Claude Universite

Bernard -Lyon

M Le Professeur

Frédéric Fleury

Hamda Ben

Hadid M Le Professeur Didier

Revel M Le Professeur

Philippe Chevalier

M Fabrice

Vallée M Alain Helleu

Composantes Sante

J Etienne

La Mme

C Professeure

Burillon

D Bourgeois

Vinciguerra

Y Matillon

Roubi, thank you for your unconditional support. Having you by my side made the last 4 years full of valuable and unforgettable moments. I have really enjoyed working, lunching, discussing research and life with you. I am

COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE

Abstract

The lack of adequate clinical trials in paediatrics has generated many issues in medicine use for hospitalised children, such as the prescription of off-label or unlicensed drugs, the lack of suitable dosage forms, inadequate safety information, and the lack of evidence-based dosing information. This challenges the prescription and administration of medicines in paediatric settings and impacts drug safety in this population. For these reasons, monitoring drug safety is particularly important in the paediatric population. Despite that, adverse drug reactions (ADRs) in hospitalised children are underestimated and underreported, suggesting the need for improving the existing detection methods.

The aim of this thesis is to promote the safe use of medicines in hospitalised children through three independent objectives. The first objective is to identify all available trigger tools, as a promising detection method of ADR in paediatric inpatients, and describe the performances of paediatric triggers in the purpose of optimising their use in paediatric settings. The second objective is to identify possible practical circumstances allowing dosage form choices to be optimized regarding safety, by replacing liquid formulations with suitable solid dosage forms in hospitalised children, and to assess the economic impact of these potential changes. The third objective is to review the available literature data on the efficacy and safety of amikacin using different dosage regimes in neonates and to attempt to identify the most appropriate dosage regimen for use.

Two systematic reviews and one analysis study of a hospital database were conducted. A total of 179 paediatric triggers detecting adverse drug events (ADEs) were identified in a systematic review study. Triggers' performances were assessed by their positive predictive values (PPVs) most of the time in the studies. These values varied significantly between studies, suggesting a need for more studies on paediatric triggers. The use of triggers could be optimised by selecting the most pertinent triggers and by creating an electronic real-time detection system. The triggers could be used for three clinical interests (to prevent, detect and report ADRs) when integrated in such a system. In a second study based on an analysis of 3-year data regarding oral drug administrations, 10 drugs, involving 19,671 administrations of liquid formulations, were selected to potentially replace liquid with suitable solid dosage forms in paediatric practice. We proved that there are opportunities to optimise current dosage form choices for hospitalised children by using available dosage forms. In a second systematic review, clinical and pharmacokinetic outcomes regarding efficacy and safety of 37 different dosage regimens of amikacin in neonates were reported. The work to select the most appropriate dosage regimen of amikacin in neonates based on the reported data is continuing.

The results of this thesis can be used by health-care professionals and health policy makers interested in promoting a safer and more appropriate use of medicines in hospitalised children.

Keywords: Paediatric, hospitalised children, pharmacovigilance, adverse drug reaction, trigger tool, detection, drug formulation, dosage form, drug safety, substitution to solid dosage form, amikacin, neonates, drug monitoring, optimal dosage regimen, pharmacokinetics.

Résumé en français

Titre : Sécurisation de l'usage des médicaments chez les enfants hospitalisés Résumé : Le nombre insuffisant d'essais cliniques en pédiatrie engendre plusieurs problèmes lors de l'utilisation des médicaments chez les enfants hospitalisés, tels que le recours aux prescriptions de médicaments hors Autorisation de Mise sur le Marché (AMM), le manque de formes galéniques adaptées à l'enfant, des informations insuffisantes en matière de sécurité des médicaments et le manque de posologies basées sur de hauts niveaux de preuves. Ceci remet en question la prescription et l'administration de médicaments en pédiatrie et influence la sécurité des médicaments dans cette population particulière. Dans ce contexte, la surveillance de la sécurité des médicaments est particulièrement importante chez les enfants. Malgré cela, les événments indésirables médicamenteux (EIM) chez les enfants hospitalisés sont sousestimés et sous-déclarés, suggérant un besoin d'améliorer les méthodes de détection actuelles.

