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.     

Radical Distrust: Are Economic Policy Attitudes Tempered by Social Trust?

Social Indicators Research - Debates about the appropriate role of markets and governments are often shaped by sharply contrasting opinions. Based on individual data from the World Values Survey...     

Nested exposure case-control sampling: a sampling scheme to analyze rare time-dependent exposures

For large cohort studies with rare outcomes, the nested case-control design only requires data collection of small subsets of the individuals at risk. These are typically randomly sampled at the observed event times and a weighted, stratified analysis takes over the role of the full cohort analysis. Motivated by observational studies on the impact of hospital-acquired infection on hospital stay outcome, we are interested in situations, where not necessarily the outcome is rare, but time-dependent exposure such as the occurrence of an adverse event or disease progression is. Using the counting process formulation of general nested case-control designs, we propose three sampling schemes where not all commonly observed outcomes need to be included in the analysis. Rather, inclusion probabilities may be time-dependent and may even depend on the past sampling and exposure history. A bootstrap analysis of a full cohort data set from hospital epidemiology allows us to investigate the practical utility of the proposed sampling schemes in comparison to a full cohort analysis and a too simple application of the nested case-control design, if the outcome is not rare.

     

Ethical Numbers: Ethics Training in U.S. Graduate Statistics Programs, 2013–2014

As important members of research teams, statisticians bear an ethical responsibility to analyze, interpret, and report data honestly and objectively. One way of reinforcing ethical responsibilities is through required courses covering a variety of ethics-related topics at the graduate level. We assessed ethics requirements for graduate-level statistics training programs in the United States for the 2013–2014 academic year using the websites of 88 universities, examining 103 biostatistics programs, and 136 statistics degree programs. We categorized programs’ ethics training requirements as required or not required. Thirty-one (35.1%) universities required an ethics course for at least some degree students. Sixty-two (25.5%) degree programs required an ethics course for at least some students. The majority (77.4%) of required courses were worth 0 or 1 credit. Of the 177 programs without an ethics requirement, 19 (10.7%) listed an ethics elective. Although a single ethics course is insufficient for instilling an ethical approach to science, degree programs that model expectations through coursework point to the value of ethics in science. More training programs should prepare statisticians to consider the ethical dimensions of their work through required coursework. Supplementary materials for this article are available online.     

Sex Related Factors in the Perception of Threatening Facial Expressions

This study replicated and extended previously reported sex differences involving both viewer and target in the recognition of threatening facial expressions. Based on the assumption that the evolved cognitive mechanisms mediating anger recognition would have been designed by natural selection to operate quickly in the interests of survival, brief tachistoscopic presentation of stimulus photographs was used. Additionally, in contrast to prior published studies, the statistical methods of signal detection research were used to control for the confounding effects of non-random guessing. The main hypothesis, that anger posed by males would be more accurately perceived than anger posed by females, was supported. A secondary hypothesis, that female-posed anger would be more accurately perceived by women than by men, received partial support. Testosterone levels, measured inferentially in terms of diurnal cycles, failed to show the hypothesized positive relationship to accuracy of anger perception.     

