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.     

Developing a Broadly Applicable Measure of Risk Perception

Decades of research identify risk perception as a largely intuitive and affective construct, in contrast to the more deliberative assessments of probability and consequences that form the foundation of risk assessment. However, a review of the literature reveals that many of the risk perception measures employed in survey research with human subjects are either generic in nature, not capturing any particular affective, probabilistic, or consequential dimension of risk; or focused solely on judgments of probability. The goal of this research was to assess a multidimensional measure of risk perception across multiple hazards to identify a measure that will be broadly useful for assessing perceived risk moving forward. Our results support the idea of risk perception being multidimensional, but largely a function of individual affective reactions to the hazard. We also find that our measure of risk perception holds across multiple types of hazards, ranging from those that are behavioral in nature (e.g., health and safety behaviors), to those that are technological (e.g., pollution), or natural (e.g., extreme weather). We suggest that a general, unidimensional measure of risk may accurately capture one's perception of the severity of the consequences, and the discrete emotions that are felt in response to those potential consequences. However, such a measure is not likely to capture the perceived probability of experiencing the outcomes, nor will it be as useful at understanding one's motivation to take mitigation action.     

The Persistent Problem of Colorism: Skin Tone, Status, and Inequality

Colorism is a persistent problem for people of color in the USA. Colorism, or skin color stratification, is a process that privileges light-skinned people of color over dark in areas such as income, education, housing, and the marriage market. This essay describes the experiences of African Americans, Latinos, and Asian Americans with regard to skin color. Research demonstrates that light-skinned people have clear advantages in these areas, even when controlling for other background variables. However, dark-skinned people of color are typically regarded as more ethnically authentic or legitimate than light-skinned people. Colorism is directly related to the larger system of racism in the USA and around the world. The color complex is also exported around the globe, in part through US media images, and helps to sustain the multibillion-dollar skin bleaching and cosmetic surgery industries.     

Social Antecedents of Medical Fraud and Over-Servicing: What Makes A Doctor Criminal?

Medical fraud and overservicing are estimated to cost the Australian community between $130 and $200 million per annum, a figure far greater than the national cost of burglary and almost the same as the total property loss from all conventional crime. An examination of the social antecedents of medical fraud and overservicing suggests that the predisposition of some doctors to engage in these practices occurs because of the following: (1) medical training and professional socialization that orientate student doctors away from altruistic health issues towards narrower self-interested professional concerns; (2) career expectations of a high pattern of material consumption that are often frustrated by an increasingly competitive medical market place; and (3) professional medical organizations that lobby for national health policies which reflect the mercenary self-interest of doctors rather than the health interest of the nation.     

The Determinants of Racial Disparities in Perceived Job Insecurity: A Test of Three Perspectives

Why do African Americans report higher levels of perceived job insecurity than whites? We analyze data from the 1996 and 1998 General Social Survey to test alternative predictions from the compositional, inclusive‐discrimination, and dispositional perspectives concerning the sources of the racial gap in perceived insecurity. Results from ordered probit regressions provide most support for the inclusive‐discrimination perspective, which maintains that employment practices associated with “modern racial prejudice” induce perceived insecurity on a widespread and generalized basis among African Americans. Accordingly, compared to whites, African Americans experience perceived insecurity net of human capital credentials and job/labor market characteristics. Additional analyses provide one qualification to these findings: dynamics associated with the inclusive‐discrimination perspective are more pronounced in the private sector than the public sector.     

Assessing accuracy of a continuous screening test in the presence of verification bias

Summary.  In studies to assess the accuracy of a screening test, often definitive disease assessment is too invasive or expensive to be ascertained on all the study subjects. Although it may be more ethical or cost effective to ascertain the true disease status with a higher rate in study subjects where the screening test or additional information is suggestive of disease, estimates of accuracy can be biased in a study with such a design. This bias is known as verification bias. Verification bias correction methods that accommodate screening tests with binary or ordinal responses have been developed; however, no verification bias correction methods exist for tests with continuous results. We propose and compare imputation and reweighting bias-corrected estimators of true and false positive rates, receiver operating characteristic curves and area under the receiver operating characteristic curve for continuous tests. Distribution theory and simulation studies are used to compare the proposed estimators with respect to bias, relative efficiency and robustness to model misspecification. The bias correction estimators proposed are applied to data from a study of screening tests for neonatal hearing loss.