Chiara Pandolfini

Survey of unlicensed and off label drug use in paediatric wards in European countries

Abstract Objective: To determine the extent of use of unlicensed and off label drugs in children in hospital in five European countries. Design: Prospective study of drugs administered to children in general paediatric medical wards over four weeks. Setting: Childrens wards in five hospitals (one each in the United Kingdom, Sweden, Germany, Italy, and the Netherlands). Subjects: Children aged 4 days to 16 years admitted to general paediatric medical wards. Main outcome measure: Proportion of drugs that were used in an unlicensed or off label manner. Results: 2262 drug prescriptions were administered to 624 children in the five hospitals. Almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label. Of these 1036, 872 were off label and 164 were unlicensed. Over half of the patients (421; 67%) received an unlicensed or off label drug prescription. Conclusions: Use of off label or unlicensed drugs to treat children is widespread. This problem is likely to affect children throughout Europe and requires European action. Key messages Many drugs are not tested in children, which means that they are not specifically licensed for use in children Licensed drugs are often prescribed outside the terms of the product license (off label) in relation to age, indication, dose of frequency, route of administration, or formulation Over two thirds (67%) of 624 children admitted to wards in five European hospitals received drugs prescribed in an unlicensed or off label manner 39% of the 2262 drug prescriptions given to children were off label The problem of off label and unlicensed drug prescribing in children is a European problem that requires European action

Reliability of health information for the public on the World Wide Web: systematic survey of advice on managing fever in children at home.

Abstract Objective: To assess the reliability of healthcare information on the world wide web and therefore how it may help lay people cope with common health problems. Methods: Systematic search by means of two search engines, Yahoo and Excite, of parent oriented web pages relating to home management of feverish children. Reliability of information on the web sites was checked by comparison with published guidelines. Main outcome measures: Minimum temperature of child that should be considered as fever, optimal sites for measuring temperature, pharmacological and physical treatment of fever, conditions that may warrant a doctors visit. Results: 41 web pages were retrieved and considered. 28 web pages gave a temperature above which a child is feverish; 26 pages indicated the optimal site for taking temperature, most recommending rectal measurement; 31 of the 34 pages that mentioned drug treatment recommended paracetamol as an antipyretic; 38 pages recommended non-drug measures, most commonly tepid sponging, dressing lightly, and increasing fluid intake; and 36 pages gave some indication of when a doctor should be called. Only four web pages adhered closely to the main recommendations in the guidelines. The largest deviations were in sponging procedures and how to take a childs temperature, whereas there was a general agreement in the use of paracetamol. Conclusions: Only a few web sites provided complete and accurate information for this common and widely discussed condition. This suggests an urgent need to check public oriented healthcare information on the internet for accuracy, completeness, and consistency. Key messages Fever in children is a common problem, and accurate information on home management of feverish children could be useful for parents A systematic search on the world wide web for such parent oriented information retrieved 41 web pages, but only four adhered closely to published guidelines for home management of childhood fever These findings suggest the urgent need to check public oriented healthcare information on the internet for accuracy, completeness, and consistency Information on the internet should not be a substitute for routine care by family doctors

A literature review on off-label drug use in children.

The aim was to compare results of studies performed in different settings worldwide and identify common therapeutic areas to allow for focused interventions, because off-label drug use can be a measure of the lack of knowledge concerning paediatric treatments. A secondary objective was to provide a brief review of efforts to date. A literature review of articles on off-label and unlicensed drug use in children involving general prescription samples was performed using Medline and Embase. In all, 30 studies from 1985–2004 were included. Eleven involved paediatric hospital wards, seven neonatal hospital wards, and 12 the community setting. The off-label and unlicensed classification methods varied, making results difficult to compare. In general, off-label/unlicensed prescription rates ranged from 11%–80%, and higher rates were found in younger versus older patients and in the hospital versus community settings. On the paediatric hospital wards, off-label/unlicensed prescriptions ranged from 16%–62% and most often concerned acetaminophen, cisapride, chloral hydrate, and salbutamol. In the neonatal wards, rates ranged from 55%–80% and often involved caffeine. In the community setting, rates ranged from 11%–37% and the most commonly implicated drugs were salbutamol and amoxicillin. Conclusion:A lack of harmonisation between the evidence, the information available to doctors, and its use in clinical practice exists and this is part of the reason off-label therapies are so common. Attempts have been made to improve knowledge concerning paediatric treatments, but more focused interventions are needed, also taking into consideration this lack of harmonisation.

