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.     

Media Disaster Reporting Effects on Public Risk Perception and Response to Escalating Tornado Warnings: A Natural Experiment

Previous research has evaluated public risk perception and response to a natural hazards in various settings; however, most of these studies were conducted either with a single scenario or after a natural disaster struck. To better understand the dynamic relationships among affect, risk perception, and behavioral intentions related to natural disasters, the current study implements a simulation scenario with escalating weather intensity, and includes a natural experiment allowing comparison of public response before and after a severe tornado event with extensive coverage by the national media. The current study also manipulated the display of warning information, and investigated whether the warning system display format influences public response. Results indicate that (1) affect, risk perception, and behavioral intention escalated as weather conditions deteriorated, (2) responses at previous stages predicted responses at subsequent stages of storm progression, and (3) negative affect predicted risk perception. Moreover, risk perception and behavioral intention were heightened after exposure to the media coverage of an actual tornado disaster. However, the display format manipulation did not influence behavioral responses. The current study provides insight regarding public perception of predisaster warnings and the influence of exposure to media coverage of an actual disaster event.     

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.     

BUILDING THE EVIDENCE BASE FROM LONGITUDINAL DATA

Survey data from cross-sectional snapshots give an incomplete picture of the social fabric. Without longitudinal information, planners, practitioners, social scientists and policy makers would be in the dark about dynamics, durations and pathways of human development. Longitudinal data collected in birth cohort studies give a better guide to long-term processes and outcomes and are more informative about the causal relations that are the drivers of disadvantage or success. The content and structure of Britain's Birth Cohort Studies are described to illustrate the challenges of creating and studying longitudinal evidence. Examples of findings and policies based on these prospective longitudinal studies are given, along with a discussion of the practical decisions that have to be confronted in undertaking them.     

Overcoming the Effects of Variation in Infant Speech Segmentation: Influences of Word Familiarity

Previous studies have shown that 7.5‐month‐olds can track and encode words in fluent speech, but they fail to equate instances of a word that contrast in talker gender, vocal affect, and fundamental frequency. By 10.5 months, they succeed at generalizing across such variability, marking a clear transition period during which infants' word recognition skills become qualitatively more mature. Here we explore the role of word familiarity in this critical transition and, in particular, whether words that occur frequently in a child's listening environment (i.e., “Mommy” and “Daddy”) are more easily recognized when they differ in surface characteristics than those that infants have not previously encountered (termed nonwords). Results demonstrate that words are segmented from continuous speech in a more linguistically mature fashion than nonwords at 7.5 months, but at 10.5 months, both words and nonwords are segmented in a relatively mature fashion. These findings suggest that early word recognition is facilitated in cases where infants have had significant exposure to items, but at later stages, infants are able to segment items regardless of their presumed familiarity.     

Secondary analysis of dangerousness among death sentenced capital murderers

The theory of incapacitation involves reducing an offender's ability or capacity to commit further crimes. Capital punishment accomplishes this goal. An executed murderer never murders again. However, we do not execute all murderers, only capital murderers. This policy produces several research questions. Do capital murderers present a special risk to society? Are capital murderers more likely to murder or commit other violent crimes again than other murderers or the average citizen? To answer these questions, many states require a prediction of future dangerousness of a newly convicted murderer. To what extent has the judgment of future dangerousness matched actuarial data of subsequent murders and serious crimes? Using a secondary analysis, this investigation attempted to assemble available data of postconviction dangerousness of death sentenced capital murderers to create a more comprehensive actuarial account of subsequent dangerousness and to present the data in a common format used by the Federal Bureau of Investigation and the Bureau of Justice Statistics. Across 14 studies identified with relevant data, there were 13 instances of subsequent murder and 462 serious crime or prison rule violations.     

A Re-Introduction to Family Therapy Clarification of Three Schools

Family therapy is not easily understood, especially by the beginner therapist. This is not surprising given the confusing overlap between the various models and proliferation of new and often unexplained concepts and terms. This article serves to reverse this trend by presenting an overview of family therapy that can be understood by the novice. It clarifies the assumptions, terms, methods and goals of the main three schools of thought, namely structural, strategic and systemic. The similarities and differences between these schools are discussed and a summary table has been inserted for comparison purposes. A glossary has been included to assist the reader in defining commonly used terms and concepts.     

Social Cognitive Factors,Support, and Engagement: Early Adolescents’ Math Interests as Precursors to Choice of Career

The authors examined the central hypothesis that students’ early perceptions of support and sense of engagement in math classes and math activities strongly influence the broadening or narrowing of their math interest. The focus was on the first wave of qualitative data collected from 5th‐, 7th‐, and 9th‐grade students during the 2007–2008 academic year as part of a longitudinal study. Findings indicate the importance of using group work and extrinsic motivation in middle school math classes to broaden interest; peer classroom behavior was often a detractor of math interest.     

Social Constructionism and Supervision: Experiences of AAMFT Supervisors and Supervised Therapists

A phenomenological research process was used to investigate the supervision experience for supervisors and therapists when supervisors use a social constructionist perspective. Participants of the one‐to‐one interviews were six AAMFT Approved Supervisors and six therapists providing counseling to individuals, couples and families. The findings suggest supervisors were committed to their self‐identified supervision philosophy and intentionally sought out congruence between epistemology and practice. The shared experience of therapists indicates they associated desirable supervision experiences with their supervisors’ social constructionist perspective. Our findings also indicated that supervisors’ and therapists’ understanding of social constructionism included the more controversial concepts of agency and extra‐discursiveness. This research has taken an empirical step in the direction of understanding what the social constructionist supervision experience is like for supervisors and therapists. Our findings suggest a linkage between epistemology and supervision practice and a satisfaction with the supervision process.