L'objectif de cette thèse est de promouvoir la sécurisation de l'usage des médicaments chez les enfants hospitalisés à travers trois sous-objectifs indépendants. Le premier est d'identifier tous les « triggers » disponibles, en tant que méthode prometteuse de détection des EIMs chez les enfants hospitalisés, et de décrire les performances des « triggers » utilisables en pédiatrie dans le but d'optimiser leur utilisation en milieu hospitalier pédiatrique. Le deuxième est d'identifier les circonstances pratiques possibles permettant d'optimiser les choix de formes galéniques, en remplaçant les formulations liquides par des formes solides adaptées, chez les enfants hospitalisés et d'évaluer l'impact économique de ses changements potentiels. Le troisième est d'examiner les données disponibles dans la littérature sur l'efficacité et la sécurité des posologies d'amikacine chez les nouveau-nés et tenter d'identifier la posologie la plus appropriée à utiliser.

Deux revues systématiques de la littérature et une étude d'analyse d'une base de données hospitalière ont été menées. Un total de 179 « triggers » utilisables en pédiatrie pour détecter des EIM a été identifié par une revue systématique de la littérature. Les performances des « triggers » ont été estimées par leurs valeurs prédictives positives la plupart du temps dans les études. Ces valeurs variaient considérablement d'une étude à l'autre, suggérant la nécessité de mener plus d'études sur les « triggers » en pédiatrie. L'utilisation des « triggers » pourrait être optimisée en sélectionnant les « triggers » les plus pertinents et en créant un système électronique de détection en temps réel. L'utilisation des « triggers » dans un tel système pourraient servir à trois objectifs cliniques (la prévention, la détection et le signalement des EIM). Dans une deuxième étude basée sur une analyse des données d'administrations des médicaments oraux recueillies sur 3 ans, dix médicaments, impliquant 19 671 administrations de formulations liquides, ont été sélectionnés dans le but de pouvoir remplacer ces formes liquides par des formes solides appropriés dans la pratique hospitalière pédiatrique. Dans cette étude, nous avons prouvé qu'il existe des opportunités pour optimiser les choix actuels des formes galéniques chez les enfants hospitalisés, en utilisant des formes galéniques disponibles sur le marché. Dans une deuxième revue systématique de la littérature, les résultats cliniques et pharmacocinétiques concernant l'efficacité et la sécurité de 37 posologies d'amikacine pour les nouveau-nés ont été rapportés. Le travail consistant à sélectionner la posologie d'amikacine la plus appropriée chez les nouveau-nés en se basant sur les données rapportées se poursuit.

Les résultats de cette thèse peuvent être utilisés par les professionnels de santé et les décideurs politiques dans le domaine de la santé intéressés par la sécurisation de l'usage des médicaments chez les enfants hospitalisés.

Mots clés : Pédiatrie, enfants hospitalisés, pharmacovigilance, événments indésirables médicamenteux, détection, formulation du médicament, forme galénique, sécurité du médicament, substitution à la forme solide, amikacine, nouveau-nés, posologie optimale, pharmacocinétique.

List of publications

List of scientific communications

List of Tables

Tables of the general introduction

Table 1: Comparison between the four detection methods according to the results of the systematic review conducted by Meyer-Massetti et al.

Tables of the article I

Figures of the general introduction

Figures of the article III

. Physiological differences between paediatric and adult populations

There is a large spectrum of physiological differences between the paediatric and adult populations. There are also differences in the paediatric population between paediatric age groups from newborns to adolescents. (4-6).

Impact of the physiological differences on the pharmacokinetic properties

All pharmacokinetic properties of the drugs (i.e., absorption, distribution, metabolism, and excretion) could be impacted by the physiological particularities of children.

The absorption of orally administered drugs could differ in children because of the changing concentrations of gastric PH through the first 3 years of life (7), the slow gastric emptying within the first 6 months in preterm infants (8,9), the prolonged intestinal transit time in neonates or the reduced one in older infants (10). The bioavailability of intramuscularly administered drugs could also change in neonates by the decreased blood flow to muscles, which varies quite considerably over the first 2-3 weeks of life, the less muscular mass and the higher proportion of body water. In newborns, this route of administration is therefore unreliable, and the pharmacokinetics are unpredictable (11,12).

