Lise Aagaard

Consumer reporting of adverse drug reactions: a retrospective analysis of the Danish adverse drug reaction database from 2004 to 2006.

AbstractBackground: Reporting adverse drug reactions (ADRs) has traditionally been the sole province of healthcare professionals. Since 2003 in Denmark, consumers have been able to report ADRs directly to the authorities. The objective of this study was to compare ADRs reported by consumers with ADRs reported from other sources, in terms of their type, seriousness and the suspected medicines involved.n Methods: The number of ADRs reported to the Danish ADR database from 2004 to 2006 was analysed in terms of category of reporter, seriousness, category of ADRs by system organ class (SOC) and the suspected medicines on level 1 of the anatomical therapeutic chemical (ATC) classification system. ADR reports from consumers were compared with reports from other sources (physicians, pharmacists, lawyers, pharmaceutical companies and other healthcare professionals). Chi-square and odds ratios (ORs) were calculated to investigate the dependence between type of reporter and reported ADRs (classified by ATC or SOC).n Findings: We analysed 6319 ADR reports corresponding to 15 531 ADRs. Consumers reported 11% of the ADRs. Consumers’ share of’serious’ ADRs was comparable to that of physicians (approximately 45%) but lower than that of pharmacists and other healthcare professionals. When consumer reports were compared with reports from other sources, consumers were more likely to report ADRs from the following SOCs: ‘nervous system disorders’ (OR =1.27; 95% CI 1.05, 1.53); ‘psychiatric disorders’ (OR =1.70; 95% CI 1.31, 2.20) and ‘reproductive system and breast disorders’ (OR = 2.02; 95% CI 1.13, 3.61) than other sources. Compared with other sources, consumers reported fewer ADRs from the SOCs ‘blood and lymphatic system disorders’ (OR = 0.22; 95% CI 0.08, 0.59) and ‘hepatobiliary system disorders’ (OR = 0.14; 95% CI 0.04, 0.57). Consumers were more likely to report ADRs from the ATC group N (nervous system) [OR = 2.72; 95% CI 2.34, 3.17], ATC group P (antiparasitic products) [OR = 2.41; 95% CI 1.32, 4.52] and ATC group S (sensory organs) [OR = 4.79; 95% CI 2.04, 11.23] than other sources. Consumers reported fewer ADRs from the ATC group B (blood and blood-forming organs) [OR = 0.04; 95% CI 0.006, 0.32] and the ATC groups J (anti-infective for systemic use) [OR=0.44; 95% CI 0.33, 0.58], L (antioneoplastic and immunomodulating agents) [OR= 0.19; 95% CI 0.12,0.30] and V (various) [OR = 0.03; 95% CI 0.004, 0.21] than other sources. In the SOC ‘nervous system disorders’, consumers reported seven categories of ADRs that were not reported by the other sources.n Conclusion: This study showed that compared with other sources, consumers reported different categories of ADRs for different types of medicines. Consumers should be actively included in systematic drug surveillance systems, including clinical settings, and their reports should be taken as seriously as reports from other sources.

Adverse Drug Reactions in the Paediatric Population in Denmark

AbstractBackground: The potential risk of adverse drug reactions (ADRs) in the paediatric population has become a public health concern and regulatory agencies in Europe and the US have acknowledged that there is a need for more research in this area. Spontaneous reporting systems can provide important new information about ADRs.n Objective: To characterize ADRs in children reported in Denmark over a period of one decade.n Methods: We analysed ADRs reported to the Danish Medicines Agency from 1998 to 2007 for individuals aged from birth to 17 years. Data were analysed with respect to time, age and sex, category of ADR (System Organ Class [SOC]), seriousness, suspected medicines (level 2 of the Anatomical Therapeutic Chemical [ATC] Classification System) and type of reporter.n Results: 2437 ADR reports corresponding to 4500 ADRs were analysed. On average, 234 ADR reports were submitted annually, corresponding to approximately two ADRs per report. From 2003 to 2005, an increasing number of ADRs submitted per report were observed, but after 2005 the reporting rate decreased. One-half of ADRs were reported for infants from birth to 2 years of age. Similar total numbers of ADRs were reported for boys and girls. The majority of ADRs reported were from the following SOCs: general disorders and administration site conditions (31%), skin and subcutaneous tissue disorders (18%) and nervous system disorders (15%). Reports encompassed medicines from ATC group J: vaccines and anti-infectives for systemic use (65%); and ATC group N: nervous system (17%). On average, 42% of ADRs were classified as serious. ATC group N had the highest proportion of ADRs that were classified as serious. Although physicians reported approximately 90% of the ADRs, a relatively large proportion of serious ADRs were reported by other sources.n Conclusion: In Denmark, the ADR reporting rate in the paediatric population has declined since 2005. The majority of ADRs reported in young children were reported for vaccines and anti-infectives, but also a high number of serious ADRs were reported for medicines from ATC group N. The Danish Medicines Agency should monitor prescribing patterns more tightly to identify potential risks in the paediatric population in relation to the evolving pattern of medicine use among children.

