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.     

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.     

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.     

Informed decision making: the new paradigm

Health care cannot survive in its present form. It is becoming unaffordable for a large share of the country's population. Its quality and effectiveness inexplicably vary between communities and across time. With all these problems, the process of health care can be understood. All that are needed are good, basic data; its access, management, and analysis; and then presentation of facts and observations. Together, these functions describe the translation of data into information--the field of medical informatics. Information about such management concerns as clinical efficiency (which largely is related to appropriateness and cost-effectiveness) and about the realities of day-to-day medical practice can be used to improve the value of health care. Informed decision making is based solely on confidence that, given the right information and understanding, we can all make the right decisions. The right decisions mean better patient acceptance and satisfaction, a sense of value enhancement by payers, and support of the Hippocratic tradition.     

ATSDR Science Panel on the Bioavailability of Mercury in Soils: Lessons Learned

On the basis of discussion and analysis during and following an ATSDR science panel on the bioavailability of mercury in soils, it is apparent that the default assumption of 100% relative bioavailability for mercury-contaminated soils is excessively conservative. However, current knowledge does not allow the development of default assumptions or guidelines for determining relative bioavailability of mercury in soils. Until such default assumptions or guidelines can be developed, site-specific assays of bioavailability, preferably using either animal bioassays or validated in vitro techniques, may provide the best approach for estimating soil-mercury bioavailability.     

Fitting Hierarchical Holographic Modeling into the Theory of Scenario Structuring and a Resulting Refinement to the Quantitative Definition of Risk

A point of view is suggested from which the Hierarchical Holographic Modeling (HHM) method can be seen as one more method within the Theory of Scenario Structuring (TSS), which is that part of Quantitative Risk Assessment having to do with the task of identifying the set of risk scenarios. Seen in this way, HHM brings strongly to our attention the fact that different methods within TSS can result in different sets of risk scenarios for the same underlying problem. Although this is not a problem practically, it is a bit awkward conceptually from the standpoint of the "set of triplets" definition of risk, in which the scenario set is part of the definition. Accordingly, the present article suggests a refinement to the set of triplets definition, which removes the specific set of scenarios, found by any of the TSS methods, from the definition of risk and casts it, instead, as an approximation to the "true" set of scenarios that is native to the problem at hand and not affected by the TSS method used.     

Outward bound: a treatment modality unexplored by the social work profession.

The Outward Bound Experience has a strong yet time-limited impact on delinquent youths. Social workers could help maintain the impact by establishing community-based followup programs that would reinforce and sustain the positive attitudes and behaviors developed.