The proportions of body fat, plasma proteins, total and extracellular body water change significantly and continuously during the first year of life, which affect the distribution of drugs.

The percentage of the total body water reaches 80-90% of body weight in newborns. It decreases to 55-60% by adulthood (13). The extracellular water content is about 45% in neonates compared with 20% in adulthood. Consequently, the volume of distribution in the paediatric population is relatively higher for water-soluble drugs such as gentamicin (10) and lower for fat-soluble drugs such as diazepam (14).

Additionally, the concentration of binding proteins is lower in neonates and infants than adults, as well as their binding capacities. This results in a greater free fraction of the drug in the blood, which increases the drug activity (15,16). Furthermore, neonates often present increased plasma concentrations of bilirubin and free fatty acid, which reduce the drug binding even more (13).

The liver is the most important organ for drug metabolism. In children, liver blood flow and many drug-metabolizing enzymes are reduced. The former reaches adult rates by around one year of age (17). This may result in higher or lower drug plasma levels than those reached in adults and in other paediatric age groups (18). For example, CYP1A2 is an isoenzyme involved in metabolizing many drugs such as caffeine and theophylline. This enzyme is hardly detectable in neonates. It becomes more detectable in infants aged one to three months. Its presence in infants <1 year old is at about 30% of that in adults , at 81% in two year olds and comparable to adult values in children of three years or more (10). The varying levels of CYP1A2 with age explain the changing values of the half-life of caffeine at different ages (95 hours in neonates, 7 hours in infants, 3 hours in children and 4 in adults) (19).

The decreased renal blood flow in children under two years old and the immaturity of glomerular filtration and renal tubular secretion during the neonatal period restrict the renal excretion of drugs in these age groups. It has been shown that in late infancy and/or childhood, for many drugs such as for cimetidine and levetiracetam, children have a similar or higher rate of clearance from plasma than adults. This often makes administration of a higher dose necessary in this population (20-22).

Impact of the physiological differences on the pharmacodynamic properties

The effect of drugs in paediatric populations including drug action and toxicity could be different from that in adult populations for reasons not related to pharmacokinetic changes.

Many changes on drug targets (e.g., receptors, transporters, and channels) occur during the developmental process in children and generate different clinical responses. For example, changes in the receptors of prostanoids, angiotensin II and catecholamines were observed in children (23,24). Some frequent adverse drug reactions (ADRs) in children were found related to these changes.

For example, the respiratory depression and bradycardia related to the administration of opioids are more frequent in newborns despite their insufficient analgesic effect. This is explained by the fact that the opioid receptors in the medulla and pons, where respiratory and cardiovascular centres are located, are developed earlier than those in other parts of the brain (25). Other examples are the acute dystonic reactions or seizures, which are reported more frequently in young children after the administration of the dopamine 2-antagonists metoclopramide or prochlorperazine. This higher level of drug reactions is explained by the developmental changes that occur in dopamine receptors in this age group (24). Moreover, the therapeutic effect of other drugs could still be achieved in children with decreased concentrations, which is the case of ciclosporin. A greater immunosuppressive response to ciclosporin is reported in infants than in older children and adults (26).

Challenges in conducting paediatric clinical trials

Randomized clinical trials (RCT) are considered as the gold standard trials for evaluating efficacy and safety of drugs (27). They provide data of the highest degree of evidence, needed in paediatric population. However, conducting such trials has many ethical, scientific and financial issues in the aforementioned population (28,29) (Figure 3). This is reflected by the low number of RCTs conducted in children compared to adults. A study shows that only 12% of clinical trials for the conditions representing high burden paediatric diseases were conducted in paediatric populations (30).

The field of clinical trials in children suffers from a lack of adequate funding. Many pharmaceutical industries do not find enough commercial interest in these trials because of the high costs of studies and the small market size. In addition, paediatric trials are subject to a stringent regulatory scrutiny (31). It was found that the pharmaceutical industry funds only 41% of clinical trials conducted in children, whereas it funds 65% the clinical trials in adults (30).

