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.     

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.     

Spatial variation in soil inorganic nitrogen across an arid urban ecosystem

We explored variations in inorganic soil nitrogen (N) concentrations across metropolitan Phoenix, Arizona, and the surrounding desert using a probability-based synoptic survey. Data were examined using spatial statistics on the entire region, as well as for the desert and urban sites separately. Concentrations of both NO₃-N and NH₄-N were markedly higher and more heterogeneous amongst urban compared to desert soils. Regional variation in soil NO₃-N concentration was best explained by latitude, land use history, population density, along with percent cover of impervious surfaces and lawn, whereas soil NH₄-N concentrations were related to only latitude and population density. Within the urban area, patterns in both soil NO₃-N and NH₄-N were best predicted by elevation, population density and type of irrigation in the surrounding neighborhood. Spatial autocorrelation of soil NO₃-N concentrations explained 49% of variation among desert sites but was absent between urban sites. We suggest that inorganic soil N concentrations are controlled by a number of ‘local’ or ‘neighborhood’ human-related drivers in the city, rather than factors related to an urban-rural gradient.     

TERRITORIAL RESTRICTIONS IN FRANCHISE CONTRACTS

Efficient contracts set incentives through the assignment of rights and profit shares., Although efficient contracts have been used to explain the nature of the firm, the use of contractual rights in specific business contracts is relatively unexplored. We analyze contractual rights in franchise systems, in particular the right to add franchisees. An exclusive territory assigned to an initial franchisee is not an immutable guarantee, but rather a starting point for subsequent renegotiation in the franchise relationship. Exclusivity is therefore profitable when franchisee efforts are critical to the venture. A sample of franchise contracts reveals evidence consistent with the model's prediction.     

Small Town in Mass Society Revisited1

Abstract The case study of a small New York town that dramatized the thesis that the secular expansion of macro forces—urbanization, industrialization, bureaucratization—has permanently reduced the autonomy of all small communities is an example of a special type of discovery/persuasion strategy in the social sciences: the “opposition case study.” In contrast to the more rigorous “competitive test” or the atheoretical “negative case,” opposition case studies confront the dominant perspective with a qualitative illustration of a new theory in the context of a zero-sum game. When they are successful, opposition cases meet four criteria: the dominant view is immediately rendered obsolete; the origin of the new idea supports its plausibility; the new perspective is shown to be testable; and the new perspective quickly generates new lines of research. Small Town in Mass Society meets the first criterion, and may have been heuristic, but its probable origin in populist ideology undermines its testability.     

Qualified privilege: A defense for the public relations function

Technology continues to challenge the public relations practitioner to find ways to inform key constituents. The new technology has given rise to the “new journalism” that includes a declining traditional media and exploding internet media filled with websites and bloggers. The question posed by this research asks: Does the public relations practitioner inherit the same protection offered by “qualified privilege” that is most often associated with the traditional “press” or “reporter?” The research lays a foundation with an examination of defamation and the defense of qualified privilege. The research concludes that if information gathered by the public relations practitioner meets the “intent” and “content” tests, the information qualifies as news. Passing the “news” test, the defense of “qualified privilege” also attaches to the public relations practitioner.     

Statistics for weighing benefits and harms in a proposed genetic substudy of a randomized cancer prevention trial

Summary.  When evaluating potential interventions for cancer prevention, it is necessary to compare benefits and harms. With new study designs, new statistical approaches may be needed to facilitate this comparison. A case in point arose in a proposed genetic substudy of a randomized trial of tamoxifen versus placebo in asymptomatic women who were at high risk for breast cancer. Although the randomized trial showed that tamoxifen substantially reduced the risk of breast cancer, the harms from tamoxifen were serious and some were life threaten-ing. In hopes of finding a subset of women with inherited risk genes who derive greater bene-fits from tamoxifen, we proposed a nested case–control study to test some trial subjects for various genes and new statistical methods to extrapolate benefits and harms to the general population. An important design question is whether or not the study should target common low penetrance genes. Our calculations show that useful results are only likely with rare high penetrance genes.