Managing Migration: The Role of Economic Instruments

This paper reviews economic policies and instruments available to the developed countries to reduce unwanted migration from developing countries, not all of which is irregular migration. Countries generally welcome legal immigrants and visitors, try to make it unnecessary for people to become refugees and asylum seekers, and try to discourage, detect, and remove irregular foreigners. There are three major themes: 1. There are as many reasons for migration as there are migrants, and the distinction between migrants motivated by economic and non–economic considerations is often blurred. Perhaps the best analogy is to a river – what begins as one channel that can be managed with a dam can become a series of rivulets forming a delta, making migration far more difficult to manage. 2. The keys to reducing unwanted migration lie mostly in emigration countries, but trade and investment fostered by immigration countries can accelerate economic and job growth in both emigration and immigration countries, and make trading in goods a substitute for economically motivated migration. Trade and economic integration had the effect of slowing emigration from Europe to the Americas, between southern Europe and northern Europe, and in Asian Tiger countries such as South Korea and Malaysia. However, the process of moving toward freer trade and economic integration can also increase migration in the short term, producing a migration hump, and requiring cooperation between emigration and immigration destinations so that the threat of more migration does not slow economic integration and growth. 3. Aid, intervention, and remittances can help reduce unwanted migration, but experience shows that there are no assurances that such aid, intervention, and remittances would, in fact, lead migrants to stay at home. The better use of remittances to promote development, which at US$65 billion in 1999 exceeded the US$56 billion in official development assistance (ODA), is a promising area for cooperation between migrants and their areas of origin, as well as emigration and immigration countries. There are two ways that differences between countries can be narrowed: migration alone in a world without free trade, or migration and trade in an open economy. Migration will eventually diminish in both cases, but there is an important difference between reducing migration pressures in a closed or open world economy. In a closed economy, economic differences can narrow as wages fall in the immigration country, a sure recipe for an anti–immigrant backlash. By contrast, in an open economy, economic differences can be narrowed as wages rise faster in the emigration country. Areas for additional research and exploration of policy options include: (1) how to phase in freer trade, investment, and economic integration to minimize unwanted migration; (2) strategies to increase the job–creating impacts of remittances, perhaps by using aid to match remittances that are invested in job–creating ways.     

Best Practice Options: Yugoslavia

Several Cooperative Efforts to Manage Emigration (CEME) members visited the Federal Republic of Yugoslavia (FRY) in early June 2001 to examine the new Government's approach to migration issues. We found that both the Federal Government and the Serb Republic are faced with three principal issues related to immigration and refugees that require substantial cooperation with North American and European countries that are donors of international aid, as well as recipients of Yugoslav migrants and third country nationals transiting the FRY.
First, they are faced with migration issues that the international community considers priorities, including demilitarizing border management; combating human smuggling and trafficking; and drafting and implementing an aliens law, which includes asylum policies and procedures consistent with international standards.
Second, they need to plan for the return or integration of 350,000 refugees from Croatia and Bosnia, and another 150,000 internally displaced Yugoslavs from Kosovo, primarily by offering dual citizenship in the FRY, and Croatia and Bosnia so refugees can integrate in the FRY, but retain rights and privileges according to Croatians or Bosnians.
Third, it is important to build bridges to Yugoslavs abroad in order to attract remittances and the return of the professionals needed to rebuild the FRY.     

Adolescents' and Mothers' Understanding of Children's Rights in the Home

Adolescents' and mothers' understanding of children's self‐determination and nurturance rights was examined in the context of the home. In individual interviews, 141 sixth, eighth, and tenth graders and their mothers responded to hypothetical vignettes in which a child story character wished to exercise a right that conflicted with parental practices. For each vignette, participants were asked to judge whether the story character should have the right in question and to provide a justification for their decision. Generally, eighth and tenth graders were more likely than their mothers to endorse requests for self‐determination and less likely than their mothers to support requests for nurturance. Mothers of tenth graders were more likely to support requests for self‐determination and less likely to favor adolescents' request for nurturance in the home than were mothers of sixth and eighth graders. In terms of reasoning, adolescents and mothers were more likely to consider the individuals' rights when discussing self‐determination situations, whereas nurturance situations elicited responses pertaining to participants' understanding of familial roles and relationships. Furthermore, mothers' reasoning about childrenà s rights reflected sensitivity to the developmental level of their children. The findings are discussed in terms of previous research on the development of children's understanding of rights and adolescent autonomy.     

Why sociology does not need to be saved: Analytic reflections on public sociologies

After reviewing the debate about public sociologies in the American Sociological Association over the past few years, we offer a response to calls for “saving sociology” from the Burawoy approach as well as an analytic critique of the former ASA president's “For Public Sociology” address. While being sympathetic to the basic idea of public sociologies, we argue that the “reflexive” and “critical” categories of sociology, as Burawoy has conceptualized them, are too ambiguous and value-laden to allow for empirical investigation of the different major orientations of sociological research and the ways the discipline can address non-academic audiences. Debates about the future of sociology should be undertaken with empirical evidence, and we need a theoretical approach that can allow us to compare both disciplines and nations as well as taking into account the institutional context of the universities in which we operate. Research into the conditions under which professional, critical, policy, and public sociologies could work together for the larger disciplinary and societal good is called for instead of overheated rhetoric both for and against public sociologies.