Faculty Bibliography

To investigate spontaneous reporting relationships between representative antifungal agents and congestive heart failure (CHF)-related adverse events (AE) we performed multiple disproportionality analyses of the US FDA AERS database. Specifically we performed analysis of drug-AE associations (2D) plus drug-drug-AE and drug-AE-AE-associations (3D), the latter two to explore the potential contribution of reported pharmacodynamic interactions, overexposure from pharmacokinetic interactions, and drug overdose. Itraconazole displayed a pattern of statistical reporting dependencies across multiple analyses (2D and 3D). Amphotericin B was the only other antifungal that demonstrated a 2D SDR with CHF-related events. Itraconazole demonstrated multiple SDRs with calcium channel blockers in suspect drug-only 3D analysis. There was one other SDR with fluconazole and propanolol and three SDRs involving valproate and fluconazole that may have been do at least in part to duplicate reporting. Less specific 3D analysis including both suspect plus concomitant medications showed a greater number and variety of SDRs with multiple antifungals. Statistical reporting dependencies with CHF-related events did not appear to be a consistent pharmacological (e.g., azole/triazole)/therapeutic (i.e., antifungal) class effect. Itraconzole was unique in the pattern of statistical reporting dependencies with CHF-related events which is consistent with findings from independent data sets.

Introduction: Pneumothorax is either primary or secondary. Secondary pneumothorax is usually due to trauma, including various non-pharmacologic iatrogenic triggers. Although not normally thought of as an adverse drug event (ADE) secondary pneumothorax is associated with numerous drugs, though it is often difficult to determine whether this association is causal in nature, or reflects an epiphenomenon of efficacy or inefficacy, or confounding by indication (CBI). Herein we explore this association in a large health authority drug safety surveillance database. Methods: A quantitative pharmacovigilance (PhV) methodology known as disproportionality analysis was applied to the United States Food and Drug Administration (US FDA) Adverse Event Reporting System (AERS) database to explore the quantitative reporting dependencies between drugs and the adverse event pneumothorax as well the corresponding reporting dependencies between drugs and reported indications that may be risk factors for pneumothorax themselves in order to explore the potential contribution of CBI. Results: We found 1. Multiple drugs are associated with pneumothorax; 2. Surfactants and oncology drugs account for most statistically distinctive associations with pneumothorax; 3. Pulmonary surfactants, pentamidine and nitric oxide have the largest statistical reporting associations 4. CBI may play a prominent role in reports of drug-associated pneumothorax. Conclusions: Disproportionality analysis (DA) can provide insights into the spontaneous reporting dependencies between drugs and pneumothorax. CBI assessment based on DA and Cornfield's inequality presents an additional novel option for the initial exploration of potential safety signals in PhV.

MOTIVATION: A principal objective of pharmacovigilance is to detect adverse drug reactions that are unknown or novel in terms of their clinical severity or frequency. One method is through inspection of spontaneous reporting system databases, which consist of millions of reports of patients experiencing adverse effects while taking one or more drugs. For such large databases, there is an increasing need for quantitative and automated screening tools to assist drug safety professionals in identifying drug-event combinations (DECs) worthy of further investigation. Existing algorithms can effectively identify problematic DECs when the frequencies are high. However these algorithms perform differently for low-frequency DECs. RESULTS: In this work, we provide a method based on the multinomial distribution that identifies signals of disproportionate reporting, especially for low-frequency combinations. In addition, we comprehensively compare the performance of commonly used algorithms with the new approach. Simulation results demonstrate the advantages of the proposed method, and analysis of the Adverse Event Reporting System data shows that the proposed method can help detect interesting signals. Furthermore, we suggest that these methods be used to identify DECs that occur significantly less frequently than expected, thus identifying potential alternative indications for these drugs. We provide an empirical example that demonstrates the importance of exploring underexpected DECs. AVAILABILITY: Code to implement the proposed method is available in R on request from the corresponding authors. CONTACT: kjell@arboranalytics.com or Mark.M.Gosink@Pfizer.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The concept of surveillance in pharmacovigilance and pharmacoepidemiology has evolved from the concept of surveillance in epidemiology, particularly of infectious diseases. We have surveyed the etymology, usages, and previous definitions of 'surveillance' and its modifiers, such as 'active' and 'passive'. The following essential definitional features of surveillance emerge: (i) surveillance and monitoring are different - surveillance involves populations, while monitoring involves individuals; (ii) surveillance can be performed repeatedly and at any time during the lifetime of a medicinal product or device; (iii) although itself non-interventional, it can adduce any types of evidence (interventional, observational, or anecdotal, potentially at different times); (iv) it encompasses data collection, management, analysis, and interpretation; (v) it includes actions to be taken after signal detection, including initial evaluation and communication; and (vi) it should contribute to the classification of adverse reactions and their prevention or mitigation and/or to the harnessing of beneficial effects. We conclude that qualifiers add ambiguity and uncertainty without enhancing the idea of surveillance. We propose the following definition of surveillance of health-care products, which embraces all the surveyed ideas and reflects real-world pharmacovigilance processes: 'a form of non-interventional public health research, consisting of a set of processes for the continued systematic collection, compilation, interrogation, analysis, and interpretation of data on benefits and harms (including relevant spontaneous reports, electronic medical records, and experimental data).' As a codicil, we note that the purposes of surveillance are to identify, evaluate, understand, and communicate previously unknown effects of health-care products, or new aspects of known effects, in order to harness such effects (if beneficial) or prevent or mitigate them (if harmful).

A paradoxical drug reaction constitutes an outcome that is opposite from the outcome that would be expected from the drug's known actions. There are three types: 1. A paradoxical response in a condition for which the drug is being explicitly prescribed. 2. Paradoxical precipitation of a condition for which the drug is indicated, when the drug is being used for an alternative indication. 3. Effects that are paradoxical in relation to an aspect of the pharmacology of the drug but unrelated to the usual indication. In bidirectional drug reactions, a drug may produce opposite effects, either in the same or different individuals, the effects usually being different from the expected beneficial effect. Paradoxical and bidirectional drug effects can sometimes be harnessed for benefit; some may be adverse. Such reactions arise in a wide variety of drug classes. Some are common; others are reported in single case reports. Paradoxical effects are often adverse, since they are opposite the direction of the expected effect. They may complicate the assessment of adverse drug reactions, pharmacovigilance, and clinical management. Bidirectional effects may be clinically useful or adverse. From a clinical toxicological perspective, altered pharmacokinetics or pharmacodynamics in overdose may exacerbate paradoxical and bidirectional effects. Certain antidotes have paradoxical attributes, complicating management. Apparent clinical paradoxical or bidirectional effects and reactions ensue when conflicts arise at different levels in self-regulating biological systems, as complexity increases from subcellular components, such as receptors, to cells, tissues, organs, and the whole individual. These may be incompletely understood. Mechanisms of such effects include different actions at the same receptor, owing to changes with time and downstream effects; stereochemical effects; multiple receptor targets with or without associated temporal effects; antibody-mediated reactions; three-dimensional architectural constraints; pharmacokinetic competing compartment effects; disruption and non-linear effects in oscillating systems, systemic overcompensation, and other higher-level feedback mechanisms and feedback response loops at multiple levels. Here we review and provide a compendium of multiple class effects and individual reactions, relevant mechanisms, and specific clinical toxicological considerations of antibiotics, immune modulators, antineoplastic drugs, and cardiovascular, CNS, dermal, endocrine, musculoskeletal, gastrointestinal, haematological, respiratory, and psychotropic agents.