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.     

Urban cultivation in Accra: an examination of the nature, practices, problems, potentials and urban planning implications

The literature on urban farming in Sub-Saharan African cities reveals that most studies have been conducted in Eastern, Southern and Central African cities. A few have focused on West Africa, including Sierra Leone, Guinea Bissau, and Cameroon. In Ghana there is a paucity of information on urban farming. The purpose of this paper is to examine the status of urban cultivation in Accra, Ghana's capital, reviewing existing research, and to present new empirical findings on urban cultivation emphasizing on its history, nature, practices, problems, potentials and urban planning implications.     

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.     

Type I error rates from likelihood‐based repeated measures analyses of incomplete longitudinal data

The last observation carried forward (LOCF) approach is commonly utilized to handle missing values in the primary analysis of clinical trials. However, recent evidence suggests that likelihood‐based analyses developed under the missing at random (MAR) framework are sensible alternatives. The objective of this study was to assess the Type I error rates from a likelihood‐based MAR approach – mixed‐model repeated measures (MMRM) – compared with LOCF when estimating treatment contrasts for mean change from baseline to endpoint (Δ). Data emulating neuropsychiatric clinical trials were simulated in a 4 × 4 factorial arrangement of scenarios, using four patterns of mean changes over time and four strategies for deleting data to generate subject dropout via an MAR mechanism. In data with no dropout, estimates of Δ and SE_Δ from MMRM and LOCF were identical. In data with dropout, the Type I error rates (averaged across all scenarios) for MMRM and LOCF were 5.49% and 16.76%, respectively. In 11 of the 16 scenarios, the Type I error rate from MMRM was at least 1.00% closer to the expected rate of 5.00% than the corresponding rate from LOCF. In no scenario did LOCF yield a Type I error rate that was at least 1.00% closer to the expected rate than the corresponding rate from MMRM. The average estimate of SE_Δ from MMRM was greater in data with dropout than in complete data, whereas the average estimate of SE_Δ from LOCF was smaller in data with dropout than in complete data, suggesting that standard errors from MMRM better reflected the uncertainty in the data. The results from this investigation support those from previous studies, which found that MMRM provided reasonable control of Type I error even in the presence of MNAR missingness. No universally best approach to analysis of longitudinal data exists. However, likelihood‐based MAR approaches have been shown to perform well in a variety of situations and are a sensible alternative to the LOCF approach. MNAR methods can be used within a sensitivity analysis framework to test the potential presence and impact of MNAR data, thereby assessing robustness of results from an MAR method. Copyright © 2004 John Wiley & Sons, Ltd.     

Choice of the primary analysis in longitudinal clinical trials

Missing data, and the bias they can cause, are an almost ever‐present concern in clinical trials. The last observation carried forward (LOCF) approach has been frequently utilized to handle missing data in clinical trials, and is often specified in conjunction with analysis of variance (LOCF ANOVA) for the primary analysis. Considerable advances in statistical methodology, and in our ability to implement these methods, have been made in recent years. Likelihood‐based, mixed‐effects model approaches implemented under the missing at random (MAR) framework are now easy to implement, and are commonly used to analyse clinical trial data. Furthermore, such approaches are more robust to the biases from missing data, and provide better control of Type I and Type II errors than LOCF ANOVA. Empirical research and analytic proof have demonstrated that the behaviour of LOCF is uncertain, and in many situations it has not been conservative. Using LOCF as a composite measure of safety, tolerability and efficacy can lead to erroneous conclusions regarding the effectiveness of a drug. This approach also violates the fundamental basis of statistics as it involves testing an outcome that is not a physical parameter of the population, but rather a quantity that can be influenced by investigator behaviour, trial design, etc. Practice should shift away from using LOCF ANOVA as the primary analysis and focus on likelihood‐based, mixed‐effects model approaches developed under the MAR framework, with missing not at random methods used to assess robustness of the primary analysis. Copyright © 2004 John Wiley & Sons, Ltd.     

Public Perceptions about Food Safety in the United States and Japan1

Abstract Consumer concerns over pesticide residues and food additives have been growing in industrialized societies, including the United States and Japan. However, little comparative research has been carried out to determine which household characteristics may be significantly associated with these heightened concerns, and whether or not the same factors are useful for understanding variation in these worries in more than one society. This paper examines food safety attitudes in Seattle, Washington, and Kobe, Japan, and discovers that while the absolute level of expressed concern is higher in Kobe, the predictive power of household characteristics in explaining attitudinal differences within countries is similar. Implications for rural areas and future research on family structures in capitalist societies are discussed.     

Maintaining the connection: Parenting as a noncustodial father

The purpose of this study was to identify relevant factors associated with the noncustodial father's frequency of contact with his child following divorce. The findings of the research revealed that a combination of demographic, personal characteristics, and psychosocial factors are related to the father's frequency of contact with the child.     

Erroneous perceptions and arousal among regular and occasional video poker players

This study investigated the relationship between the level of arousal (Heart Rate) and the number of erroneous perceptions among video poker players. Twelve regular and twelve occasional gamblers participated in a gambling session conducted in a natural environment. It was hypothesised that 1) a significant positive correlation would be observed between arousal and the number of erroneous verbalizations, 2) regular players would show a higher level of arousal than occasional players, and 3) they would emit more erroneous verbalizations. Results showed that hypotheses one and three were confirmed. Theoretical and practical implications of these results for the psychology of gambling are discussed.This study was supported by a grant from Loto-Québec.     

Using computers to develop concept models of social situations

Concept modeling is presented as a way to describe and understand social situations. Concepts are developed from field data and supported by sets of exemplars drawn from the data which illustrate the various concepts. The computer is considered an essential tool for conducting this type of qualitative data analysis and displaying the resulting concept models. Two sample concept models are presented along with a discussion of how concept models can be related to teaching and learning, as well as to the nonlinear presentation of research results. Assessment of concept models is then considered. Three types of assessment are suggested: empirical, qualitative and quantitative.