Medicinal Products In Children Research Articles

Reflections on the regulatory field covering the development of paediatric medicinal products: a brief overview of current status and challenges.

Many medicinal products are initially developed and tested in adults, and often, only a limited amount of data on their safety and efficacy in children exist. Consequently, paediatric healthcare providers sometimes need to make informed decisions about using medicinal products in children based on available fragmentary data. Ethical guidelines emphasise the importance of protecting children and ensuring they receive safe and effective medical treatments. Paediatric clinical trials should be conducted to provide evidence-based care with specific attention to minimise risks to children. This highlights the dilemma of finding a balance between protecting children and adolescents (and avoiding unnecessary clinical trials) and obtaining reliable, robust and justified data to treat them adequately and not in an off-label manner with unknown risks. For years, paediatricians maintained that children and adolescents are not treated based on up-to-date scientific knowledge and justification. The slogan "children are not small adults" summarised the concerns in a catch phrase. Different stakeholders have taken a variety of actions to address this concern.

Management of the interactions’ risks when using phytomedicines in children

phytomedicines play an essential role in the treatment of children's diseases. Means of
 plant origin have a better safety profile, and due to the content of biologically active substances, they af-fect various links of pathological processes. However, data on the safety and efficacy of phytomedicines
 in children are limited and mostly derived from studies in adults. In addition, there are risks of pharma-cokinetic and pharmacodynamic drug interactions. This study aims to study the risks of interaction when
 using phytomedicines and drugs in children. 100 parents participated in the study, most of whom had1 or 2 children. An analysis of the pharmacotherapy courses of 50 children was also done. It has beenestablished that parents when choosing medicines for children, consider their origin. Thus, more than70% of respondents consider phytomedicines to be safer for children and choose them for the treatmentof acute respiratory viral infections (73%), diseases of the throat (64%), oral cavity (59%), disorders ofthe gastrointestinal tract (28%) and others. The phytomedicines of choice were: Chlorophyllip, Sinupret,Wormil Phyto, Proteflazid, Darsil, Cholelesan, etc., which 80% of respondents used in combination withother medicinal products and without a doctor's prescription (75% of respondents). It was revealed that
 10% of respondents noted the appearance of undesirable reactions after using phytomedicines, in com-bination with other medicinal products in children, the manifestations of which were: allergic reactions,
 digestive disorders, headache/dizziness. Based on the results of the analysis of the pharmacotherapycourses, it was established that the children received an average of 5.8 ± 1.7 medicines. In particular,28% received 2 or more phytomedicines. In more than 40% of children, the risks of pharmacokineticinteraction of phytomedicines with other medicinal products were revealed. Thus, 10% received herbal
 remedies based on St. John's wort, which is a CYP3A4 inducer and reduces the effectiveness of albenda-zole, omeprazole, pantoprazole, and levocetirizine. While more than 30% of children received products
 based on turmeric, silymarin, or grapefruit extract, which are strong CYP3A4 inhibitors. Risks of phar-macokinetic interaction at the stage of absorption (6% of children) were associated with the use of flax
 and plantain seeds. In 10% of children, the risk of pharmacodynamic interaction due to the use of thickeucalyptus leaf extract and an antiseptic agent was revealed. Therefore, when using phytomedicines in
 children, it is necessary to consider the risks of drug interactions. Phytomedicines can affect the pharmacokinetics of other drugs and change the realization of the clinical effect. When choosing and usingphytomedicines the interaction of the doctor-pharmacist-parent is essential.

Off-Label Prescribing in Paediatric Cardiology: Regulatory Aspects and Safety Assessment by Spontaneous Reporting

