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.     

An Interview with Joyce Edward: Exemplary Clinician, Advocate, and Scholar

Over the years, noteworthy social workers have been interviewed for the Clinical Social Work Journal. This article features an interview with Joyce Edward who is recognized for her many extraordinary contributions to clinical social work. Joyce has co-written or co-edited three exceptional books for the social work clinician, she has been an esteemed teacher and a vocal activist for quality mental health care. In this interview Joyce reflects on family influences, her work as a social caseworker, the psychoanalytic luminaries with whom she trained, her concerns about the clinical education of today's social work students, and finally, her perspective on managed mental health care.     

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.     

Maintaining the connection: Parenting as a noncustodial father

The purpose of this study was to identify relevant factors associated with the noncustodial father's frequency of contact with his child following divorce. The findings of the research revealed that a combination of demographic, personal characteristics, and psychosocial factors are related to the father's frequency of contact with the child.     

The gambling market in the Federal Republic of Germany and the helpseeking of pathological gamblers

The development of the gambling market in the Federal Republic of Germany since the middle of the seventies and data on pathological gamblers seeking help are described. The continuously increasing supply, together with increases in turnover, was followed-with some temporal delay-by an increase in the number of gamblers who sought advice and treatment. Preliminary measures taken by the health authorities as well as some consequences of pathological gambling are discussed.This article is a translation of a German article published in: Deutsche Hauptstelle gegen die Suchtgefahren (1990): Jahrbuch '91 zur Frage der Suchtgefahren. Hamburg: Neuland-Verlag.     

Consistent maximum likelihood estimation of a unimodal density using shape restrictions

It is well known that the unimodal maximum likelihood estimator of a density is consistent everywhere but at the mode. The authors review various ways to solve this problem and propose a new estimator that is concave over an interval containing the mode; this interval may be chosen by the user or through an algorithm. The authors show how to implement their solution and compare it to other approaches through simulations. They show that the new estimator is consistent everywhere and determine its rate of convergence in the Hellinger metric.     

ATSDR Science Panel on the Bioavailability of Mercury in Soils: Lessons Learned

On the basis of discussion and analysis during and following an ATSDR science panel on the bioavailability of mercury in soils, it is apparent that the default assumption of 100% relative bioavailability for mercury-contaminated soils is excessively conservative. However, current knowledge does not allow the development of default assumptions or guidelines for determining relative bioavailability of mercury in soils. Until such default assumptions or guidelines can be developed, site-specific assays of bioavailability, preferably using either animal bioassays or validated in vitro techniques, may provide the best approach for estimating soil-mercury bioavailability.     

An Assessment of Change in Risk Perception and Optimistic Bias for Hurricanes Among Gulf Coast Residents

This study focuses on levels of concern for hurricanes among individuals living along the Gulf Coast during the quiescent two‐year period following the exceptionally destructive 2005 hurricane season. A small study of risk perception and optimistic bias was conducted immediately following Hurricanes Katrina and Rita. Two years later, a follow‐up was done in which respondents were recontacted. This provided an opportunity to examine changes, and potential causal ordering, in risk perception and optimistic bias. The analysis uses 201 panel respondents who were matched across the two mail surveys. Measures included hurricane risk perception, optimistic bias for hurricane evacuation, past hurricane experience, and a small set of demographic variables (age, sex, income, and education). Paired t‐tests were used to compare scores across time. Hurricane risk perception declined and optimistic bias increased. Cross‐lagged correlations were used to test the potential causal ordering between risk perception and optimistic bias, with a weak effect suggesting the former affects the latter. Additional cross‐lagged analysis using structural equation modeling was used to look more closely at the components of optimistic bias (risk to self vs. risk to others). A significant and stronger potentially causal effect from risk perception to optimistic bias was found. Analysis of the experience and demographic variables’ effects on risk perception and optimistic bias, and their change, provided mixed results. The lessening of risk perception and increase in optimistic bias over the period of quiescence suggest that risk communicators and emergency managers should direct attention toward reversing these trends to increase disaster preparedness.     

The reification of celebrity: global newspaper coverage of the death of David Bowie*

This paper examines global English-language newspaper coverage of the death of David Bowie. Drawing upon the concept of reification, it is argued that the notion of celebrity is discursively (re)produced and configured through a ‘public face’ that is defined, maintained and shaped via media reports and public responses that aim to know and reflect upon celebrity. The findings highlight how Bowie’s reification was supported by discourses that represented him as an observable, reified form. Here, Bowie’s ‘reality’, that is, his authentic/veridical self, was obscured behind a façade of mediation, interpretation and representation that debated and decided his ‘authenticity’ as a cultural icon. Such debates, however, were engagements with a reified image, enveloped in continual (re)interpretation. As a result, Bowie’s reification was grounded in a polysemous process that allowed numerous versions of ‘himself’ to be aesthetically reimagined, reinvented and repeated.     

Impact of an Overt Response System on Staff Performance and Maintenance of Computer-Based Instruction

Interactive Computer Based Instruction (CBI) systems involve teaching strategies to facilitate greater response opportunities during training in an effort to improve learner performance. The current study investigated the effect of online staff training videos with and without overt response requirements on posttest and maintenance test scores across six block-randomized instructional modules for four employees of a university located in the southeastern region of the United States. The overt response consisted of multiple-choice questions administered throughout select teaching modules using an alternating treatment design. Findings suggest that learning occurred as a result of the CBI training; however, the effectiveness of the overt response system varied across individuals, with no discernible differentiation between learning gains associated with response requirements. Other areas of research for expanding the efficacy of CBI and overt response systems are highlighted.