As a consequence, the limited funds of non-profit organizations are frequently used to sponsor paediatric trials (30).

Patient recruitment is the first practical difficulty in conducting a paediatric clinical trial because of the small patient population. Nonetheless, finding the adequate number of paediatric participants is important to provide statistical power for the study. This difficulty becomes major when stratification by age groups is required. This refers to the necessity of allocating a specific number of patients of each age group. Stratification is used to reduce imbalance between randomized groups when it is known that age factors influence the outcome (32).

Recruiting paediatric patients is the hardest in rare diseases when very little number of participants are available (33).

Obtaining proper informed consents from children is an important and critical ethical element.

Until now, obtaining a child's consent is not required. Parents or legal guardians are asked to make the decision in their place (32). However, some recommendations encourage involving children as much as possible in the decision-making process, and collecting written assents at school ages (34). Furthermore, paediatric expertise capable of recognizing the individuality and unpredictability of children's responses is needed in these clinical trials. This expertise is also crucial for assessing the research protocols and monitoring safety (35). In the paediatric population, long-term follow-up is needed because of the numerous adverse effects that can manifest later in life (36,37) .

The other main challenges in designing and conducting a paediatric trial are the lack of validated quantitative and quantitative tools for outcome evaluation to use in children and the limited volume of biological specimens allowed (29).

The current situation in paediatric practice

The lack of clinical trials in children reflects on the paediatric daily practice. It takes form in the seeking of off-label and unlicensed medicines, the lack of appropriate paediatric drug formulations, the poor prescribing information that leads to the increased risk of medication errors (MEs) and unanticipated ADRs (38).

Off-label and unlicensed medicine use

"Children are therapeutic orphans", with these words Dr. Harry Shirkey, in 1963, described the fact that most of essential medicines are not adequately tested and labelled for paediatric use (39).

The role of the licensing process of a drug is to ensure that the drug has been demonstrated to be well tolerated, effective, and of good quality. With unlicensed or off-label medicines, we do not have this assurance as well as the necessary information for its use (38).

The use of a drug is considered "off-label" when it is outside the Summary of Product Characteristic (SmPC) conditions (the package insert recommendations), as its use (40): The drug is "unlicensed" when:

2. The dosage form of the medicine is modified before use.

3. It is an extemporaneous preparation.

In absence of labelled medicines, the children's therapeutic needs are covered by medicines labelled for adult-use or for other paediatric population use. For decades, the use of unlicensed or off-label medicines has been common practice in children This practice has been adopted all around the world whether children were hospitalised or treated at home.

According to a systematic review of studies published between 2007 and 2017, the rate of offlabel prescriptions ranged between 3.2% and 95% in paediatric studies (40). The probability of receiving an off-label prescription is reduced with increased age. It is reduced by 3% for every year in age increase, starting at 51.6% probability for less than one-year olds and 29.3% probability for 20-year olds. This probability is even higher when children are hospitalised. In general, inpatient children are 2.9 times more likely to receive an off-label medicine than outpatients (41).

The prescriptions for an unapproved age range or an unapproved indication were generally the main reasons of off-label classification in children, followed by the use of an unapproved dose or and the use of unapproved dosage forms (42).

Prevalence of off-label and unlicensed medicines use in hospitalised children

A systematic review including 34 studies, published in 2015, showed that 0.2 to 47.9% of prescriptions for the hospitalised children were for unlicensed medicines and 12.2 to 70.6%

were for off-label drugs. The percentage of children who received at least one off-label and/or unlicensed drug ranged from 42 to 100%. Newborns have the highest chance to receive off-label and/or unlicensed drugs. The formulation modification was the main purpose of unlicensed prescriptions (3.6-100%) and the dose modification was the main purpose of offlabel prescriptions (7.1-73.1%) (43).

A hospital database analysis showed that 78.7% of patients received off-label drugs and 40.5% of medicine cost in the hospital is spent on these medications. The most used off-label drugs in children were central or autonomic nervous system agents, fluids, nutrients, or gastrointestinal tract agents whereas off-label use of antineoplastic drugs was uncommon (44).