Parents on the Web: Risks for Quality Management of Cough in Children

Background. Health information on the Internet, with respect to common, self-limited childhood illnesses, has been found to be unreliable. Therefore, parents navigating on the Internet risk finding advice that is incomplete or, more importantly, not evidence-based. The importance that a resource such as the Internet as a source of quality health information for consumers should, however, be taken into consideration. For this reason, studies need to be performed regarding the quality of material provided. Various strategies have been proposed that would allow parents to distinguish trustworthy web documents from unreliable ones. One of these strategies is the use of a checklist for the appraisal of web pages based on their technical aspects. Objective. The purpose of this study was to assess the quality of information present on the Internet regarding the home management of cough in children and to examine the applicability of a checklist strategy that would allow consumers to select more trustworthy web pages. Methods. The Internet was searched for web pages regarding the home treatment of cough in children with the use of different search engines. Medline and the Cochrane database were searched for available evidence concerning the management of cough in children. Three checklists were created to assess different aspects of the web documents. The first checklist was designed to allow for a technical appraisal of the web pages and was based on components such as the name of the author and references used. The second was constructed to examine the completeness of the health information contained in the documents, such as causes and mechanism of cough, and pharmacological and nonpharmacological treatment. The third checklist assessed the quality of the information by measuring it against a gold standard document. This document was created by combining the policy statement issued by the American Academy of Pediatrics regarding the pharmacological treatment of cough in children with the guide of the World Health Organization on drugs for children. For each checklist, the web page contents were analyzed and quantitative measurements were assigned. Results. Of the 19 web pages identified, 9 explained the purpose and/or mechanism of cough and 14 the causes. The most frequently mentioned pharmacological treatments were single-ingredient suppressant preparations, followed by single-ingredient expectorants. Dextromethorphan was the most commonly referred to suppressant and guaifenesin the most common expectorant. No documents discouraged the use of suppressants, although 4 of the 10 web documents that addressed expectorants discouraged their use. Sixteen web pages addressed nonpharmacological treatment, 14 of which suggested exposure to a humid environment and/or extra fluid. In most cases, the criteria in the technical appraisal checklist were not present in the web documents; moreover, 2 web pages did not provide any of the items. Regarding content completeness, 3 web pages satisfied all the requirements considered in the checklist and 2 documents did not meet any of the criteria. Of the 3 web pages that scored highest in technical aspect, 2 also supplied complete information. No relationship was found, however, between the technical aspect and the content completeness. Concerning the quality of the health information supplied, 10 pages received a negative score because they contained more incorrect than correct information, and 1 web page received a high score. This document was 1 of the 2 that also scored high in technical aspect and content completeness. No relationship was found, however, among quality of information, technical aspect, and content completeness. Conclusions. As the results of this study show, a parent navigating the Internet for information on the home management of cough in children will no doubt find incorrect advice among the search results. The checklist method proposed by researchers in the field to allow lay people to select web documents of presumably higher quality is not proven to be reliable. No standards currently exist for publishing health information on the Internet; therefore, a web page cannot be expected to provide extra information that could be associated to the quality of content of the page. Because the lack of uniformity when dealing with web documents does not allow for any type of assessment based on structural components, any method for judging the trustworthiness of web documents, therefore, must base its selection directly on content. So far, the most reliable sources of information accessible to the public remain medical professionals and information packets peer-reviewed by them. The Internet holds enormous possibilities for the future of on-line health care; however, at present, it should be used as an additional, not as a primary, source of information. New strategies must be found of producing, validating, and diffusing appropriate on-line information in a manner that involves users (consumers) to guarantee a nonauthoritarian practice, access for all to health care information, and high quality information on the Internet.

