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.     

Random effects regression mixtures for analyzing infant habituation

Random effects regression mixture models are a way to classify longitudinal data (or trajectories) having possibly varying lengths. The mixture structure of the traditional random effects regression mixture model arises through the distribution of the random regression coefficients, which is assumed to be a mixture of multivariate normals. An extension of this standard model is presented that accounts for various levels of heterogeneity among the trajectories, depending on their assumed error structure. A standard likelihood ratio test is presented for testing this error structure assumption. Full details of an expectation-conditional maximization algorithm for maximum likelihood estimation are also presented. This model is used to analyze data from an infant habituation experiment, where it is desirable to assess whether infants comprise different populations in terms of their habituation time.     

Multi-valued strategy-proof social choice rules

In this paper we introduce a new definition of strategy-proofness for multi-valued social choice correspondences. We prove two Gibbard-Satterthwaite type results for strategy-proof social choice correspondences. These results show that allowing multiple outcomes as social choices will not necessarily lead to an escape from the Gibbard-Satterthwaite impossibility theorem. Received: 24 January 2001/Accepted: 19 March 2001     

Generating random variates from D-distributions via substitution sampling

Laud et al. (1993) describe a method for random variate generation from D-distributions. In this paper an alternative method using substitution sampling is given. An algorithm for the random variate generation from SD-distributions is also given.     

Small Town in Mass Society Revisited1

Abstract The case study of a small New York town that dramatized the thesis that the secular expansion of macro forces—urbanization, industrialization, bureaucratization—has permanently reduced the autonomy of all small communities is an example of a special type of discovery/persuasion strategy in the social sciences: the “opposition case study.” In contrast to the more rigorous “competitive test” or the atheoretical “negative case,” opposition case studies confront the dominant perspective with a qualitative illustration of a new theory in the context of a zero-sum game. When they are successful, opposition cases meet four criteria: the dominant view is immediately rendered obsolete; the origin of the new idea supports its plausibility; the new perspective is shown to be testable; and the new perspective quickly generates new lines of research. Small Town in Mass Society meets the first criterion, and may have been heuristic, but its probable origin in populist ideology undermines its testability.