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.     

Measuring agreement between two statistics with applications to age standardization

Summary.  We detail a general method for measuring agreement between two statistics. An application is two ratios of directly standardized rates which differ only by the choice of the standard. If the statistics have a high value for the coefficient of agreement then the expected squared difference between the statistics is small relative to the variance of the average of the two statistics, and inferences vary little by changing statistics. The estimation of a coefficient of agreement between two statistics is not straightforward because there is only one pair of observed values, each statistic calculated from the data. We introduce estimators of the coefficient of agreement for two statistics and discuss their use, especially as applied to functions of standardized rates.     

Bayesian analysis of mixture modelling using the multivariate t distribution

A finite mixture model using the multivariate t distribution has been shown as a robust extension of normal mixtures. In this paper, we present a Bayesian approach for inference about parameters of t-mixture models. The specifications of prior distributions are weakly informative to avoid causing nonintegrable posterior distributions. We present two efficient EM-type algorithms for computing the joint posterior mode with the observed data and an incomplete future vector as the sample. Markov chain Monte Carlo sampling schemes are also developed to obtain the target posterior distribution of parameters. The advantages of Bayesian approach over the maximum likelihood method are demonstrated via a set of real data.     

Consumption and Saving Behavior of Older and Younger Baby Boomers in Korea

The 1998 Korean Survey of Family Income and Expenditures was used to examine the overall consumption and saving behavior of Korean baby boomers and compared the differences in consumption and saving behavior between older and younger boomers. The t -test results indicated that the younger boomers allocated a significantly higher percentage of their expenditures on food away from home, household appliances, transportation and communication than did the older boomers, whereas the older boomers spent higher amounts and allocated larger budget shares on their children's education than did the younger boomers. The results of Ordinary Least-Squares (OLS) regression analysis showed that, holding other factors constant, older boomers not only spent significantly more in the total consumption expenditures and education expenditures, but older boomers also saved significantly less than did younger boomers.     

Assessment of influence in non-linear measurement error models

We consider the assessment of outliers and influential observation in non-linear measurement error models. Residuals, leverage measures and case-deletiondiagonostics are examined. The method of local influence is also applied to the models. In particular, the perturbation of measurement error variances has been found useful in assessing the adequancy of the model assumptions. A numerical example is given to illustrate the application of the diagonostics.     

An analysis of other countries’ international public relations in the U.S.

The purpose of this study was to examine the various aspects of international public relations by other countries in the U.S. Based on the Foreign Agency Registration Act (FARA) report in 2002, this study analyzed client, activity types, purpose of activity, and key U.S. partners for activity. This study found that (1) business organizations and central governments were major clients of international public relations in the U.S., (2) meeting with governmental officials and congressional leaders was the primary type of activity followed by information dissemination, and (3) economic purpose led by trade promotion was the primary motive for these activities.     

Seemingly unrelated regression on the autoregressive (Ar(p)) singular equation system

This paper studies the estimation of seemingly unrelated regressions (SUR) of singular equation systems with an autoregressive error process (AR(p)) for each equation.Parameter estimates of the autoregressive singular equation system are not generally invariant to the equation deleted. Under the model specification restriction on the autoregressive parameters, the invariance property is preserved, and this paper shows that a single equation generalized least squares (GLS) estimation for a general autoregressive error process is equivalent to the SURGLS estimation of the AR(p) singular equation system.     

Cognitive and interpersonal abilities related to the primary activities of R&D managers

This study attempted to identify the primary activities performed by R&D managers at different supervisory levels, and the cognitive and interpersonal ability requirements that underlie these activities. A task inventory containing 244 managerial tasks was completed by 117 R&D managers in nine organizations. The 48 tasks which managers rated as having spent the most time were factor analyzed, resulting in the identification of three primary activities: project management, personnel supervision, and strategic planning. Furthermore, these activities varied with supervisory level, with R&D managers performing a wider range of these activities with the progression from first-line to upper-level management.Thirty R&D managers later rated the degree to which 19 cognitive and interpersonal abilities were required for performing these primary activities. Strategic planning was rated as requiring significantly higher levels of oral expression, logical reasoning, originality, fluency of ideas, oral defense, and resistance to premature judgement than was required for the other two primary activities. Personnel supervision required a higher level of social sensitivity than was required for the other two activities. Project management required high levels of information ordering, oral fact- finding ability, problem sensitivity, and oral and written comprehension. Implications of the findings for understanding R&D managerial performance and personnel staffing functions are discussed.     

Racial differences in urban neighboring

Despite mixed expectations generated by existing theories and evidence, this analysis documents clear racial differences in urban neighboring behavior. Using data from a survey of Nashville, Tennessee, residents, we show that blacks interact with their neighbors more often than whites do, and in a greater variety of ways. The only noteworthy similarity between the two groups is the positive impact of neighboring on feelings of community affect. Overall, our results support the view that neighbor relations — like other kinds of informal participation — have helped blacks cope with constrained social opportunities and provided them with access to resources unavailable through formal institutional channels.Revised version of a paper presented at the annual meeting of the American Sociological Association, San Francisco, August 1989.