Off‐label use of drugs in Italy: a prospective, observational and multicentre study

The aims of the study were to measure the paediatric, off‐label use of drugs in the Italian hospital setting and to reveal areas for priority intervention by investigating the therapeutic indications most involved. Prescriptions given to all children admitted to nine general paediatric hospital wards from December 1998 to February 1999 were analysed. In total, 4265 prescriptions were given to 1461 children, 10 of which were unlicensed and excluded from further analysis. Sixty percent of prescriptions (range between centres: 44‐71%) were off‐label and concerned 89% of children receiving medications (80–96%). The main drug classes were antibacterials, antiasthmatics and analgesics, and represented 56% of off‐label prescriptions. Paracetamol (385 prescriptions) and beclomethasone (339) were the generic substances most often used off‐label. The most common off‐label categories were dosage/frequency (50% of prescriptions), indication and lack of paediatric licence (7% each). Fifty‐four per cent of all indications that led to off‐label prescribing involved only respiratory problems, fever, respiratory tract infections and bronchospasm.

Follow up of quality of public oriented health information on the world wide web: systematic re-evaluation.

In 1997 one of the first studies to evaluate the quality of health information on the internet was published.1 This article assessed the reliability of information for managing fever in children at home and found that the quality of information was poor. Four years after publication these findings were mentioned in 78 journals (from Journal Citation Report ), and the message should therefore have reached a wide audience. We investigated the effects of the earlier findings by re-evaluating the quality of the original web pages four years later, as well as that of a more recent sample of pages, using the same methods. On 28 June 2001 we searched articles through the Institute for Scientific Informations citation index for references to the earlier study. …

Adverse Drug Reactions to Off-label Drugs on a Paediatric Ward: an Italian Prospective Pilot Study

Recently published studies examining the extent of off-label drug prescribing in various European paediatric wards have reported that off-label use is widespread and particularly high in Italy. So far, however, no studies have investigated the extent to which adverse drug reactions (ADRs) due to off-label drug use occur in Italy. To evaluate the risk associated with off-label drug use in paediatric inpatients, a prospective surveillance study was carried out in the paediatric ward of a teaching hospital over a 9 month period. Forty-one children (mean age: 7.2 years, 58% male ), out of a study population of 1619 patients, experienced ADRs. In 29 children the ADRs were due to in hospital drug therapies, while in 12 they were due to medicines administered in the community. Urticaria (11 cases), vomiting and rash (5 cases each ) and tremor (4 cases) were the most common ADRs. Eight ADRs (20%) were classified as severe. The drugs most frequently associated with ADRs were salbutamol (5 cases) and coamoxiclav (4 cases). Off-label drug prescriptions were responsible for 38% of inpatient ADRs and for 42% of the ADRs occurring in the community that led to hospitalisation. The use of drugs not licensed for paediatric use (8 cases) or for indications for which the drug was not licensed (6 cases) were the off-label categories most frequently associated with ADRs. Drugs used for diagnostic tests in endocrinology were responsible for one third of ADRs due to off-label uses. The results of this study suggest a high risk of ADRs associated with offlabel prescribing in children, both in the hospital and in the community. This pilot study also demonstrates the feasibility of an ADR monitoring system that could take into account important issues relating to rational drug prescribing in paediatric patients. In order to achieve a comprehensive risk assessment of off-label drug interventions in children, the study should be continued and expanded to involve the community setting as well.

