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     

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.     

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.     

Threshold decisions: how social workers prioritize referrals of child concern

This paper examines local authority social workers' decision‐making when considering referrals of children, where the concerns are on the margin of child protection procedures. In doing so, it describes the findings of a qualitative research study undertaken in the policy context of attempts to ‘refocus’ social work practice in the late 1990s and early twenty‐first century. Data collection involved interviews with social workers and parents in 23 cases. Conclusions are that referrals were evaluated on the basis of five key factors, specificity, severity, risk, parental accountability and corroboration, the use of which determined whether an initial assessment or an investigation of alleged abuse took place. The analysis builds on previous work in the child protection field, but demonstrates how the application of these factors differs between cases of child concern and cases of child protection. Policy implications concern the complexity of decision‐making in the uncertain context of limited referral information and it is proposed that the simplistic notion of a continuum of abuse is now outdated. Copyright © 2006 John Wiley & Sons, Ltd.