In paediatrics, it is a common practice to use pharmaceuticals outside the approved Summary of Product Characteristics (i.e. off-label). According to the literature, up to 45% of inpatient paediatric prescriptions and 10–20% of outpatient ones are for off-label uses. It is essential to analyse such uses, as it helps medical practitioners act reasonably and professionally. The aim of the study was to explore the possibility of using spontaneous reports to assess the risks of the off-label use of cardiac medicinal products in children in the Irkutsk region. Materials and methods . The authors analysed 25 reporting forms on adverse drug reactions (ADRs) in paediatric cardiac patients from the database of the Regional Centre for Drug Safety Monitoring of the Irkutsk Region and regional data from the Automated Information System (AIS) of the Federal Service for Surveillance in Healthcare of the Russian Federation (Roszdravnadzor) submitted in 2009–2020. The inclusion criterion for reporting forms was a causal relationship between the off-label use of a medicinal product and the ADR that was scored as “possible” or higher on the Naranjo probability scale. Results . According to the reporting forms, the off-label use of cardiac medicinal products in children was associated with ADRs, such as angiooedema, cutaneous symptoms, and bronchospasm. The majority of ADRs (84%) were considered severe. The medicinal products were prescribed for heart failure, arterial hypertension, and cardiac arrhythmias. The majority of ADR reports (75%) were submitted by inpatient medical organisations. Conclusions . The analysis of spontaneous ADR reporting databases is a simple and informative method for studying the safety of medicinal products. It is necessary to raise awareness of ADRs associated with off-label prescribing amongst paediatric cardiologists in order to reduce the incidence of ADRs. The following contributions will improve the quality of medical care: all parties involved with pharmaceuticals should adhere to good pharmacovigilance practices, medical practitioners should be actively involved in treatment safety monitoring, and the professional training curricula of paediatric cardiologists and paediatricians should include specific units on the practical functioning of pharmacovigilance.

Surfactant-Free Chitosan/Cellulose Acetate Phthalate Nanoparticles: An Attempt to Solve the Needs of Captopril Administration in Paediatrics.

The Paediatric Committee of the European Medicines Agency encourages research into medicinal products for children, in particular, the development of an age-appropriate formulation of captopril is required in the cardiovascular therapeutic area. The aim of this study was the development of a liquid formulation using nanoparticles based only on chitosan and cellulose acetate phthalate containing captopril for the treatment of hypertension, heart failure and diabetic nephropathy in paediatric patients. Nanoparticles were prepared by a nanoprecipitation method/dropping technique without using surfactants, whose use can be associated with toxicity. A range of different cellulose to chitosan weight ratios were tested. A good encapsulation efficiency (61.0 ± 6.5%) was obtained when a high chitosan concentration was used (1:3 ratio); these nanoparticles (named NP-C) were spherical with a mean diameter of 427.1 ± 32.7 nm, 0.17 ± 0.09 PDI and +53.30 ± 0.95 mV zeta potential. NP-C dispersion remained stable for 28 days in terms of size and drug content and no captopril degradation was observed. NP-C dispersion released 70% of captopril after 2 h in pH 7.4 phosphate buffer and NP-C dispersion did not have a cytotoxicity effect on neonatal human fibroblasts except at the highest dose tested after 48 h. As a result, chitosan/cellulose nanoparticles could be considered a suitable platform for captopril delivery in paediatrics for preparing solid/liquid dosage forms.

INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

BackgroundThe INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials.MethodsIn this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow.DiscussionThe Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

Dosage Problems in Children: Well-Known Facts and Unresolved Issues

The problem of dosing drugs at an early age is conditioned by specific metabolism of medicinal products (MP) in the child's body. Currently, there are a few clinical trials on the study of physiological characteristics in different periods of childhood and systematised data. It is still relevant to understand the characteristic differences that affect the bioavailability, distribution and excretion of MP, especially in children over one month of life. The results of such studies are necessary in order to formulate the recommendations for use of MP in children taking into account their age and compensate for the lack of data from direct clinical trials in pediatrics. The possibility of using a dose calculation method regarding the fat content of the body in different periods of childhood and the chemical properties of the substance has been discussed.

Improving drug licensing for children and adolescents : Position paper from the More Medicines forMinors Symposion 8 June 2015 in Bonn

In Germany and throughout Europe, medicinal products for adults have been developed and evaluated systematically for decades. Medicinal products for children and adolescents, however, have only been researched for the past ten years. As aresult, many medicinal products have been administered to children without systematic clinical trials, for example regarding dosage or pharmaceutical form.EU Regulation 1901/2006 aimes to close the gaps in the medical treatment of children and adolescents. In order to do so, the regulation provides for paediatric use marketing authorisations (PUMA) for previously authorised products no longer covered by intellectual property rights and also grants holders of such PUMA licenses further property rights. However, only two PUMA licenses have been applied for. Thus, the PUMA license instrument is hardly being used despite the fact that many medicinal products have agreat potential for closing medical gaps for children and adolescents.In order to improve the situation regarding medicinal products for children and adolescents, this scientific symposium "More Medicines for Minors" intended to promote dialogue among the parties involved and to provide an opportunity to discuss reasons for the reluctance to apply for PUMA licenses. Speakers specialised in paediatric and adolescent medicine as well as those from licensing authorities, the Federal Joint Committee (Gemeinsamer Bundesausschuss, G‑BA), the pharmaceutical industry and the federal ministries presented problems and possible solutions from their point of view with the aim of making the PUMA license instrument more attractive.