Un registro europeo de ensayos clínicos en niños

Para registrar y comercializar un farmaco se requiere una documentacion que asegure que llega al mercado con ciertas garantias de eficacia y toxicidad. Sin embargo, la investigacion puede no haber sido tan completa como seria deseable debido, entre otras causas, a la falta de estudios en ninos. Raramente se han realizado ensayos clinicos en poblacion pediatrica cuando el farmaco esta destinado al tratamiento de enfermedades mas frecuentes en adultos. Incluso con farmacos para el tratamiento de enfermedades mas propias de la infancia pueden faltar estudios en algunos subgrupos de edad. De los farmacos que autorizo la Agencia Europea del Medicamento (EMEA) en los primeros 3 anos de funcionamiento, solo se aprobaron en ninos el 34% de los destinados a enfermedades que podian afectar tanto a adultos como a ninos1. En cambio, es previsible que el pediatra se plantee el uso de farmacos no aprobados en esta poblacion en algunas ocasiones. En los ultimos anos, varios trabajos han puesto de manifiesto que entre el 25 y el 66 % de los ninos hospitalizados y entre el 11 y el 33% de los atendidos en atencion primaria reciben farmacos en estas condiciones2,3. La utilizacion de medicamentos en indicaciones o condiciones de uso no autorizadas es tambien un problema relevante en nuestro medio4 y preocupa especialmente porque, a pesar de que pueda ser necesaria, se realiza en condiciones de incertidumbre. Realizar ensayos clinicos en ninos entrana mas dificultades eticas, practicas y economicas que en adultos. Por ejemplo, es dificil obtener el consentimiento “informado” de los pacientes de mas corta edad y es necesario involucrar a los padres en su lugar5-7. Ademas, el hecho de que existan variaciones farmacocineticas y farmacodinamicas relevantes en los distintos grupos de edad pediatrica hace necesaria la realizacion de ensayos en diferentes edades. Por otro lado, tampoco constituyen un mercado muy rentable para la industria farmaceutica, porque la utilizacion de farmacos en ninos es bastante limitada. En Europa, las primeras medidas para mejorar esta situacion se plantearon en 1997, cuando el Comite de Especialidades Farmaceuticas de la Union Europea (CPMP), que forma parte de la EMEA, publico unas guias para la investigacion clinica de medicamentos en ninos en las que se describia cuando y como se deben evaluar los farmacos en esta poblacion8. A pesar de ello, estudios realizados entre los anos 1999 y 2002 mostraron que el numero de farmacos aprobados por la EMEA con indicaciones pediatricas solo habia aumentado ligeramente9,10. En el ano 2000, la Comision Europea asumio un papel mas activo y, para reducir la falta de farmacos adecuados para la poblacion pediatrica, propuso nuevas acciones reguladoras que se recogen en el documento titulado Better Medicines for Children11. En este documento se exponen fundamentalmente seis objetivos:

Public disclosure of clinical trials in children

Abstract Background: Although randomized controlled trials (RCTs) are considered the most reliable way to assess a drugs safety and effectiveness, they are not always necessary or feasible for assessing the effects of health care on pediatric patients. Recent legislation passed in the United States has led to an increase in the number of RCTs in pediatric populations, but the drugs studied in these trials have not always proven useful to pediatric patients. Objective: This study was undertaken to identify the specific areas addressed by clinical research in the European pediatric therapeutic field. Methods: A literature search was conducted on EMBASE for therapeutic clinical trials in children, performed in the 15 European Union countries and published from 1995 to 2000, using the search terms child, infant, clinical trial, comparative studies, drug, and drug therapy . A general analysis of all the studies was performed, as well as a more in-depth analysis of the RCTs. Two researchers reviewed each study independently using a standard form. Data on methodology, diseases, and outcomes were extracted. All studies published in 5 general pediatric journals were assessed for reporting status of ethical committee approval and informed consent. Results: A total of 338 articles were identified as being therapeutic, pediatric, clinical trials. Of these, 139 were RCTs. These 139 studies were performed in 12 countries; most addressed the treatment of asthma, acute otitis media, acute upper and lower respiratory infections, and vaccine-preventable diseases. Of the 37 studies published in 5 chosen general pediatrics journals, 24 and 30 did not report ethical committee approval or informed consent, respectively. Conclusions: The diseases addressed by the RCTs identified in this review are among the leading causes of burden of disease in European children. However, ample knowledge of the physiopathologic and therapeutic variables of these diseases already exists. More research is needed on new drugs and disease states as they relate to pediatric patients. Moreover, information about these trials must be made readily available to parents and family physicians, both to increase enrollment and to uphold the highest ethical standards of providing optimal treatment to all patients.

Off-label drug use in children should be rational

The drug authorisation process was introduced in the 1960s to ensure that only quality drugs with proven safety and efficacy enter the market.1 The process was introduced as a response to adverse drug reactions that occurred, in particular, in adults, and also after the chloramphenicol and thalidomide tragedies that occurred in newborn infants. The procedures, initially defined by the Food and Drug Administration and later also by other national and European regulatory agencies, were improved over time. In general, when a pharmaceutical company submits an application to the licensing authority, safety and efficacy data originating mainly from formal clinical trials have to be provided. However, this is not always the case with children, who are routinely given drugs in an ‘off-label’ manner, as was documented for the first time in Europe in the 1980s.2 Although the precise definitions have changed from author to author and over time, in general, off-label drug use is the practice of prescribing drugs outside their authorised indications with respect to dosage, age, indication or route, and unlicensed drugs are those that are prepared as extemporaneous preparations, which are imported or used before an authorisation (license) is granted, or are chemicals …