Using text-mining techniques in electronic patient records to identify ADRs from medicine use

This literature review included studies that use text-mining techniques in narrative documents stored in electronic patient records (EPRs) to investigate ADRs. We searched PubMed, Embase, Web of Science and International Pharmaceutical Abstracts without restrictions from origin until July 2011. We included empirically based studies on text mining of electronic patient records (EPRs) that focused on detecting ADRs, excluding those that investigated adverse events not related to medicine use. We extracted information on study populations, EPR data sources, frequencies and types of the identified ADRs, medicines associated with ADRs, text-mining algorithms used and their performance. Seven studies, all from the United States, were eligible for inclusion in the review. Studies were published from 2001, the majority between 2009 and 2010. Text-mining techniques varied over time from simple free text searching of outpatient visit notes and inpatient discharge summaries to more advanced techniques involving natural language processing (NLP) of inpatient discharge summaries. Performance appeared to increase with the use of NLP, although many ADRs were still missed. Due to differences in study design and populations, various types of ADRs were identified and thus we could not make comparisons across studies. The review underscores the feasibility and potential of text mining to investigate narrative documents in EPRs for ADRs. However, more empirical studies are needed to evaluate whether text mining of EPRs can be used systematically to collect new information about ADRs.

Information about adverse drug reactions reported in children: a qualitative review of empirical studies.

AIMnTo review the literature on adverse drug reactions (ADRs) in children with respect to occurrence, seriousness, type, therapeutic group, age and gender of the child and category of reporter.nnnMETHODSnMedline and Embase databases were searched from origin and updated until February 2010. We included empirically based articles on ADRs in populations aged 0 to 17 years. Studies monitoring ADRs in patients with particular conditions or drug exposure were excluded. We extracted information about types and seriousness of ADRs, therapeutic groups, age and gender of the child and category of reporter. ADR occurrence was calculated as incidence rate and prevalence.nnnRESULTSnWe included 33 studies monitoring ADRs in general paediatric populations. The highest numbers of ADRs were reported in national ADR databases where data were collected over a longer period than in studies monitoring inpatients and outpatients. However, prevalence and incidence were much lower in the national databases. Types of reported ADRs, seriousness of ADRs and types of medicines differed substantially between studies due to differences in time periods and patient populations. Information about ADRs was mainly provided by health care professionals, although parents also contributed reports.nnnCONCLUSIONSnWe found a higher incidence rate of ADRs in hospitalized children and outpatients than in national databases. There seems to be considerable potential for increasing the knowledge of ADRs by advocating the submission of reports to the spontaneous reporting systems. Our study underscores that ADRs in children constitute a significant public health problem.

Information about ADRs explored by pharmacovigilance approaches: a qualitative review of studies on antibiotics, SSRIs and NSAIDs

