Pharmacovigilance in Clinical Trials: Current Practice and Challenges

In view of the MENA increasing participation in multinational trials and the increasing number of national/regional trials, this article explores potential areas of pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. Regulatory silence on expedited reporting requirements creates confusion for local sites that are part of multinational trials. Not allowing waiver for serious adverse events that are protocol specified or are study endpoints, along with lack of emphasis on causality as reporting criteria, adds substantial burden of uninformative cases for regulatory review. Despite global focus on Development Safety Update Report, local regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. Finally, the need to formulate an all-encompassing local pharmacovigilance guideline, in sync with global practice cannot be overemphasized.     

Improving Risk Management: From Lame Excuses to Principled Practice

The three classic pillars of risk analysis are risk assessment (how big is the risk and how sure can we be?), risk management (what shall we do about it?), and risk communication (what shall we say about it, to whom, when, and how?). We propose two complements as important parts of these three bases: risk attribution (who or what addressable conditions actually caused an accident or loss?) and learning from experience about risk reduction (what works, and how well?). Failures in complex systems usually evoke blame, often with insufficient attention to root causes of failure, including some aspects of the situation, design decisions, or social norms and culture. Focusing on blame, however, can inhibit effective learning, instead eliciting excuses to deflect attention and perceived culpability. Productive understanding of what went wrong, and how to do better, thus requires moving past recrimination and excuses. This article identifies common blame‐shifting “lame excuses” for poor risk management. These generally contribute little to effective improvements and may leave real risks and preventable causes unaddressed. We propose principles from risk and decision sciences and organizational design to improve results. These start with organizational leadership. More specifically, they include: deliberate testing and learning—especially from near‐misses and accident precursors; careful causal analysis of accidents; risk quantification; candid expression of uncertainties about costs and benefits of risk‐reduction options; optimization of tradeoffs between gathering additional information and immediate action; promotion of safety culture; and mindful allocation of people, responsibilities, and resources to reduce risks. We propose that these principles provide sound foundations for improving successful risk management.     

Dose‐Response Models Incorporating Aerosol Size Dependency for Francisella tularensis

The effect of bioaerosol size was incorporated into predictive dose‐response models for the effects of inhaled aerosols of Francisella tularensis (the causative agent of tularemia) on rhesus monkeys and guinea pigs with bioaerosol diameters ranging between 1.0 and 24 μm. Aerosol‐size‐dependent models were formulated as modification of the exponential and β‐Poisson dose‐response models and model parameters were estimated using maximum likelihood methods and multiple data sets of quantal dose‐response data for which aerosol sizes of inhaled doses were known. Analysis of F. tularensis dose‐response data was best fit by an exponential dose‐response model with a power function including the particle diameter size substituting for the rate parameter k scaling the applied dose. There were differences in the pathogen's aerosol‐size‐dependence equation and models that better represent the observed dose‐response results than the estimate derived from applying the model developed by the International Commission on Radiological Protection (ICRP, 1994) that relies on differential regional lung deposition for human particle exposure.     

Relations Between Alphabetized Name Order and Nomination Counts in Peer Nomination Measures

Peer nominations, a central method for measuring peer relationships in developmental research, typically involve asking children or adolescents to choose peers who fit various criteria from an alphabetized roster of classmates or grade‐mates. Although such measures have been used for decades, very little research has investigated the effects of alphabetical name order on the number of nominations received by peers. This study collected peer nominations for 20 items among 607 eighth grade participants in two schools. Regression analyses showed that earlier name order significantly predicted higher nomination counts for eight of the items, and explained over 5 percent of the variance in four affective variables (friendship, acceptance, acquaintanceship, and received liking). Across variables, name order effects were negatively correlated with internal reliability of nominations, implying that order effects may be related to the consensus of the peer group. Name order also had a minimal effect on inter‐correlations among a subset of variables. Implications and concrete recommendations for controlling and reducing name order effects in future research are discussed.     

Symptoms of Eating Disorders Among Females in Drug Addiction Treatment

The aim of this study is to measure and describe symptoms of eating disorders among females in treatment for drug addiction in Norway. Previous clinical and epidemiological studies have revealed coprevalence between eating disorders and substance use or abuse. However, few studies have measured eating disorders in drug-using samples and even fewer within the context of drug treatment. In this study, 29 females with drug use disorder in residential treatment were tested with the Eating Disorder Inventory–2. A subgroup of 9 females (31%) with significant symptoms of eating disorders was identified. The characteristics of this group and possible clinical consequences are discussed.     

Why Frequency is Not Well Defined for Engineering Systems with Nonexponential Failure Times

Dr. Yellman proposes to define frequency as “a time‐rate of events of a specified type over a particular time interval.” We review why no definition of frequency, including this one, can satisfy both of two conditions: (1) the definition should agree with the ordinary meaning of frequency, such as that less frequent events are less likely to occur than more frequent events, over any particular time interval for which the frequencies of both are defined; and (2) the definition should be applicable not only to exponentially distributed times between (or until) events, but also to some nonexponential (e.g., uniformly distributed) times. We make the simple point that no definition can satisfy (1) and (2) by showing that any definition that determines which of any two uniformly distributed times has the higher “frequency” (or that determines that they have the same “frequency,” if neither is higher) must assign a higher frequency number to the distribution with the lower probability of occurrence over some time intervals. Dr. Yellman's proposed phrase, “time‐rate of events … over a particular time interval” is profoundly ambiguous in such cases, as the instantaneous failure rates vary over an infinitely wide range (e.g., from one to infinity), making it unclear which value is denoted by the phrase “time‐rate of events.”     

Infill asymptotics for adaptive kernel estimators of spatial intensity

We apply the Abramson principle to define adaptive kernel estimators for the intensity function of a spatial point process. We derive asymptotic expansions for the bias and variance under the regime that n independent copies of a simple point process in Euclidean space are superposed. The method is illustrated by means of a simple example and applied to tornado data.