Prevalence of off-label and unlicensed medicines use in newborns

Higher rates of off-label and unlicensed drug use in neonates compared to any other population were reported in several studies; A prospective cohort study showed that 96.4% of neonates in neonatal intensive care units (NICUs) were exposed to off-label drugs and 66.8% of them to unlicensed medicines. It indicated that about one-half (49.3%) of medicines were off-label and 24.6% were unlicensed. The main reasons for the off-label and unlicensed classification in neonates were the frequency of administration and the administration of adaptations of pharmaceutical forms (45).

According to a recent national survey comprising 214 perinatal centres in Germany, an approved alternative medication was available for one out of three of the off-label and unlicensed medicines used in neonates. Interestingly, the costs of alternative approved medicines increased in median 405-fold compared with the corresponding off-label/ unlicensed medicines (46).

Studies showed that off-label drug use is associated with an increased frequency of adverse drug events (ADEs). A prospective study involving six paediatric and neonatal centres including 5060 patients showed that a higher risk of an ADE was expected when children received off-label drug treatment [7.3% vs. 1.2%; P < 0.01] (47). This correlation was confirmed by another prospective study (48).

A systematic review found that between 23 and 60% of unlicensed and/or off-label prescriptions were involved in an ADR (49).

Lack of child-friendly dosage forms

In paediatrics, the choice of a dosage form is an important issue. It impacts the acceptability, compliance, and effectiveness of drug treatment (50).

A main result of the historical underinvestment in paediatric pharmaceutical research by the pharmaceutical industry was the lack of dosage forms designed specifically for children (51).

The optimal dosage form for children (child-friendly dosage form) must be safe (e.g., without toxic excipients), well tolerated, easy to use (i.e., palatable and requiring few manipulations), acceptable by children, transportable, easily produced and cost-effective. It must also respect the child's lifestyle, avoid MEs and deliver variable and accurate doses (52-55). Many of the existing dosage forms used in children are originally designed to be used in adults (conventional dosage forms) and none of them meets all these criteria for all pediatric age groups. For example, oral liquid formulations are easy to swallow by children but may contain inappropriate excipients. They are also harder to administer (i.e., require complicated calculations and measurements) (Figure 4).

An Australian study showed that dosage forms of 21.9% to 25% of medicines licensed for paediatric use were not appropriate (56).

The main concerns associated with the use of adult drugs in children are the increased risk of MEs, the excipient safety and the low medicine acceptability by children (57-60).

Increased risk of dosing errors

Conventional dosage forms often need to be manipulated to meet the smaller required dose in children. Liquid formulations require complex calculations and dilutions to reach the appropriate formulation and dose for children (56,61). Manipulations of some solid dosage forms are also common to obtain an appropriate dose/form for children such as splitting or crushing tablets and opening capsules (62,63).

Such practices are associated with a high risk of dosing errors and could lead to inaccurate doses and unknown drug stability (57). Dosing-related problems were found the most frequent reason of the occurrence of drug-related problems in children (64).

Safety of excipients

Excipients are commonly utilised to improve the palatability, shelf life, and/or manufacturing processes of medicines. Children's responses to excipients differ from adults' and vary by paediatric age group. Certain excipients are not safe for children because they can slow organ development (e.g., ethanol, propylene glycol, benzyl alcohol and parabens) (58).

Low acceptability

The acceptability of a medicine is defined by the European Medicines Agency (EMA) as "the overall ability and willingness of the patient to use and its care giver to administer the medicine as intended" (65). The notion of acceptability is particularly important in designing and prescribing medicines in children. When a medicine is not accepted by a child, it has low chance to be taken correctly, which impacts its safety and efficacy. Acceptability is a multifaceted concept that depends on therapeutic product characteristics such as the route of administration, appearance, swallowability, palatability and the required dose and frequency as well as patient factors such as age and pathological state (54,65).