BackgroundDespite surveillance efforts, unexpected and serious adverse drug reactions (ADRs) repeatedly occur after marketing. The aim of this article is to analyse ADRs reported by available ADR signal detection approaches and to explore which information about new and unexpected ADRs these approaches have detected.MethodsWe selected three therapeutic cases for the review: antibiotics for systemic use, non-steroidal anti-inflammatory medicines (NSAID) and selective serotonin re-uptake inhibitors (SSRI). These groups are widely used and represent different therapeutic classes of medicines. The ADR studies were identified through literature search in Medline and Embase. The search was conducted in July 2007. For each therapeutic case, we analysed the time of publication, the strengths of the evidence of safety in the different approaches, reported ADRs and whether the studies have produced new information about ADRs compared to the information available at the time of marketing.Results79 studies were eligible for inclusion in the analysis: 23 antibiotics studies, 35 NSAID studies, 20 SSRI studies. Studies were mainly published from the end of the 1990s and onwards. Although the drugs were launched in different decades, both analytical and observational approaches to ADR studies were similar for all three therapeutic cases: antibiotics, NSAIDs and SSRIs. The studies primarily dealt with analyses of ADRs of the type A and B and to a lesser extent C and D, cf. Rawlins classification system. The therapeutic cases provided similar results with regard to detecting information about new ADRs despite different time periods and organs attacked. Approaches ranging higher in the evidence hierarchy provided information about risks of already known or expected ADRs, while information about new and previously unknown ADRs was only detected by case reports, the lowest ranking approach in the evidence hierarchy.ConclusionAlthough the medicines were launched in different decades, approaches to the ADR studies were similar for all three therapeutic cases: antibiotics, NSAIDs and SSRIs. Both descriptive and analytical designs were applied. Despite the fact that analytical studies rank higher in the evidence hierarchy, only the lower ranking descriptive case reports/spontaneous reports provided information about new and previously undetected ADRs. This review underscores the importance of systems for spontaneous reporting of ADRs. Therefore, spontaneous reporting should be encouraged further and the information in ADR databases should continuously be subjected to systematic analysis.

The occurrence of adverse drug reactions reported for attention deficit hyperactivity disorder (ADHD) medications in the pediatric population: a qualitative review of empirical studies

Background To review empirical studies of adverse drug reactions (ADRs) reported to be associated with the use of medications generally licensed for treatment of attention deficit hyperactivity disorder (ADHD) symptoms in the pediatric population. Methods PubMed, Embase, and PsycINFO® databases were searched from origin until June 2011. Studies reporting ADRs from amphetamine derivates, atomoxetine, methylphenidate, and modafinil in children from birth to age 17 were included. Information about ADR reporting rates, age and gender of the child, type, and seriousness of ADRs, setting, study design, ADR assessors, authors, and funding sources were extracted. Results The review identified 43 studies reporting ADRs associated with medicines for treatment of ADHD in clinical studies covering approximately 7000 children, the majority of 6- to 12-year-old boys, and particularly in the United States of America (USA). The most frequently reported ADRs were decrease in appetite, gastrointestinal pain, and headache. There were wide variations in reported ADR occurrence between studies of similar design, setting, included population, and type of medication. Reported ADRs were primarily assessed by the children/their parents, and very few ADRs were rated as being serious. A large number of children dropped out of studies due to serious ADRs, and therefore, the actual number of serious ADRs from use of psychostimulants is probably higher. A large number of studies were conducted by the same groups of authors and sponsored by the pharmaceutical companies manufacturing the respective medications. Conclusion Reported ADRs from use of psychostimulants in children were found in clinical trials of short duration. Since ADHD medications are prescribed for long-term treatment, there is a need for long-term safety studies. The pharmaceutical companies should make all information about ADRs reported for these medications accessible to the public, and further studies are needed on the impact of the link between researchers and the manufacturers of the respective products.

Prescribing of medicines in the Danish paediatric population outwith the licensed age group: characteristics of adverse drug reactions

AIMnTo identify adverse drug reactions (ADRs) associated with off-label prescribing of medicines in a paediatric population.nnnMETHODSnWe analysed spontaneous ADR reports for children from ages 0 to 17 years submitted to the Danish national ADR database from 1998 to 2007. We defined off-label prescribing as prescriptions outside the licensed age group. Off-label ADRs were categorized by therapeutic group, age of child, type and severity. The unit of analysis was one ADR.nnnRESULTSnWe analysed 4388 ADRs for children reported in the national database. Approximately 17% of reported ADRs were associated with off-label use, 60% of them serious. More than one half of off-label ADRs were reported in adolescents. Serious ADRs due to off-label prescribing are more likely to be reported for hormonal contraceptives (ATC group G), anti-acne preparations (ATC group D) and allergens (ATC group V).nnnCONCLUSIONnOne-fifth of all ADRs reported over a decade in Danish children was associated with off-label prescribing, and serious ADRs due to off-label prescribing were primarily present in three therapeutic groups: sex hormones, dermatologicals and allergens. There is a need for more research into the prescribing of these medicines in the teenage population, as well as tighter reporting and monitoring of ADRs for medicines prescribed off-label in the paediatric population.

