Nancy Yuen

Perspectives on the Use of Data Mining in Pharmacovigilance

In the last 5 years, regulatory agencies and drug monitoring centres have been developing computerised data-mining methods to better identify reporting relationships in spontaneous reporting databases that could signal possible adverse drug reactions. At present, there are no guidelines or standards for the use of these methods in routine pharmacovigilance. In 2003, a group of statisticians, pharmacoepidemiologists and pharmacovigilance professionals from the pharmaceutical industry and the US FDA formed the Pharmaceutical Research and Manufacturers of America-FDA Collaborative Working Group on Safety Evaluation Tools to review best practices for the use of these methods.In this paper, we provide an overview of: (i) the statistical and operational attributes of several currently used methods and their strengths and limitations; (ii) information about the characteristics of various postmarketing safety databases with which these tools can be deployed; (iii) analytical considerations for using safety data-mining methods and interpreting the results; and (iv) points to consider in integration of safety data mining with traditional pharmacovigilance methods. Perspectives from both the FDA and the industry are provided.Data mining is a potentially useful adjunct to traditional pharmacovigilance methods. The results of data mining should be viewed as hypothesis generating and should be evaluated in the context of other relevant data. The availability of a publicly accessible global safety database, which is updated on a frequent basis, would further enhance detection and communication about safety issues.

Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase Unified List Based on International Collaborative Work

Background: Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans.Objective: (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase™).Data Sources and Extraction: (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase™, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, ‘overall liver injury’ and ‘ALF’. EBGM of ≥2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of ‘overall liver injury’ and ‘ALF’ calculated from VigiBase™.Data Synthesis: After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase™, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of ‘overall liver injury’ and 83.1% were associated with at least one reported case of ALF.Conclusions: This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.

Comparative performance of two quantitative safety signalling methods: implications for use in a pharmacovigilance department.

AbstractBackground and objectives: There is increasing interest in using disproportionality-based signal detection methods to support postmarketing safety surveillance activities. Two commonly used methods, empirical Bayes multi-item gamma Poisson shrinker (MGPS) and proportional reporting ratio (PRR), perform differently with respect to the number and types of signals detected. The goal of this study was to compare and analyse the performance characteristics of these two methods, to understand why they differ and to consider the practical implications of these differences for a large, industry-based pharmacovigilance department. Methods: We compared the numbers and types of signals of disproportionate reporting (SDRs) obtained with MGPS and PRR using two postmarketing safety databases and a simulated database. We recorded signal counts and performed a qualitative comparison of the drug-event combinations signalled by the two methods as well as a sensitivity analysis to better understand how the thresholds commonly used for these methods impact their performance. Results: PRR detected more SDRs than MGPS. We observed that MGPS is less subject to confounding by demographic factors because it employs stratification and is more stable than PRR when report counts are low. Simulation experiments performed using published empirical thresholds demonstrated that PRR detected false-positive signals at a rate of 1.1%, while MGPS did not detect any statistical false positives. In an attempt to separate the effect of choice of signal threshold from more fundamental methodological differences, we performed a series of experiments in which we modified the conventional threshold values for each method so that each method detected the same number of SDRs for the example drugs studied. This analysis, which provided quantitative examples of the relationship between the published thresholds for the two methods, demonstrates that the signalling criterion published for PRR has a higher signalling frequency than that published for MGPS. Discussion and conclusion: The performance differences between the PRR and MGPS methods are related to (i) greater confounding by demographic factors with PRR; (ii) a higher tendency of PRR to detect false-positive signals when the number of reports is small; and (iii) the conventional thresholds that have been adapted for each method. PRR tends to be more ‘sensitive’ and less ‘specific’ than MGPS. A high-specificity disproportionality method, when used in conjunction with medical triage and investigation of critical medical events, may provide an efficient and robust approach to applying quantitative methods in routine postmarketing pharmacovigilance.

Drug-induced liver injury following positive drug rechallenge

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, can lead to serious or fatal liver injury. A retrospective review of a large pharmaceutical safety database was conducted to assess clinical outcomes of positive drug rechallenge following possible drug-induced liver injury. Positive rechallenge with suspect drug was reported in 770 of 36,795 hepatic adverse events. A total of 88 cases met inclusion criteria for analysis. Mean age was 44 years (range 0.5-83) and 56% were male. A broad spectrum of suspect drugs were identified. Many patients exhibited hepatitis symptoms or jaundice on the initial and rechallenge liver event. Twelve patients (14%) exhibited clinically worrisome severe hepatocellular injury and jaundice on either initial or rechallenge event and two died, reflecting a 2.3% fatality rate in those with positive rechallenge. The two fatalities developed severe hepatocellular injury with jaundice only upon rechallenge. Liver injury recurred in most rechallenges. Improved identification and communication of possible drug-induced liver injury is needed to avoid potentially serious and/or fatal drug rechallenges. Clinicians should generally avoid such rechallenges.

Spontaneous adverse event reports of Stevens–Johnson syndrome/toxic epidermal necrolysis: detecting associations with medications

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are medically serious skin reactions that are often drug induced. The mainstay of therapy and future prevention is to discontinue and avoid the use of the suspected inducing drug. However, many cases of SJS/TEN occur in patients who are taking multiple medications, and it is often difficult to determine which drug to stop. This analysis was conducted to identify drugs that were most associated with SJS/TEN in the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database and to identify medications that were likely innocent bystanders.