The acceptability of existing oral dosage forms varies among children; low acceptability of existing dosage forms is reported for children under 6 years old. The age of the patient, the size of tablets/capsules and the taste of liquids appears to play the main role in determining the dosage form acceptability (59,60). For that, many studies were conducted to define acceptability the existing adult-designed dosage forms by children (59,66,67).

Inadequate evidence-based dosing information

The use of off-label or unapproved medicines in children is associated with a lack of prescribing information based on a high level of evidence (44). A study shows that the monographs of 72% of the drugs approved between 2007 and 2016 in Canada did not contain any paediatric-specific information and indication (68). A recent survey on paediatric information have found that the SmPCs of 42.4% of the medicines currently available in Germany contained contraindications or warnings for at least one paediatric age group medicinal products (69).

The inadequacy of prescribing information reaches 80% of medicines in neonates according to an Australian study (56).

The lack of high-quality information about medicines in children leads to absence of evidencebased dosing guidelines and to high variabilities in drug use conditions in practice, in addition to discrepancies between existing dosing recommendations (70). For example, large variation in dexamethasone paediatric dosing practices were found between hospitals, according to a recent study (71) With these discrepancies in dosing recommendations, practitioners are unable to identify the most appropriate using conditions of these medicines and they rely on one available recommendation such as an expert opinion for the age group they are treating, or even on evidence from a different population to guide practice.

A systematic review published in 2022, comprising 18 studies, demonstrated that the inappropriate selection of drug dosage is the main cause of drug-related problems in paediatric patients (64).

This problem is more present in paediatric settings, such as NICUs, where the off-label prescribing practice is more frequent, . A survey comprising 199 NICUs located in 25 European countries reported a great variability in using ciprofloxacin and fluconazole for the treatment of sepsis within and between countries. The detected differences concerned dosage regimens including daily doses, frequency of administrations, unit dose, route of administration and treatment duration. In many NICUs (27%), even a local standard written protocol of a drug use was not established (72). Antibiotics are also largely concerned by this problematic (73,74) (75). Similar results regarding antibiotics were met by many other studies (74,76-78) suggesting the need to optimize the evaluation of drugs in neonates (5).

Consequences on child safety

3.1. Drug related problems (DRPs) in children

Definitions of different untoward events

There is a large variety of names in medical publications for the untoward symptoms that follow the use of drugs or the medical interventions. With the same detection methods, some studies could focus on detecting ADEs while others focused on adverse events (AEs) or MEs. In addition, different definitions could be found for each term. Therefore, it would be appropriate to mention the different terms used to describe events associated with drugs and medical care interventions, and provide the different definitions for each one of them. Figure 3 represents the relationship between AE, ADE ADR, and ME.

Drug-related problem

The term of drug-related problem was adopted from van Mil et al. to encompass all medicationrelated events (i.e., ADEs, ADRs, AEs, processes (causes), and outcomes (effects)), and is not limited to events causing harm (79)

Adverse event

The Institute for Healthcare Improvement (IHI) defines AE as an "unintended physical injury resulting from or contributed to by medical care that requires additional monitoring, treatment or hospitalization, or that results in death" (80) . . This definition is widely admitted since it implicates events induced by drugs or other medical interventions, and it specifies a minimum level of harm to be detected.

Adverse drug event

The Institute of Medicine defines ADE as "an injury resulting from medical intervention related to a drug". This definition encompasses harms that arise from MEs as well as conventional ADRs (81)(83). Nydert et al. adopted this definition considering that it also includes any suspicion of a relation to drug therapy (both preventable and non-preventable). For example, infections, vascular harm or pressure ulcers related to devices used for intravenous delivery or to devices used for enteral feeding (84).

The term ADE is the most confusing term because it is usually used to describe a suspected ADR during which the causality link between the drug and the event is not confirmed or assessed. When this causality is assessed and the event is attributed to the drug, the ADE becomes an ADR and when it is not, it becomes an AE caused by a procedure of care. Using the term ADE always implies that the drug has been directly or indirectly implicated (81) but contrary to an ADR, a confirmed causality link is not required.

The Institute of Medicine also provided another wider definition of ADEs, which integrates the part that the disease of the patient plays in the outcomes: an ADE is "an injury due to medication management rather than the underlying condition of the patient".

