AimsEvaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research.MethodsWe searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non‐European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted.ResultsFrom 1246 screened articles, 229 were eligible for full‐text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%); 55% of studies measured changes in drug utilization patterns, 27% evaluated health outcomes, and 18% targeted knowledge, behaviour or changes in clinical practice. Unintended consequences like switching therapies or spill‐over effects were rarely evaluated. Two‐thirds used before–after time series and 15.7% before–after cross‐sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%).ConclusionWhilst impact evaluation of pharmacovigilance and product‐specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs.
Hydrochlorothiazide-induced photosensitivity may increase squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and lip cancer risk. The aim was to quantify these risks.Methods: Nested case-control studies using data from the UK THIN database from 01 January 1999 to 01 May 2016. Adults with incident SCC, BCC, melanoma, lip cancer and oral cancer were matched (on age, sex and calendar year of cohort entry) to controls using incidence density sampling. Incidence rate ratios (IRR) for each outcome were calculated for ever and cumulative hydrochlorothiazide exposure, measuring the impact of additionally adjusting for smoking and body mass index (BMI). Adjusted rate differences were estimated, including the number needed to harm.Results: Cumulative hydrochlorothiazide doses ≥50 000 mg were associated with a significantly increased risk of SCC IRR = 3.05 (1.93-4.81) and BCC IRR = 1.34 (1.06-1.69).Using a 5-year lag-period, hydrochlorothiazide exposure was also associated with a significantly increased risk of lip cancer (IRR 2.85, 95% confidence interval 1.32-6.15). No significantly increased risk of melanoma or oral cavity cancer was observed. Following adjustment for smoking and BMI, which had inverse associations with several skin cancer types, associations for hydrochlorothiazide remained significant. The overall number needed to harm with high-dose cumulative hydrochlorothiazide exposure was: 804 for SCC; 2463 for BCC, and 200 000 for lip cancer but varied by age and sex. Conclusion:Hydrochlorothiazide exposure was associated with an increased risk of SCC, BCC and lip cancer that is not explained following adjustment for smoking and BMI. These findings may support clinical and regulatory decision making.
Background and Objective Tendon rupture can result from fluoroquinolone exposure. The objective of this study was to quantify relative and absolute risk and determine how risk is affected by timing of exposure. Methods The UK Health Improvement Network primary care database was used to perform a nested case–control study measuring the association between fluoroquinolone exposure and tendon rupture. Adults with tendon rupture were matched on age, sex, general practice and calendar time to four controls selected from a cohort prescribed systemic fluoroquinolone or co-amoxiclav antibiotics. The relative and absolute risk of tendon rupture with fluoroquinolone exposure was calculated. Results Current fluoroquinolone exposure was associated with an increased risk of any tendon rupture (adjusted incidence rate ratio [aIRR] 1.61, 95% CI 1.25–2.09) and Achilles tendon rupture (aIRR 3.14, 95% CI 2.11–4.65) that persisted for 60 days. Risk increased with cumulative exposure and was greatest when co-prescribed with oral corticosteroids (aIRR 19.36, 95% CI 7.78–48.19 for Achilles tendon rupture). The adjusted rate difference (aRD) with fluoroquinolone exposure was 2.9 and 2.1 per 10,000 patients for any and Achilles tendon rupture, respectively, and was greatest in people aged ≥ 60 years prescribed concomitant oral corticosteroid therapy (aDR 19.6 for any tendon and 6.6 Achilles tendon rupture per 10,000). No association was seen with co-amoxiclav or statin exposure, or with biceps or other tendon ruptures. Conclusions Risk of tendon rupture with fluoroquinolones depends on timing, cumulative dose and concomitant exposure to oral corticosteroids. Absolute risk significantly varied by age and concomitant corticosteroid exposure, affecting elderly patients the greatest. Electronic supplementary material The online version of this article (10.1007/s40261-018-0729-y) contains supplementary material, which is available to authorized users.
ObjectiveElectronic healthcare databases (EHDs) are useful tools for drug development and safety evaluation but their heterogeneity of structure, validity and access across Europe complicates the conduct of multidatabase studies. In this paper, we provide insight into available EHDs to support regulatory decisions on medicines.MethodsEHDs were identified from publicly available information from the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance resources database, textbooks and web-based searches. Databases were selected using criteria related to accessibility, longitudinal dimension, recording of exposure and outcomes, and generalisability. Extracted information was verified with the database owners.ResultsA total of 34 EHDs were selected after applying key criteria relevant for regulatory purposes. The most represented regions were Northern, Central and Western Europe. The most frequent types of data source were electronic medical records (44.1%) and record linkage systems (29.4%). The median number of patients registered in the 34 data sources was 5 million (range 0.07–15 million) while the median time covered by a database was 18.5 years. Paediatric patients were included in 32 databases (94%). Completeness of information on drug exposure was variable. Published validation studies were found for only 17 databases (50%). Some level of access exists for 25 databases (73.5%), and 23 databases (67.6%) can be linked through a personal identification number to other databases with parent–child linkage possible in 7 (21%) databases. Eight databases (23.5%) were already transformed or were in the process of being transformed into a common data model that could facilitate multidatabase studies.ConclusionA Few European databases meet minimal regulatory requirements and are readily available to be used in a regulatory context. Accessibility and validity information of the included information needs to be improved. This study confirmed the fragmentation, heterogeneity and lack of transparency existing in many European EHDs.
The importance of spontaneous reporting in signal detection and monitoring of safety issues throughout the entire life cycle of a medicinal product is confirmed in this study. The amount of time a drug has been on the market is correlated with the number of signals detected. The PRAC decision-making process seems efficient particularly with respect to serious concerns; its role in improving signal prioritization and real-time signal management will be further clarified in its subsequent years of operation.
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