The role of databases in drug postmarketing surveillance

This paper describes the role of databases used for postmarketing surveillance of drugs at the United States Food and Drug Administration (FDA). First we describe the Adverse Event Reporting System (AERS), the largest database of adverse event reports in the world. Next, we explain the methods we have used for assembling these adverse event reports into a case series and analysing them, as well as techniques for employing drug use databases to construct reporting rates in the evaluation of drug safety issues. Finally, we discuss the FDA's use of the databases it accesses through its Cooperative Agreement Program to conduct high priority studies to support regulatory decision‐making. Published in 2001 by John Wiley & Sons, Ltd.     

Clinical perspectives in drug safety and adverse drug reactions

Adverse drug reactions (ADRs) remain a common clinical problem since they can mimic many diseases and cause significant morbidity and mortality. Judicious prescribing is important to minimize their occurrence. Apart from the recent identification of a few pharmacogenomic biomarkers for serious reactions, many remain unpredictable. Spontaneous reporting continues to play an important role in pharmacovigilance and the value of astute clinical observation and well-documented reports of suspicions of a causal link cannot be underestimated. Many national reporting schemes have developed considerable experience and expertise over many years and have large ADR databases, which are national assets. Despite advances in pharmacovigilance, numerous deficiencies have been identified; postmarketing surveillance remains the weakest link in the regulatory process. Regulatory authorities have tended to act later rather than sooner in response to safety signals, and this, when combined with under-reporting, may have led to exposure of a large number of patients to drug-related harm before restriction or withdrawal. In an attempt to improve vigilance, international surveillance may benefit by moving from its current passive/reactive mode toward active surveillance systems with a prospective, comprehensive and systematic approach to monitoring, collecting, analyzing and reporting data on ADRs. This will include increased pressure on pharmaceutical companies to conduct postmarketing studies. Such an active/proactive approach, while maintaining focus on ADR detection, could also aim to extend knowledge of safety, such that emerging changes in risk–benefit during a drug’s marketed life are effectively communicated to clinicians and patients. Drug safety monitoring and its regulation are now undergoing an overhaul and it is hoped that vigilance, public safety and trust will improve as a result.     

Pediatric drug safety signal detection of non-chemotherapy drug-induced neutropenia and agranulocytosis using electronic healthcare records

Objectives: This study aimed to develop a procedure to explore the adverse drug reaction signals of drug-induced neutropenia (DIN) or drug-induced agranulocytosis (DIA) in children using an electronic health records (EHRs) database.

Methods: A two-stage design was presented. First, the suspected drugs to induce DIN or DIA were selected. Second, the associations were evaluated by a retrospective cohort study.

Results: Ten and five drugs were potentially identified to be associated with DIN and DIA, respectively. Finally, five (oseltamivir, chlorpheniramine, vancomycin, meropenem, and ganciclovir) and two (chlorpheniramine, and vancomycin) drugs were found to be associated with DIN and DIA, respectively. Of these, the association between oseltamivir and neutropenia (P = 9.83 × 10^–9; OR, 2.10; 95% CI, 1.62?2.69) was considered as a new signal for both adults and children. Chlorpheniramine-induced neutropenia (P = 3.01 × 10^–8; OR, 1.59; 95% CI, 1.35?1.87) and agranulocytosis (P = 3.16 × 10^–7; OR, 3.76; 95% CI, 2.25?6.26) were considered as new signals in children. Other drugs associated with DIN or DIA were confirmed by previous studies.

Conclusion: A method to detect signals for DIN and DIA has been described. Several pediatric drugs were found to be associated with DIN or DIA.     

Methods for safety signal detection in healthcare databases: a literature review

Introduction: With increasing availability, the use of healthcare databases as complementary data source for drug safety signal detection has been explored to circumvent the limitations inherent in spontaneous reporting.

Areas covered: To review the methods proposed for safety signal detection in healthcare databases and their performance.

Expert opinion: Fifteen different data mining methods were identified. They are based on disproportionality analysis, traditional pharmacoepidemiological designs (e.g. self-controlled designs), sequence symmetry analysis (SSA), sequential statistical testing, temporal association rules, supervised machine learning (SML), and the tree-based scan statistic. When considering the performance of these methods, the self-controlled designs, the SSA, and the SML seemed the most interesting approaches. In the perspective of routine signal detection from healthcare databases, pragmatic aspects such as the need for stakeholders to understand the method in order to be confident in the results must be considered. From this point of view, the SSA could appear as the most suitable method for signal detection in healthcare databases owing to its simple principle and its ability to provide a risk estimate. However, further developments, such as automated prioritization, are needed to help stakeholders handle the multiplicity of signals.     