A more complete definition of ADE was presented by the Committee of Experts on Management of Safety and Quality in Health Care as "any injury occurring during the patient's drug therapy and resulting either from appropriate care, or from unsuitable or suboptimal care".

The committee also explained that an ADE can result in different outcomes, notably in the worsening of an existing pathology, in the lack of any expected health status improvement, in the outbreak of a new pathology or a one could have been prevented, in the change of an organic function, or in a noxious response due to the medicine taken (85)

Adverse drug reaction

The World Health Organization (WHO) defines ADR as "a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function". Laurence defines it as "a harmful or significantly unpleasant effect caused by a drug at doses intended for therapeutic effect (or prophylaxis or diagnosis), which warrants reduction of dose or withdrawal of the drug and/or foretells hazard from future administration." (86). By using the words "response" and "caused by", both definitions require a causal link between the event and the drug to be an ADR. This causality link is what distinguishes an ADR from an ADE. Itis usually complicated to confirm or decline this causality link, and when an event is attributed to a medicinal product, the attribution should also be accompanied by a statement of the degree of probability of the attribution. Therefore, all ADRs are ADEs, but not all ADEs s are ADRs. This distinction is important in clinical trials, in which not all events are necessarily drug induced. In order to avoid this complexity, the term ADE is more often used.

The seriousness of the harm should always be considered when identifying an ADR. Aronson and Ferner consider that the WHO definition has some defects because it excludes all doses that are not used in the way described by the definition and all adverse reactions that may be inconvenient but not harmful (81). Laurence also requires a minimum level of harm by excluding minor unwanted reactions.

In case of death, life-threatening event, hospitalisation or prolongation of existing hospitalisation, disability or incapacity or a congenital anomaly or birth defect, the ADR becomes a serious ADR. ( 86)

Medication error

The definition of ME, which was proposed by Ferner et al. in 2006, and has been widely accepted is "a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient" (87) ME includes all types of errors that could occur from the prescription to post administration: The ADR-related mortality in children is 0.8% according to a UK study comprising data collected for 37 years (91). However, ADR-related mortality rates differ widely between countries; a systematic review identified rates between 3.4 and 13.0% in North America and between 0.1 and 2.2% in Europe (92).

The high incidence rates of ADRs lead to prolonged hospital stays and additional costs (93).

According to a systematic review, ADRs come at a substantial cost to health systems, with an estimated cost of USD 2 401 per hospitalised patient, equating to a 19.86 % increase in overall cost and a 8.25 % increase in hospitalisation time (94).

Beside the higher mortality and morbidity rates as well as the significant financial costs, ADRs have other important consequences, including loss of trust in the health-care system and greater non-adherence to treatment (95).

Prevalence of MEs

Because of their unique physiology and developmental needs, children are particularly vulnerable to MEs, which are very common in paediatric inpatient settings. A meta-analysis published in 2019, comprising 56 studies, estimated the rate of MEs of 1 per 7 medication orders in paediatric wards using paper medication charts, with at least 1 error experienced every 2 or 3 paediatric admission. This rate is reduced when using electronic charts. The rate of MEs was found to differ between setting wards; it ranged from 24 to 75% of the admissions in multiple ward studies, from 62 to 75% in general ward studies, from 5.6 to 94.9% in paediatric intensive care units (PICU) studies, from 70 to 91% in NICU studies and from 0.9 to 51% in Emergency Department (ED) studies (96).

According to a systematic review, the most common MEs in the UK hospitals are the drug administration errors, with a median prevalence of 16.3% (IQR 6.4-23), wrong administration techniques represented 53% (IQR 52.7-67.4) of these errors. Prescribing errors came in the second place, with a median prevalence of 6.5% (IQR 4.7-13.3); of which the median rate of dose prescribing errors was 11.1% (IQR 2.9-13) (88). Prescribing errors seemed higher in NICUs, EDs and PICUs than in general wards (96,97).

