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.     

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.     

‘There’s a lot of places I’d like to go and things I’d like to do’: the daily living experiences of adults with mild to moderate intellectual disabilities during a time of personalised social care reform in the United Kingdom

Adult social care services in the United Kingdom have undergone a period of transformation over recent years, characterised by a drive towards personalised care. Concurrently, social care budgets have been significantly reduced. This study aimed to explore the daily living experiences of adults with mild/moderate intellectual disabilities, who are at risk of no longer meeting eligibility criteria for statutory support. Focus group discussions, which included both people with intellectual disabilities and support workers, were analysed thematically. Two broad themes are presented: independence and agency; and social capital and well-being. While some participants echoed ideas central to the personalisation narrative, a number of contextual barriers to achieving greater independence and agency were discussed. Moreover, greater independence was not a desired goal for all participants. The findings highlight the potential mismatch between personalised social care, as delivered within significant budget constraints, and the needs of adults with intellectual disabilities.     

Documenting Pornography Use in America: A Comparative Analysis of Methodological Approaches

Estimates of pornography use in the United States range widely. We explore the reasons for the variation in such estimates among U.S. adults using data from four different recent nationally representative samples—each of which asked a different type of question about pornography use. We attribute the notable variation in estimates to differences in question wording and answer options, and assert that a survey question asking respondents about their most recent use of pornography minimizes recall bias and is better poised to assess the overall prevalence of pornography in a population than is the more common approach of asking respondents about their historical general-use pattern. When we privileged the most-recent-use approach, survey data from 2014 reveal that 46% of men and 16% of women between the ages of 18 and 39 intentionally viewed pornography in a given week. These numbers are notably higher than most previous population estimates employing different types of questions. The results have ramifications for methods of surveying sensitive self-reported behaviors and for contextualizing scholars’ claims as well as popular conversations about the reach and implications of pornography use in the United States.     

The influence of FDA advisory information and black box warnings on individual use of prescription antidepressants

We examine how use of antidepressant medications is influenced by Food and Drug Administration (FDA) warnings about the increased risk of suicidality associated with pediatric antidepressant use. With individual-level data on antidepressant use from the Medical Expenditure Panel Survey, we consider whether consumer responses to FDA warnings differ among targeted (children) and non-targeted (adult) age-groups. Because the warning labels specifically mentioned new users, we examine separately the effects of the warnings on initiations of antidepressant therapy and on continued use of antidepressants. We find evidence consistent with reduced initiation of antidepressant use among the intended population of children, and that usage among children with more highly educated parents responded earlier to FDA information. However, we also find spillover effects of reduced initiation among the non-targeted population of adults. Overall, our results indicate that the FDA warning may have led consumers to perceive risks beyond those specifically mentioned.     

Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation

Children represent a large underserved population of “therapeutic orphans,” as an estimated 80% of children are treated off‐label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or “borrowing”) of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure‐response information for antiepileptic drugs to pediatrics.     

Girlz II women: Age‐grading,language change and stylistic variation

Informed by abstract models of language change or stability over time, we present a longitudinal study of two African American females, first interviewed as teenagers, and re‐recorded twenty years later. As teenagers, they used morpho‐syntactic features of AAVE voraciously. But as working adults, these women distance themselves from their teenage activities and social networks, and display a considerably reduced vernacular usage that accords with their articulated concern to get ahead. The diachronic interpretation that best characterizes their transformation is age‐grading rather than generational change, since change at the individual level is accompanied by stability at the community level. The picture is complicated by intermediate recordings showing that one of the speakers is a stylistic chameleon, capable since her teenage years of varying copula absence rates depending on addressee, topic, and projected persona. But the age‐grading interpretation of change at the individual level remains valid based on the evidence of her reduced use of habitual be2, and third singular present tense –s absence. The case highlights the importance of paying more attention to stylistic variation and including more than two time points in sociolinguistic studies of change in real and apparent time.     

Partisan Political Identification among White Ethnic Groups: An Historical Analysis

Abstract

This article presents evidence and argument dealing with partisan political identification among white ethnic groups. Recently, numerous political commentators and analysts have argued that the ethnic-labor component of the New Deal coalition is in the midst of collapse and decay, and that white ethnics are re-aligning with the Republican Party. Through an analysis of public opinion data gathered between 1936 and 1974, the partisan re-alignment theory is critically examined. The data show little or no support for the idea that Catholic and Jewish ethnics are identifying more closely with the Republican Party. Data show that degree of identification with the Democrats is nearly the same in 1974 as it was in 1936.