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     

Multi-valued strategy-proof social choice rules

In this paper we introduce a new definition of strategy-proofness for multi-valued social choice correspondences. We prove two Gibbard-Satterthwaite type results for strategy-proof social choice correspondences. These results show that allowing multiple outcomes as social choices will not necessarily lead to an escape from the Gibbard-Satterthwaite impossibility theorem. Received: 24 January 2001/Accepted: 19 March 2001     

Hidden Resources and Barriers in Career Learning Assessment With Adolescents Vulnerable to Discrimination

The authors maintain that the social learning theory of career development and counseling has not been applied to diverse populations. To address this gap in the literature, the authors conducted a qualitative analysis of interviews with 21 middle school students in a low‐income, culturally diverse, inner‐city public school. Four themes emerged, reflecting the influence of discrimination on participants' career learning: contextual barriers and resources for learning, and psychological barriers and resources for learning. The authors provide a conceptual framework for assessing resources and barriers and a rationale for why these aspects often remain hidden or unexamined in career assessment with clients who are vulnerable to discrimination.     

Book Review: The Other Feminists: Activists in the Liberal Establishment,by Susan M. Hartmann. Yale University Press,New Haven,CT, 1998

VOLUNTAS: International Journal of Voluntary and Nonprofit Organizations -     

The residual effect of a growth-decay mechanism and the distributions of covariance structures

The product of two independent or dependent scalar normal variables, sums of products, sample covariances, and general bilinear forms are considered. Their distributions are shown to belong to a class called generalized Laplacian. A growth-decay mechanism is also shown to produce such a generalized Laplacian. Sets of necessary and sufficient conditions are derived for bilinear forms to belong to this class. As a generalization, the distributions of rectangular matrices associated with multivariate normal random vectors are also discussed.     

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.     

Relations Between Measures of Irritability and Contingency Detection at 6 Months

The hypothesis that irritability and contingency detection are negatively correlated was examined in thirty‐one 6‐month‐old infants. Observation and maternal report‐based assessments of irritability were correlated with both a criterion score and a continuous score of contingency detection. Results indicated that greater irritability in infants was associated with lower contingency detection scores. Discussion focuses on identifying processes by which the 2 constructs may be associated.     

Editor's Introduction: Conflict

Sociological Practice -