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.     

Stigma, HIV/AIDS and prevention of mother-to-child transmission in Zambia

This report evaluates the extent of perceived and enacted HIV/AIDS-related stigma in a rural setting in Zambia. Stigmatisation is abundant, ranging from subtle actions to the most extreme degradation, rejection and abandonment. Women with HIV and pregnant women assumed to be HIV positive are repeatedly subjected to extensive forms of stigma, particularly once they become sick or if their child dies. Despite increasing access to prevention of mother to child transmission initiatives, including anti-retroviral drugs, the perceived disincentives of HIV testing, particularly for women, largely outweigh the potential gains from available treatments. HIV/AIDS related stigma drives the epidemic underground and is one of the main reasons that people do not wish to know their HIV status. Unless efforts to reduce stigma are, as one peer educator put it, “written in large letters in any HIV/AIDS campaign rather than small”, stigma will remain a major barrier to curbing the HIV/AIDS pandemic.     

GENDER AND RACE PATTERNS IN THE PATHWAYS FROM SPORTS PARTICIPATION TO SELF-ESTEEM

Athletics is the most prominent extracurricular activity in U.S. secondary schools in terms of student participation and school budgets. The latter is often justified on the grounds that healthy bodies produce healthy minds, that school sports boost school spirit, and that participation in school-based sports increases students' self-esteem. In this article we examine the interrelationships among participation in a school-based sport and the benefits assumed to be associated with it. Specifically, we test a model that postulates that school spirit, operationalized as attachment to school, and healthy bodies, operationalized as a sense of physical well-being, mediate the relationship between school sports and self-esteem. Data from the National Longitudinal Study of Adolescent Health on Caucasian and African American girls and boys were employed to test the model. School attachment and physical well-being absorbed the statistical effect of participating in a sport for all four gender-by-race groups. Among Caucasian girls a negative residual effect of sports participation was observed, which suggests that sports participation encapsulates multiple effects with contradictory influences. For African American girls school attachment by itself was not a significant mediator of the effect of sports participation on self-esteem. For all groups a sense of physical well-being was the more powerful mediator.     

Peer Crowd Affiliation and Internalizing Distress in Childhood and Adolescence: A Longitudinal Follow‐Back Study

Concurrent and longitudinal associations between peer crowd affiliation and internalized distress were examined in a sample of 246 youth (148 girls, 98 boys). Children completed measures of depression, social anxiety, loneliness, and self‐esteem when they were in grades 4 to 6 (Time 1), and again 6 years later during adolescence (grades 10 – 12; Time 2). At Time 2, adolescents also reported their self‐concept and their identification with reputation‐based peer crowds, including Populars, Jocks, Brains, Burnouts, Non‐Conformists, and None/Average crowds. Results indicated that adolescents' report of peer crowd affiliation was concurrently associated with self‐concept and levels of internalizing distress. Follow‐back analyses of internalizing trajectories revealed that Populars/Jocks had experienced significant declines in internalizing distress across development, whereas Brains exhibited some increases in internalizing distress between childhood and adolescence.     

Transnational religion: Hindu and Muslim movements

In this article I deal with transnational Hindu and Muslim movements. I reject the common assertion that migrant communities are conservative in religious and social matters by arguing that ‘traditionalism’ requires considerable ideological creativity and that this significantly transforms previous practices and discourses. I suggest that religious movements, active among migrants, develop cosmopolitan projects that can be viewed as alternatives to the cosmopolitanism of the European Enlightenment. This raises a number of challenges concerning citizenship, integration and political loyalty for governmentality in the nation‐states in which these cosmopolitan projects are carried out. I suggest that rather than looking at religious migrants as at best conservative and at worst terrorist one should perhaps pay some attention to the creative moments in human responses to new challenges and new environments.     

THE EAST END, THE WEST END, AND KING'S CROSS: ON CLUSTERING IN THE FOUR-PLAYER HOTELLING GAME

We study experimentally a standard four-player Hotelling location game with a uniform density of consumers and inelastic demand. The pure strategy Nash equilibrium configuration consists of two firms located at one quarter of the "linear city," and the other two at three quarters. We do not observe convergence to such an equilibrium. In our experimental data we find three clusters. Besides the direct proximity of the two equilibrium locations, this concerns the focal midpoint. Moreover, we observe that whereas this midpoint appears to become more notable over time, other focal points fade away. We explain how these observations are related to best-response dynamics, and to the fact that the players rely on best-responses in particular when they are close to the equilibrium configuration.     

Media Publicity and the Voluntary Sector: The Case of Nonprofit Organizations in New York City

Media publicity is an important resource for contemporary voluntary associations, but very little is actually known about the resources and organizational characteristics that are most important for getting media attention. To address this question, we collected and analyzed data on the organizational attributes and news publicity of 739 nonprofit organizations in New York City. We find that an organization's income, paid staff, membership size, and library resources are significantly related to getting media publicity, whereas the number of chapter affiliations is inversely related to publicity. Association type is also a significant factor that influences an organization's ability to get publicity. We discuss the implications that these findings have for current debates about advocacy and civic engagement in the nonprofit sector.     

Lives in limbo: Temporary Protected Status and immigrant identities

The United States formulates much of its immigration and refugee policy to match economic and political circumstances. We interpret these policy shifts as a set of graduated positions on immigration and refugee flows that attempts to discipline the lives of newcomers and, in so doing, shapes immigrant identities. In this article, we analyse the interplay between the US government and Salvadoran asylum applicants negotiating procedures that grant only temporary relief from deportation via the policy of Temporary Protected Status (TPS). We find that each policy shift results in the strategic renegotiation of asylum applicants’ identities so as to achieve the best opportunity for a successful outcome. Based on Foucault’s ideas of governmentality and Ong’s concept of flexible citizenship, we argue that what appears more superficially as a patchwork strategy of immigration laws and asylum practices may be theorized more deeply as a set of flexible responses by the state that turn on identity construction at different scales, and that aim to mediate transnational relations.