Regulatory exclusivities for medicinal products for human use in the EU.

The placing on the market of medicinal products for human use in the EU is strictly regulated and harmonized by Regulation (EC) number 726/2004 and Directive 2001/83/ EC . The main objective of this legislation is the protection of public health and therefore the key principle is that no medicinal product may be placed on the market before the quality, safety and efficacy of the product has been assessed and approved by the competent authorities in a marketing authorization procedure. A marketing authorization is granted on the basis of an application dossier containing extensive data, including clinical research data, to document and demonstrate the quality, safety and efficacy of the medicinal product under evaluation. The development and placing on the market of medicinal products, including the compilation of the marketing authorization dossier, requires a significant amount of time, resources and money. The European legislature has recognized that it was necessary to offer proper protection in the form of data and market protection to enable adequate recovery of and return on investment for the costs of these research requirements. Furthermore, additional incentives in the form of special exclusivities or extension of data or market protection periods were introduced to stimulate new research in specific areas, for example, research of new therapeutic uses of known substances which bring a significant benefit to patients or the bringing to the market of medicinal products for patients suffering from rare (orphan) diseases in accordance with Orphan Regulation (EC) number 141/2000. Finally, the Pediatric Regulation (EC) number 1901/2006 introduced, on one hand, an obligation for pharmaceutical companies to research the use of their medicinal products in children and, on the other hand, a special reward for the fulfillment of this obligation. These different protection and exclusivity rights, which are without prejudice to existing intellectual property rights (e.g., patents), are often referred to as ‘regulatory exclusivities’. In this article, we will provide a brief overview of these regulatory exclusivities and their main features.

Clinical trials with herbal medicinal products in children: a literature analysis.

Herbal medicinal products have been used since several decades for the health care of children. Nevertheless, well-controlled clinical studies with herbal medicinal products for children are rare. The authors' objective therefore was to evaluate clinical trials with herbal medicinal products in children, based on a literature search in PubMed and Web of Science. A total of 133 trials were identified. 90 studies were randomized, 32.2% were randomized and double-blinded. Most studies were performed in China, in the age group 6-12 years, and in children with respiratory diseases, most often herbal medicinal products with Hedera helix were tested. The analysis revealed that studies on herbal medicinal products were feasible in children. Although clinical trials have been found, this literature search have limitations and did not cover all studies performed. However, only few clinical trials of high quality were identified. Further studies therefore are urgently needed to support the good empirical findings.

Drug Development

Drug Development

Salbutamol original contra salbutamol similar en niños con crisis de asma. Estudio aleatorizado, controlado y doble ciego

There is clinical evidence suggesting that original salbutamol is more effective than a similar salbutamol product to revert symptoms in acute asthma exacerbation.. To evaluate the bronchodilator response of both salbutamol medicinal products in children with asthma and to establish, based on the forced expiratory volume, if there is a difference between the group treated with the original salbutamol and the group treated with similar salbutamol. Prospective, randomized, controlled, double-blind study. One hundred and twenty six children (63 boys, age 9.18 ± 2.83 years old) were included. They were administered a dose of 20 drops (5 mg) of the original salbutamol or similar salbutamol product in nebulizing solution diluted only once in 2 ml saline solution. Pre- and post-bronchodilator, intra- and inter-group forced expiratory volume was compared at baseline and at 30 minutes. The weight of salbutamol drops was determined by gravimetry, the concentration by chromatography and the number of drops by bottle. The bronchodilator response between the pre- and post-bronchodilator forced expiratory volume was 225 ml (95% CI: 164-286) and 224 ml (95% CI: 163-284) for original salbutamol and similar salbutamol, respectively (p < 0.001). The Delta difference was 1.3 ml (95% CI: -86+83) (p = 0.97). The mean, standard deviation and variation coefficient percentage of the weight of the drop was 364.75 mg (± 6.01, 1.65) and 543.88 mg (± 56.09, 10.31) (p < 0.001) for original salbutamol and similar salbutamol, respectively. There were no differences in the bronchodilator response measured by FEV1 between the original salbutamol and a similar salbutamol product.

