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.     

Cohabitation and commitment: partnership plans of young men and women

Popular commentators on marriage and the family often interpret the increase in heterosexual couples living together without marrying as reduced willingness to create and honour life‐long partnerships. Survey and in‐depth interviews with samples of 20–29 year olds living in an urban area of Scotland finds little support for the postulated link between growing cohabitation and a weakened sense of commitment to long‐term arrangements. Most of the cohabiting couples strongly stressed their ‘commitment’. Socially acceptable vocabularies of motive undoubtedly influenced answers but interviews helped to explore deeper meanings. Many respondents’ views were consistent with previous research predictions of a weakening sense of any added value of marriage. At the same time, some respondents continued to stress the social significance of the distinction between marriage and cohabitation, consistent with research interpreting cohabitation as a ‘try and see’ strategy part‐way to the perceived full commitment of marriage. The notion that ‘marriage is better for children’ continued to have support among respondents. While, on average, cohabiting couples had lower incomes and poorer employment situations than married couples, only very extreme adverse circumstances were presented as making marriage ‘too risky’. Pregnancy‐provoked cohabitation was not always in this category. Cohabitation was maintained because marriage would ‘make no difference’ or because they ‘had not yet got round to’ marriage. Most respondents were more wary of attempting to schedule or plan in their personal life than in other domains and cohabitees’ attitudes to partnership, including their generally ‘committed’ approach, do not explain the known greater vulnerability of this group to dissolution.     

On Thanksgiving and Collective Memory: Constructing the American Tradition

Relying on the approach by Maurice Halbwachs who argued that collective memory is based on contemporary interests and concerns, this article shows how Thanksgiving has changed over time in accordance with the ideas of the day. Aspects of the analysis support Barry Schwartz's theory that commemoration reflects the historical past. Similar to the pilgrims' celebration, many people commemorate Thanksgiving by, for example, feasting and praying. But in contrast to Schwartz's thought, this paper also shows that there are other elements of traditions that have minimal connection with the original event. Forms of commemoration like the Macy's Day Parade challenge the idea that commemoration and celebration contain some connection to the initial occasion. In general, the findings lend support to historical research and theories that implement social constructionist approaches.     

Spatial Variations in Church Burnings: The Social Ecology of Victimized Communities in the South*

Abstract In recent years, church burnings in the South have attracted a great deal of attention. Many commentators have charged that they are a product of strained race relations throughout the South, and particularly of severe racial tensions in Southern rural areas. In this study we evaluate these claims. We begin by mapping the spatial coordinates of recorded church burnings from 1990 to 1997, and find that church arsons indeed are concentrated in the South. Church burnings, however, are a more urban phenomenon than popular media accounts would suggest. Our analysis then explores the influence of contextual factors (population and locale, racial composition and inequality, so‐cioeconomic conditions, local religious ecology, and patterns of reported crime) on church burnings in counties located in the study region. Logistic regression models confirm that church arsons are most likely to occur in small metropolitan statistical areas (MSAs) and non‐MSA counties containing a city of at least 10,000 residents. Church burnings also are especially likely in counties with a higher percentage of black residents, a larger number of churches relative to the rest of the state, and a higher arson rate. We conclude by discussing the implications of these findings for future research and public policy.     

Statistical Distributions of Daily Breathing Rates for Narrow Age Groups of Infants and Children

Children may be more susceptible to toxicity from some environmental chemicals than adults. This susceptibility may occur during narrow age periods (windows), which can last from days to years depending on the toxicant. Breathing rates specific to narrow age periods are useful to assess inhalation dose during suspected windows of susceptibility. Because existing breathing rates used in risk assessment are typically for broad age ranges or are based on data not representative of the population, we derived daily breathing rates for narrow age ranges of children designed to be more representative of the current U.S. children's population. These rates were derived using the metabolic conversion method of Layton (1993) and energy intake data adjusted to represent the U.S. population from a relatively recent dietary survey (CSFII 1994–1996, 1998). We calculated conversion factors more specific to children than those previously used. Both nonnormalized (L/day) and normalized (L/kg-day) breathing rates were derived and found comparable to rates derived using energy estimates that are accurate for the individuals sampled but not representative of the population. Estimates of breathing rate variability within a population can be used with stochastic techniques to characterize the range of risk in the population from inhalation exposures. For each age and age-gender group, we present the mean, standard error of the mean, percentiles (50th, 90th, and 95th), geometric mean, standard deviation, 95th percentile, and best-fit parametric models of the breathing rate distributions. The standard errors characterize uncertainty in the parameter estimate, while the percentiles describe the combined interindividual and intra-individual variability of the sampled population. These breathing rates can be used for risk assessment of subchronic and chronic inhalation exposures of narrow age groups of children.     

Non-ignorable missing covariate data in survival analysis: a case-study of an International Breast Cancer Study Group trial

Summary.  Non-ignorable missing data, a serious problem in both clinical trials and observational studies, can lead to biased inferences. Quality-of-life measures have become increasingly popular in clinical trials. However, these measures are often incompletely observed, and investigators may suspect that missing quality-of-life data are likely to be non-ignorable. Although several recent references have addressed missing covariates in survival analysis, they all required the assumption that missingness is at random or that all covariates are discrete. We present a method for estimating the parameters in the Cox proportional hazards model when missing covariates may be non-ignorable and continuous or discrete. Our method is useful in reducing the bias and improving efficiency in the presence of missing data. The methodology clearly specifies assumptions about the missing data mechanism and, through sensitivity analysis, helps investigators to understand the potential effect of missing data on study results.     

WOMEN'S WORK:

We use in-depth interviews, participant observation, and document analysis to examine women's involvement in the Gulf War Illness movement. We find that women's cumulative grievances of health concerns, financial hardships, and emotional problems opened them to movement recruitment as they surfed the Internet for information and support. The movement's division of labor was influenced not by gender but by health status. Women used the Internet to provide medical information and emotional support to geographically dispersed veterans. Activism transformed women activists by endowing them with a sense of empowerment and a somewhat broadened concern for social justice. Although their transformations disposed the women to become active on related issues, it did not extend to concerns about gender discrimination. We suggest that the next research step is to investigate gender differences in movement processes by surveying activists across a variety of movements to test propositions and to identify the characteristics of other social contexts that structurally instigate a departure from traditional gender roles.