two statistics is not straightforward because there is only one pair of observed values, each statistic calculated from the data. We introduce estimators of the coefficient of agreement for two statistics and discuss their use, especially as applied to functions of standardized rates.     

Bayesian analysis of mixture modelling using the multivariate t distribution

A finite mixture model using the multivariate t distribution has been shown as a robust extension of normal mixtures. In this paper, we present a Bayesian approach for inference about parameters of t-mixture models. The specifications of prior distributions are weakly informative to avoid causing nonintegrable posterior distributions. We present two efficient EM-type algorithms for computing the joint posterior mode with the observed data and an incomplete future vector as the sample. Markov chain Monte Carlo sampling schemes are also developed to obtain the target posterior distribution of parameters. The advantages of Bayesian approach over the maximum likelihood method are demonstrated via a set of real data.