Active and passive surveillance of enoxaparin generics: a case study relevant to biosimilars

Objective: This retrospective analysis assessed the capability of active and passive safety surveillance systems to track product-specific safety events in the USA for branded and generic enoxaparin, a complex injectable subject to immune-related and other adverse events (AEs).

Methods: Analysis of heparin-induced thrombocytopenia (HIT) incidence was performed on benefit claims for commercial and Medicare supplemental-insured individuals newly treated with enoxaparin under pharmacy benefit (1 January 2009 – 30 June 2012). Additionally, spontaneous reports from the FDA AE Reporting System were reviewed to identify incidence and attribution of enoxaparin-related reports to specific manufacturers.

Results: Specific, dispensed products were identifiable from National Drug Codes only in pharmacy-benefit databases, permitting sensitive comparison of HIT incidence in nearly a third of patients treated with brand or generic enoxaparin. After originator medicine’s loss of exclusivity, only 5% of spontaneous reports were processed by generic manufacturers; reports attributable to specific generics were approximately ninefold lower than expected based on market share.

Conclusions: Claims data were useful for active surveillance of enoxaparin generics dispensed under pharmacy benefits but not for products administered under medical benefits. These findings suggest that the current spontaneous reporting system will not distinguish product-specific safety signals for products distributed by multiple manufacturers, including biosimilars.     

Pharmacovigilance in children: detecting adverse drug reactions in routine electronic healthcare records. A systematic review

Aims

A systematic review of the literature published in English over 10 years was undertaken in order to describe the use of electronic healthcare data in the identification of potential adverse drug reactions (ADRs) in children.

Methods

MEDLINE and EMBASE were searched using MESH headings and text words. Titles, keywords and abstracts were checked for age <18 years, potential ADRs and electronic healthcare data. Information extracted included age, data source, pharmacovigilance method, medicines and ADRs. Studies were quality assessed.

Results

From 14 804 titles, 314 had a full text review and 71 were included in the final review. Fifty were published in North America, 10 in Scandinavia. Study size ranged from less than 1000 children to more than 10 million. Sixty per cent of studies used data from one source. Comparative observational studies were most commonly reported (66.2%) with 15% using passive surveillance. Electronic healthcare data set linkage and the quality of the data source were poorly reported. ADRs were classified using the International Classification of Disease (ICD10). Multi-system reactions were most commonly studied, followed by central nervous system and mental and behavioural disorders. Vaccines were most frequently prescribed followed by corticosteroids, general anaesthetics and antidepressants.

Conclusions

Routine electronic healthcare records were increasingly reported to be used for pharmacovigilance in children. This growing and important health protection activity could be enhanced by consistent reporting of studies to improve the identification, interpretation and generalizability of the evidence base.     

欧美药品上市后安全性监测体系发展趋势分析及其启示

近年来,欧盟和美国对于监测上市后药品的安全性愈加重视,在加强各自的药品上市后安全性监测体系方面采取了不少新举措。本文分析了欧美药品上市后安全性监测体系的发展趋势,并探讨了对于我国的借鉴意义。     

Adverse drug reactions: a cohort study in internal medicine units at a university hospital

Objectives Adverse drug reactions (ADRs) are important causes of hospitalization, morbidity and mortality in hospitalized patients. In addition to the impact they have on human life, they also significantly influence health costs. This study intended to (1) identify suspected ADRs and establish their frequency of development, (2) establish a causal relationship with the suspected drug(s) and (3) verify if there is an association between the development of an ADR and factors such as age, gender, number of diagnoses and number of prescribed medications. Methods This cohort study considered hospitalized patients at five inpatient internal medicine units in a university hospital located in southern Brazil. Patients were intensively monitored in order to identify suspected ADRs during hospitalization. The types of reactions were classified and a causal relationship was established using an algorithm. Results The cohort study followed 333 patients and approximately 43% of them presented at least one suspected ADR. Three hundred and sixty suspected ADRs were identified, with 19.7% manifesting before the patient was admitted and 80.3% during hospitalization. Medications that were most commonly involved in these suspected cases were anti-infectious agents followed by drugs that act on the central nervous system (CNS). The follow-up length and number of medications in use were independent risk factors for the development of an ADR. The same relationship was not observed for age, gender and number of diagnoses. Conclusion ADRs are a major problem in our setting and measures must be adopted to minimize them. Financial support: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundo de Incentivo à Pesquisa do HCPA (FIPE), Brazil.