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.     

A majorization comparison of apportionment methods in proportional representation

From the inception of the proportional representation movement it has been an issue whether larger parties are favored at the expense of smaller parties in one apportionment of seats as compared to another apportionment. A number of methods have been proposed and are used in countries with a proportional representation system. These apportionment methods exhibit a regularity of order, as discussed in the present paper, that captures the preferential treatment of larger versus smaller parties. This order, namely majorization, permits the comparison of seat allocations in two apportionments. For divisor methods, we show that one method is majorized by another method if and only if their signpost ratios are increasing. This criterion is satisfied for the divisor methods with power-mean rounding, and for the divisor methods with stationary rounding. Majorization places the five traditional apportionment methods in the order as they are known to favor larger parties over smaller parties: Adams, Dean, Hill, Webster, and Jefferson. Received: 5 August 2000/Accepted: 24 October 2001     

Worlds come apart: Systems theory versus critical theory. Drama in the history of sociology in the twentieth century

This article places an episode in the history of sociological theory into intellectual history in the twentieth century. The perspective is chronological as well as contextual. The themes are two theoretical approaches, both embedded in both American and German history, Parsonian Systems Theory and “Frankfurt School” Critical Theory. The chronology shown spanned mainly from the 1940s to the 1960s. The context of the two theories is a period that is crucial in twentieth century history. The protagonists of the two approaches were, in the 1940s, Americans and Germans exiled in the United States. In the 1950s, both approaches were affected by McCarthyism in different ways. The 1960s, however, were the culmination. The dynamics of the two approaches led into a schism which came into the open on the occasion of the 1964 German Sociology Conference in Heidelberg celebrating Max Weber. The article shows the stages in the evolution of the schism, emulating three acts in a drama. The final split was over whether Weber or Marx should be the classic whose oeuvre was to influence sociological thinking today. My aim is to exemplify how these two authoritative approaches in sociological theory, far from escaping the vagaries and vicissitudes of their times, were embedded in twentieth-century history.     

Partial strikes under the railway labor act: The need for a doctrine of unprotected concerted activity

In light of use by airline unions of partial-strike tactics, such as concerted refusals to bid for overtime work and so-called ” CHAOS” tactics involving unannounced refusals to fly after passengers have been ticketed and are ready to board, the authors examine whether the Railway Labor Act (RLA) should be interpreted to permit employers to discipline employees for engaging in such tactics, or whether these are a protected form of economic pressure. Although in many respects bargaining duties and economic weapons under the RLA are read consonant with precedents under the National Labor Relations Act (NLRA) (which governs all industries other than rail and air transport), there are a few decisions suggesting that during the period when self-help may be resorted to, employees can engage in partial strike activities as long as they violate no court order but are subject to permanent replacement in limited circumstances. These decisions, the authors submit, fail to take account of Supreme Court decsions since the 1930s that some economic pressures by unions, such as slowdowns and sitins, may not violate the labor laws but nor are they protected by those laws so as to immunize partial strikers from employer discipline. These decisions are not based on unique features of the NLRA. Rather, they give recognition to the background assumptions of Congress that employers may act to protect their property interests as long as they do not run afoul of NLRA or RLA protections and that employees who engage in partial-strike activities are subject to employer discipline even where not strictly necessary to maintain operations. Moreover, these tactics skew the bargaining process by giving employees an essentially risk-free gambit to pressure their economic position through planned disruption of carrier operations. Professor Estreicher is also labor and employment counsel to O’Melveny & Myers, LLP. The views expressed herein are the authors’ and should not be attributed to any organization. Hannah Breshin and Tom Jerman of O’Melveny & Myers, assisted the authors with this article. We also thank Professor Herbert Northrup for his helpful comments.     

Netzwerken: Reflexionen und Erfahrungen am Beispiel eines TrainerInnen und BeraterInnen-Netzwerkes

How are social networks organized and how much structure and openess do they have? The ambiguity of networking and the grade of organization are discussed and described theoretically and with an authentic example.     

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.     

Führung durch Selbstführung

This paper outlines the conceptual bases, strategies, and psychological attributes of leadership by self-leadership. In addition, relations to other theories of leadership are drawn. Dimensions and correlates of self-leadership competence are described and discussed. Various approaches for developing self-leadership competence are discussed as well.     

Simple detection of outlying short time series

Sets of relatively short time series arise in many situations. One aspect of their analysis may be the detection of outlying series. We examine the performance of standard normal outlier tests applied to the means, or to simple functions of the means, of AR(1) series, not necessarily of equal lengths. Although unequal lengths of series implies that the means have unequal variances, that are only known approximately, it is shown that nominal significance levels hold good under most circumstances. Thus a standard outlier test can usefully be applied, avoiding the complication of estimating the time series' parameters. The test's power is affected by unequal lengths, being higher when the slippage occurs in one of the longer series     

Inference for the measurement of poverty in the presence of a stochastic weighting variable

Empirical applications of poverty measurement often have to deal with a stochastic weighting variable such as household size. Within the framework of a bivariate distribution function defined over income and weight, I derive the limiting distributions of the decomposable poverty measures and of the ordinates of stochastic dominance curves. The poverty line is allowed to depend on the income distribution. It is shown how the results can be used to test hypotheses concerning changes in poverty. The inference procedures are briefly illustrated using Belgian data. An erratum to this article can be found at     

Randomized response techniques for complex survey designs

Singh et al. ([13]) pointed out that the Randomized response (RR) technique proposed by Moors ([9]) is not desirable because it fails to protect the confidentiality of the respondents and they provided two alternative strategies free from the above drawback but limited to SRSWOR sampling only. In this paper, generalization of one of the strategies is provided for complex survey designs, wider class of estimators and for quantitative characteristics. Relative efficiency of the modified strategy is tested through empirical investigations. An erratum to this article is available at .