Ethanol in herbal medicinal products for children: Study data from 50.425 children support safety

Ethanol in herbal medicinal products for children: Study data from 50.425 children support safety

Better medicines for children: challenges and unmet needs

Better medicines for children: challenges and unmet needs This review deals with the use of medicinal products in children. Many medicinal products administered routinely to paediatric patients have been either not licensed for use in children (unlicensed use) or have been prescribed outside the terms of their product license (off-label prescribing). A lot of surveys have been conducted in the context of identifying the extent of off-label used drugs in children documenting high rates (45-60 %) of such use. Recognising and meeting challenges as development of suitable formulations for very young children and realization of clinical trials involving children present important steps in the enhancement of the present situation. To improve the health of children in Europe, the Regulation (EC) No 1901/2006 addressing the pharmaceutical industry, research teams and member states proposing important incentives and obligations was assigned. Paediatric Investigation Plan and Paediatric Use Marketing Authorisation present the key measures of the EU regulation on medicinal products for paediatric patients.

Role of modeling and simulation in pediatric investigation plans

Ethical and practical constraints encourage the optimal use of resources in pediatric drug development. Modeling and simulation has emerged as a promising methodology acknowledged by industry, academia, and regulators. We previously proposed a paradigm in pediatric drug development, whereby modeling and simulation is used as a decision tool, for study optimization and/or as a data analysis tool. Three and a half years since the Paediatric Regulation came into force in 2007, the European Medicines Agency has gained substantial experience in the use of modeling and simulation in pediatric drug development. In this review, we present examples on how the proposed paradigm applies in real case scenarios of planned pharmaceutical developments. We also report the results of a pediatric database search to further 'validate' the paradigm. There were 47 of 210 positive pediatric investigation plan (PIP) opinions that made reference to modeling and simulation (data included all positive opinions issued up to January 2010). This reflects a major shift in regulatory thinking. The ratio of PIPs with modeling and simulation rose to two in five based on the summary reports. Population pharmacokinetic (POP-PK) and pharmacodynamics (POP-PD) and physiologically based pharmacokinetic models are widely used by industry and endorsed or even imposed by regulators as a way to circumvent some difficulties in developing medicinal products in children. The knowledge of the effects of age and size on PK is improving, and models are widely employed to make optimal use of this knowledge but less is known about the effects of size and maturation on PD, disease progression, and safety. Extrapolation of efficacy from different age groups is often used in pediatric medicinal development as another means to alleviate the burden of clinical trials in children, and this can be aided by modeling and simulation to supplement clinical data. The regulatory assessment is finally judged on clinical grounds such as feasibility, ethical issues, prioritization of studies, and unmet medical need. The regulators are eager to expand the use of modeling and simulation to elucidate safety issues, to evaluate the effects of disease (e.g., renal or hepatic dysfunction), and to qualify mechanistic models that could help shift the current medicinal development paradigm.

Pflanzliche Arzneimittel für Kinder – Anspruch und Wirklichkeit

HERBAL MEDICINAL PRODUCTS FOR CHILDREN: ENTITLEMENT AND REALITYThe harmonization of herbal remedies in the European Union has led to the disappearance of therapeutic varieties, particularly for children. Based on the evaluation of the HMPC, the EMEA does not allow phytopharmaceutical agents for children aged 0-4 years. The evaluation was, however, carried out without sufficiently considering the opinion of medical doctors. This article highlights the current state of affairs with examples of selected herbal remedies for the topical and systemic application.

