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.     

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     

Social Antecedents of Medical Fraud and Over-Servicing: What Makes A Doctor Criminal?

Medical fraud and overservicing are estimated to cost the Australian community between $130 and $200 million per annum, a figure far greater than the national cost of burglary and almost the same as the total property loss from all conventional crime. An examination of the social antecedents of medical fraud and overservicing suggests that the predisposition of some doctors to engage in these practices occurs because of the following: (1) medical training and professional socialization that orientate student doctors away from altruistic health issues towards narrower self-interested professional concerns; (2) career expectations of a high pattern of material consumption that are often frustrated by an increasingly competitive medical market place; and (3) professional medical organizations that lobby for national health policies which reflect the mercenary self-interest of doctors rather than the health interest of the nation.     

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.     

The Determinants of Racial Disparities in Perceived Job Insecurity: A Test of Three Perspectives

Why do African Americans report higher levels of perceived job insecurity than whites? We analyze data from the 1996 and 1998 General Social Survey to test alternative predictions from the compositional, inclusive‐discrimination, and dispositional perspectives concerning the sources of the racial gap in perceived insecurity. Results from ordered probit regressions provide most support for the inclusive‐discrimination perspective, which maintains that employment practices associated with “modern racial prejudice” induce perceived insecurity on a widespread and generalized basis among African Americans. Accordingly, compared to whites, African Americans experience perceived insecurity net of human capital credentials and job/labor market characteristics. Additional analyses provide one qualification to these findings: dynamics associated with the inclusive‐discrimination perspective are more pronounced in the private sector than the public sector.     

Optimal orthogonal-array-based latin hypercubes

The use of optimal orthogonal array latin hypercube designs is proposed. Orthogonal arrays were proposed for constructing latin hypercube designs by Tang (1993). Such designs generally have better space filling properties than random latin hypercube designs. Even so, these designs do not necessarily fill the space particularly well. As a result, we consider orthogonal-array-based latin hypercube designs that try to achieve optimality in some sense. Optimization is performed by adapting strategies found in Morris & Mitchell (1995) and Ye et al. (2000). The strategies here search only orthogonal-array-based latin hypercube designs and, as a result, optimal designs are found in a more efficient fashion. The designs found are in general agreement with existing optimal designs reported elsewhere.