Structures and processes in spontaneous ADR reporting systems: a comparative study of Australia and Denmark

Objective To explore the organisational structure and processes of the Danish and Australian spontaneous ADR reporting systems with a view to how information is generated about new ADRs. Setting The Danish and Australian spontaneous ADR reporting systems. Method Qualitative analyses of documentary material, descriptive interviews with key informants, and observations were made. We analysed the organisational structure of the Danish and Australian ADR reporting systems with respect to structures and processes, including information flow and exchange of ADR data. The analysis was made based on Scott’s adapted version of Leavitt’s diamond model, with the components: goals/tasks, social structure, technology and participants, within a surrounding environment. Results The main differences between the systems were: (1) Participants: Outsourcing of ADR assessments to the pharmaceutical companies complicates maintenance of scientific skills within the Danish Medicines Agency (DKMA), as it leaves the handling of spontaneous ADR reports purely administrative within the DKMA, and the knowledge creation process remains with the pharmaceutical companies, while in Australia senior scientific staff work with evaluation of the ADR report; (2) Goals/tasks: In Denmark, resources are targeted at evaluating Periodic Safety Update Reports (PSUR) submitted by the companies, while the resources in Australia are focused on single case assessment resulting in faster and more proactive medicine surveillance; (3) Social structure: Discussions between scientific staff about ADRs take place in Australia, while the Danish system primarily focuses on entering and forwarding ADR data to the relevant pharmaceutical companies; (4) Technology: The Danish system exchanges ADR data electronically with pharmaceutical companies and the other EU countries, while Australia does not have a system for electronic exchange of ADR data; and (5) Environment: The Danish ADR system is embedded in the routines of cooperation within European pharmacovigilance network while the Australian system is acting alone, although they communicate with other systems. Conclusion The two systems differ with regard to reporting requirements, report handling, resources being spent and information exchange with the environment. In Denmark, learning about ADRs primarily takes place in the safety divisions of the pharmaceutical companies and the authorities have no control over the knowledge creation process. In Australia, more learning and control of the knowledge is present than in Denmark.

Adverse events following immunization in children: retrospective analysis of spontaneous reports over a decade

PurposeThere is no doubt that paediatric immunization prevents serious diseases, but the administration of these vaccines to healthy children also involves risks of adverse drug reactions (ADRs), some of which are potentially serious. The current body of evidence on ADRs from immunization therapy at the population level is partly contradictory across countries, time periods and childhood immunization programmes. The objective of our study was to characterize reported adverse events (AEFIs) following immunization in Danish children.MethodsAdverse events (AEFIs) in 0- to 17-year-old children and adolescents reported to the Danish Medicines Agency (DKMA) between 1998 and 2007 were analysed. The unit of analysis was one AEFI. Data were categorized with respect to time, age, and gender of the children, suspected vaccines, category and seriousness of the AEFIs, and reporting rate.ResultsDuring the study period, the DKMA received 1,365 reports covering 2,600 AEFIs, corresponding to 60% of all adverse events reported for children. One third of the AEFIs were classified as serious, and two deaths were reported. The annual number of serious AEFIs remained constant during the study period. Approximately 80% of AEFIs were reported in children aged 0–2xa0years. Of all reported AEs, 45% were in the category “general disorders and administration site conditions”, followed by the categories “skin and subcutaneous tissue disorders” (20% of total AEFIs) and “nervous system disorders” (16% of total AEFIs). The largest share of serious events was from the category “nervous system disorders” (33% of serious AEFIs). The most frequently reported serious AEs were febrile convulsions, pyrexia, and injection-site reactions.ConclusionsIn Denmark, a large number of AEFIs following paediatric immunization have been reported, but the majority of cases were non-serious.

