An algorithm to detect unexpected increases in frequency of reports of adverse events in EudraVigilance

Purpose

The European Medicines Agency developed an algorithm to detect unexpected increases in frequency of reports, to enhance the ability to detect adverse events that manifest as increases in frequency, in particular quality defects, medication errors, and cases of abuse or misuse.

Methods

An algorithm based on a negative binomial time‐series regression model run on 6 sequential observations prior to the monitored period was developed to forecast monthly counts of reports. A heuristic model to capture increases in counts when the previous 4 observations were null supplemented the regression. Count data were determined at drug‐event combination. Sensitivity analyses were run to determine the effect of different methods of pooling or stratifying count data. Positive retrospective detections and positive predictive values (PPVs) were determined.

Results

The algorithm detected 8 of the 13 historical concerns, including all concerns of quality defects. The highest PPV (1.29%) resulted from increasing the lower count threshold from 3 to 5 and including literature reports in the counts. Both the regression model and the heuristic model components to the algorithm contributed to the detection of concerns. Sensitivity analysis indicates that stratification by commercial product reduces the PPV but suggests that pooling counts of related events may improve it.

Conclusion

The results are encouraging and suggest that the algorithm could be useful for the detection of concerns that manifest as changes in frequency of reporting; however, further testing, including in prospective use, is warranted.     

Comparison of data mining methodologies using Japanese spontaneous reports

PURPOSE: Five data mining methodologies for detecting a possible signal from spontaneous reports on adverse drug reactions (ADRs) were compared. METHODS: The five methodologies, the Bayesian method using the Gamma Poissson Shrinker (GPS), the method employed in the UK Medicines Control Agency (MCA), the Bayesian Confidence Propagation Neural Network (BCPNN), the method using the 95% confidence interval (CI) for the reporting odds ratio (RORCI) and that using the 95% CI of the proportional reporting ratio (PRRCI) were compared using Japanese data obtained between 1998 and 2000. RESULTS: There were all in all 38,731 drug-ADR combinations. The count of drug-ADR pairs was equal to 1 or 2 for 31,230 combinations and none of them were identified as a possible signal with the MCA or BCPNN. Similarly, the GPS detected a possible signal in none of the combinations where the count was equal to 1 but in 7.5% of the combinations where the count was equal to 2. The RORCI and PRRCI detected a possible signal in more than half of the combinations where the count was equal to 1 or 2. When the pairwise agreement on whether or not a drug-ADR combination satisfied the criteria for a possible signal was assessed for the 38,731 combinations, the concordance measure kappa was greater than 0.9 between the MCA and BCPNN and between the RORCI and PRRCI. Kappa was around 0.6 between the GPS and MCA and between the GPS and BCPNN. Otherwise, kappa was smaller than 0.2. CONCLUSIONS: The drug-ADR combinations detected as a possible signal vary between different methodologies.     

Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions

AIMS: Cutaneous manifestations are frequently reported in association with drug use. The aim of this study was to analyse the skin reactions reported to the spontaneous surveillance systems of four Italian regions (Friuli Venezia Giulia, Lombardy, Sicily and the Veneto), and correlate the reports with estimated drug consumption during the same period, paying particular attention to the reactions to antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: All of the adverse drug reactions (ADRs) reported spontaneously between January 1996 and December 1997 to the surveillance systems of four Italian regions (a total population of about 20 million people) were analysed by a panel of experts including dermatologists. On the basis of the Critical Term List of the World Health Organization (WHO), the reactions were classified as either serious or nonserious events. Drug consumption was expressed as a daily defined dose (DDD)/1000 inhabitants/day. RESULTS: A total of 2224 adverse skin reaction reports (44.7% of all of the reported ADRs) were identified, making a reporting rate of about 5.5 per 100 000 inhabitants/year. The female/male ratio was 1.58, and the reporting rate progressively increased with age. The drug categories with the highest number of cutaneous reactions were antimicrobials, followed by NSAIDs, analgesics and radiology contrast media. There was a total of 372 (16.9%) serious reaction reports, the most frequent being angioedema (171 cases), erythema multiforme (68 cases) and photosensitivity (37 cases). Co-trimoxazole, followed by the cephalosporins and fluoroquinolones, were associated with the highest consumption-related reporting rate among the antimicrobials, and aspirin and dipyrone among the NSAIDs and analgesics. CONCLUSIONS: Spontaneous reports from four Italian regions revealed that the skin was the organ most frequently affected by ADRs. The paper shows the validity of a regional decentralized system in Italy.