Age-related differences in reporting of drug-associated liver injury: Data-mining of WHO Safety Report Database

BACKGROUND/AIMS Age-differences in the frequency and manifestations of drug-induced liver injury are not fully characterized. Data-mining analyses were performed to assess the impact of age on liver event reporting frequency with different phenotypes and agents. METHODS 236 drugs associated with hepatotoxicity were evaluated using the Empirical Bayes Geometric Mean (EBGM) of the relative reporting ratio with 90% confidence interval (EB05 and EB95) calculated for the age groups: 0-17, 18-64, and⩾65years (or elderly), for overall, serious (acute liver failure), hepatocellular, and cholestatic liver injury, using the WHO Safety Report Database. RESULTS Overall, cases of age 0-17, 18-64, and 65years or older comprised 6%, 62%, and 32% of liver event reports. Acute liver failure and hepatocellular injury were more frequently reported among children compared to adults and the elderly while reports with cholestatic injury were more frequent among the elderly (p<0.00001). A potential to cause mitochondrial dysfunction was more prevalent among the drugs with increased pediatric reporting frequency while high lipophilicity and biliary excretion were more common among the drugs associated with higher reporting frequency in the elderly. CONCLUSION Age-specific phenotypes and potential drug properties associated with age-specific hepatotoxicity were identified in reported liver events; further analyses are warranted.

Automated Method for Detecting Increases in Frequency of Spontaneous Adverse Event Reports over Time

A statistical methodology—focused on temporal change detection—was developed to highlight excursions from baseline spontaneous adverse event (AE) reporting. We used regression (both smooth trend and seasonal components) to model the time course of a drugs reports containing an AE, and then compared the sum of counts in the past 2 months with the fitted trend. The signaling threshold was tuned, using retrospective analysis, to yield acceptable sensitivity and specificity. The method may enhance pharmacovigilance by providing effective automated alerting of reporting aberrations when databases are small, when drugs have established safety profiles, and/or when product quality issues are of concern.

Molecular clinical safety intelligence: a system for bridging clinically focused safety knowledge to early-stage drug discovery - the GSK experience.

Drug toxicity is a major cause of late-stage product attrition. During lead identification and optimization phases little information is typically available about which molecules might have safety concerns. A system was built linking chemistry, preclinical and human safety information, enabling scientists to lever safety knowledge across multiple disciplines. The system consists of a data warehouse with chemical structures and chemical and biological properties for ∼80000 compounds and tools to access and analyze clinical data, toxicology, in vitro pharmacology and drug metabolism data. Tapping into this safety knowledge enables rapid clinically focused risk assessments of drug candidates. Use of this strategy adds value to the drug discovery process at GSK via efficient triage of compounds based on their potential for toxicity.

Online signal management : A systems-based approach that delivers new analytical capabilities and operational efficiency to the practice of pharmacovigilance

Traditional approaches to postmarketing pharmacovigilance have been primarily qualitative and paper based. We describe the development and implementation of online signal management (OSM), a new systems-based platform for pharmacovigilance that supports prioritization of safety issues, in-stream review and data retrieval, aggregate-level analysis of data patterns, and knowledge management. By providing an integrated view of the information needed to detect and evaluate safety signals, OSM enhances the efficiency of the pharmacovigilance process. The system enables pharmacovigilance professionals to triage incoming data using statistical, visualization, and alerting tools. Safety issues can be flagged and tracked, providing a streamlined approach to the retention and sharing of knowledge. We have deployed OSM to more than 100 users. User surveys and operational metrics demonstrate that OSM increases the efficiency of pharmacovigilance and that users are highly satisfied with OSM and the processes implemented for its use. In summary, this integration of state-of-the-art statistical and visualization tools with traditional, case-evaluation tools and a novel knowledge management system represents a significant advance in pharmacovigilance.

Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury

ABSTRACT We examined the effect of gender, age, and drug properties on liver events reporting frequency (RF) to assess patient‐ and drug‐related risks for drug‐induced liver injury (DILI). We performed a data‐mining analysis of the WHO VigiBase™ to 1) identify drugs with gender‐ and age‐biased RF and 2) characterize drug properties using the Liver Toxicity Knowledge Base. Age‐, gender‐specific Empirical Bayes Geometric Mean of relative reporting ratio of liver events with 90% confidence interval (CI) was calculated for 375 drugs with DILI potential. Forty‐one drugs showed an increased RF in women, which had a higher prevalence of reactive metabolite formation and mitochondrial dysfunction and transporter inhibition. Fifty‐nine drugs showed an increased RF in younger women (<50 yrs), many of which had a signature pattern of hepatocellular injury. In contrast, half of 17 drugs that showed an increased RF in men had a cholestatic pattern. In the older group (≥50 yrs), 17 drugs showed an increased RF and had higher transporter inhibition, Cmax, and plasma protein binding, yet shorter plasma elimination. Specific drug properties were associated with gender‐ and age‐biased liver events RF, suggesting possible interactions of drug properties, gender, and age in DILI development. HighlightsAge/gender‐based liver events reporting frequencies (RF) were assessed.Drugs with age/gender‐biased RF showed specific properties and injury patterns.Identified properties aid in studying drug‐host interactions in liver events. Abbreviations: DILI: drug‐induced liver injury; DILIN: drug‐induced liver injury network; HC: hepatocellular; CS/MIX: cholestatic/mixed; ALT: alanine aminotransferase; ALP: alkaline phosphatase; ULN: upper limit normal; ANA: antinuclear antibody; OR: odds ratio; CI: confidence interval; RF: reporting frequency; WHO: World Health Organization; LTKB: Liver Toxicity Knowledge Base; Cmax: maximum/peak drug concentration; T1/2: half life; MRP 2,3,4: multidrug resistance associated protein 2, 3 4; MedDRA: Medical Dictionary for Regulatory Activity; RRR: relative reporting ratio; EBGM: Empirical Bayes Geometric Mean of relative reporting ratio of liver events; FDA: food and drug administration; BDDCS: Biopharmaceutics Drug Disposition Classification System; ATP: Adenosine triphosphate; CYP: cytochrome.