Consumers' reports of suspected adverse drug reactions volunteered to a consumer magazine

In some countries, reporting of adverse drug reactions (ADRs) by patients has been incorporated into spontaneous reporting systems, primarily to increase the number of reports and detect new ADR signals earlier [1]. To date only seven countries have allowed patients to report ADRs: Sweden (since 1978 via KILEN), USA (since 1993), Australia, Canada, Denmark and the Netherlands (since 2003) and the UK (since 2005) [1]. An analysis of ADR reports to the Danish Medicines Agency (DKMA) showed that patients are more likely to report ADRs from the nervous and psychiatric system than are health professionals, that patients share of reports on serious ADRs was comparable to that of physicians, and that patients provided new and unknown information about ADRs [2]. The use of the internet as a source of information and discussion forum for health matters is rapidly increasing. Therefore we decided to investigate the information about possible ADRs provided by consumers who had easy reporting access via the internet. A consumer magazine provided the opportunity for their readers and others to report ADRs via an open access website. This letter examines whether these reports contributed with information about ADRs not previously described in the product information. n nData were collected from a questionnaire on the website of a consumer magazine during a 2-month period in autumn 2008 (September–October). If patients had experienced ADRs from the use of medicines, they were requested to answer the following questions: n n nTo which medicine did you have an ADR? n n nWhat were you being treated for? n n nWhat sort of ADRs did you experience? n n nDid you tell anyone about the ADRs you experienced either at the time or later? n n nDid you report your ADRs either via http://www.borger.dk or to the Danish Medicines Agency? n n n nWe analysed the reports with respect to therapeutic groups [Anatomical Therapeutic Chemical (ATC) system][3] and types of reported ADRs (system organ classes) [4]. The reported ADRs were checked against the official summary of product information (SPC). ADRs not mentioned in the SPC were classified as unlabelled. n nTable 1 displays the number of reported ADRs distributed on therapeutic groups and the number of unlabelled ADRs (ATC level 1). Only 11 of the reports (3%) had been reported to the DKMA. In 42% of reports, patients had shared the information about ADRs with a healthcare professional, a family member or a relative. Forty percent of all ADRs were reported for medicines belonging to ATC group N (nervous system). In total, 15% of reported ADRs (n= 188) were not mentioned in the official product information. Of these ADRs, the highest share, 34%, was reported for medicines belonging to ATC group N (nervous system disorders). The majority of reported ADRs were of the types ‘nervous system disorders’ and ‘gastrointestinal disorders’. n n n nTable 1 n nReports and ADRs of suspected medicines (ATC level 1) by therapeutic group n n n nOpen access to other patients reports as well as the simple structure of the questionnaire may have motivated many patients to report ADRs. Such a data collection method could be used as a rapid data collection instrument in the event of suspected serious or rare ADRs not previously documented. The large number of ADRs reported for psychotropic medicines (ATC group N) could reflect that people with central nervous system problems are more likely to report these symptoms than other people. Although the types of reported ADRs and suspected medicines are in line with results from other countries [1, 2, 5], patients also reported information about previously unlabelled ADRs. n nThis study has confirmed that patients report rather unspecific symptoms, e.g. indisposition, dizziness and insomnia, as they use lay terminology to describe symptoms differently from terminology used by healthcare professionals. Patients also reported several ADRs such as drowsiness, weight gain and sexual problems, which prescribers may not consider serious but are troublesome to patients and limit the full enjoyment of daily life [1] and which patients find worthy of reporting in a questionnaire. n nThe content and quality of the reported data are inappropriate for causality analysis as the reports contained no information about age, sex, diagnosis and concomitant medicines. Hence, the collected ADR data may actually consist of ADRs that patients believe to be possibly drug-related reactions rather than confirmed ADRs, and the value of these data in drug surveillance is limited. Consumer ADR reports might act as whistleblowers of new and previously undetected ADRs, but if the quality of the reports is questionable they bring too much noise rather than valuable information to the pharmacovigilance systems. n nFurther studies to explore the quality, validity and impact of consumer reports in the pharmacovigilance systems are needed and appropriate systems for patient reports of ADRs should be explored. The unlabelled ADRs should lead to further investigations and possible detection of new ADRs.