Proposals for model‐based paediatric medicinal development within the current European Union regulatory framework

The new paediatric European Union (EU) regulation and the consequent demand for paediatric studies on one hand and the ethical need for minimizing the burden of studies in children on the other hand necessitate optimal techniques in the assessment of safety/efficacy and use of drugs in children. Modelling and simulation (M&S) is one way to circumvent some difficulties in developing medicinal products in children. M&S allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/pharmacodynamics (PK/PD), extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. Together, industry, academia and regulators recognize the usefulness of modelling and simulation in this setting. However, even if M&S is an emerging science, its integration in the EU regulatory decision making is for the time being deficient and M&S expertise is concentrated in big pharmaceutical companies and academic institutions. The European Medicines Agency, acknowledging all the above conditions, organized and hosted a Workshop on Modelling in Paediatric Medicines. The article presents the personal views of the authors on the issues presented and discussed in the workshop.We attempt to identify the regulatory framework for the use of M&S in paediatric medicinal development and to make proposals for model-based paediatric medicinal development. The objective is to open the discussion between industry, academia, paediatricians and regulators on the optimal use of M&S in paediatric medicinal development.

Überblick über die Entwicklung der europäischen Rechtsetzung zur Angleichung der Arzneimittelvorschriften

The harmonisation of the legislation for medicinal products is an on-going process even after 40 years of development. The first step for harmonising the requirements for the marketing authorisation and monitoring took place with the introduction of the first pharmaceutical directive in 1965. Further components of European legislation such as directives, which have to be transposed into national law by the Member States, and regulations, which take effect immediately, have been adopted since then. The latest fundamental progress made in the process of harmonising the European market for medicinal products was the adoption of Directive 2004/27/EG in the framework of the Pharma-Review 2002. In addition to the existing centralised procedure and mutual recognition procedure a decentralised procedure and the enlargement of the area of authority of the European Medicines Agency were introduced. Lately new laws for medicinal products for children and advanced therapies were introduced through a regulation.

Development of technology and standardization of quality of sorbitol syrup as a dispersion medium of medicinal products for children

Standardization of the quality of the parent substance of sorbitol and sorbitol syrup is described. Sorbitol syrup is intended for use in the production of medicines for children of younger age. Physicochemical characteristics of the food grade powder and chemically pure grade sorbitol have been studied. The technology of sorbitol syrup production is developed and the physicochemical and technological parameters of the product are determined. The repeatability of the refractometric and spectrophotometric techniques for the quantitative analysis of sorbitol in syrup has been checked. The microbiological cleanliness of the parent substance and sorbitol syrup has been estimated. Methods for the microbiological decontamination of the parent substance and sterilization of syrup are proposed.

Medication administered to children from 0 to 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC)

ObjectiveTo present data on the parentally-reported use of all types of medicinal products in children from 0 to 7.5 years, in a large cohort in south-west England.MethodsParticipants in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) have been sent self-completion postal questionnaires since they were enrolled during pregnancy. The use of medicinal products has been obtained from questionnaires sent out when the study children were 4 weeks, 54, 78 and 91 months old.ResultsThe data included prescription, over-the-counter and complementary and alternative medicines. Around three-quarters of study children were exposed to some form of medicinal product before 8 weeks of age. Dermatological preparations were the most commonly used products in young babies. Activated dimeticone, for treatment of colic and flatulence, was given to 16% of babies and gripe water was used by 13%. Other commonly reported products included oral and topical antifungals and ophthalmic antibiotics. Several OTC products, not licensed for use in this age group, were reported. At each of the older ages surveyed, over 95% of children had used some form of medicinal product within the previous 12–18 months. Use of several product categories was higher at 54 months than at 78 or 91 months, such as topical steroids, analgesics (mostly paracetamol) and systemic antibiotics (mainly amoxicillin). Conversely, use of other categories, such as asthma medication, throat preparations (sprays and lozenges) and anti-inflammatory products, increased with increasing age.ConclusionParentally-reported use of medicinal products in the ALSPAC study children appears to be consistent with data from other sources. The use of medicinal products by young children is high and does not always conform to the product labelling.

Academic Year 2005–2006 – Fourth course ‘‘Evaluation of medicinal products in children’’PROGRAMME

Fundamental & Clinical PharmacologyVolume 19, Issue 6 p. 723-725 Academic Year 2005–2006 – Fourth course ‘‘Evaluation of medicinal products in children’’PROGRAMME First published: 18 November 2005 https://doi.org/10.1111/j.1472-8206.2005.00381.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume19, Issue6December 2005Pages 723-725 RelatedInformation