The major factors associated with medication administration errors according to paediatric nurses are being distracted and interrupted as well as being understaffed. Nurses indicated that the main reasons for not reporting MEs were focusing on the patient and the fear of adverse consequences (98). Conversely, the main factors associated with prescribing errors are the moment of consultation (e.g., weekends and early mornings), the severity of the disease, the experience level of the prescriber (99).

Paediatric pharmacovigilance

The WHO defines pharmacovigilance as "the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem" (100).

Pharmacovigilance systems should ideally take a life-cycle approach. This approach is carried out throughout the drug development process, from the beginning of research and development to post administration. We distinguish two stages of pharmacovigilance systems (figure 4): premarketing surveillance and post-marketing surveillance. Pre-marketing surveillance consists of collecting data concerning ADRs from preclinical screening to Phase I, II and III clinical trials.

Post-marketing surveillance includes collecting data on ADRs from drug approval and throughout drug market life endpoints. In addition, many adverse reactions take a long period of time to appear after drug exposure and could not be detected during a clinical trial period. Furthermore, serious adverse events are often rare, thus they are rarely detected through a paediatric clinical trial. It was detected (102). Therefore, post-marketing monitoring is the most important source of information on ADRs for licensed medicines. In unlicensed and off-label medicines, little or no information is available on clinical safety of drugs in the concerned conditions of use.

Additionally, drug safety data collected in the adult population cannot be used for the paediatric population (103). An effective monitoring regarding safety for these drugs is particularly important to rapidly identify any inappropriate and unsafe use.

Challenges of ADR-detection in children

Most of the methods to detect ADRs used in children are originally designed to be used in adults. However, in addition to pharmacokinetic and pharmacodynamic drug particularities, many other particularities inherent to challenge these methods when used in the paediatric population;

Limited communication skills

Young children are unable to communicate in the same ways that adults can. For example, infants experiencing hallucination may be irritable, but they may not be able to articulate their symptoms appropriately. A Japanese study suggests that the limited linguistic skills of patients under three years old explain the underreporting of ADEs in this age group comparing to those in children aged three years and more (104).

Child-specific ADRs Some ADRs are only seen in children, regardless of the effects of growth and development.

Other ADRs caused by certain ingredients and excipients may manifest differently in adults and children, e.g., the life-threatening gasping syndrome seen in infants exposed to benzyl alcohol (105).

Diagnostic challenges

Physical examinations and tests cannot be carried out in the same way that they are in adults (106). Detection methods need to consider the child-specific diagnostic techniques as well as the specific biological values when used for the paediatric population.

Therefore, the validity of detection methods in the paediatric population should be tested. The person or the machine carrying out the detection or the evaluation process should master the Diagnostic particularities in children. (107).

Post-marketing detection methods in hospitalised children

Post-marketing pharmacovigilance can be conducted through passive and active surveillance systems. In passive surveillance, health-care professionals or patients send spontaneous reports to the marketing authorisation holder or regulatory authority in which they describe the ADE after one or more medicinal products are used. Active surveillance involves enhanced or targeted monitoring for certain events or drugs and seeks to ascertain completely the number of ADEs through a pre-planned process. Active surveillance methods include computerised ADE reporting systems, trigger tools and medical note reviews. In general, adopting passive ADEdetection methods is simple and cheap while adopting active methods may be more costly but generates more informative results (101).

Pharmacovigilance consists of two main steps: safety signal identification and risk assessment (108). Safety signal is information on a new or known AE that may be caused by a medicine and requires further investigation. In post-marketing phase, safety signals depend on the number of reports of an ADE and consequently of detected ones.

Many studies were conducted to describe and compare the most commonly used ADE-detection methods in the paediatric population. Four detection methods are commonly used to detect ADEs: incident report review, direct observation, chart review and trigger tools.

Incident report review

Incident report review is defined as voluntary reporting of incidents by health-care professionals (HCPs), patients, or parents. Reporting can be done on paper, through e-mail, fax, phone, or through an interactive computer system (109). It is the most ancient and the most common detection method used in daily practice. An incident report describes one or more ADEs in a patient who was given or took one or more medical products, and is out of any research perspective or any other structured data collection. This method is based on the reporters' awareness of the presence of a potential drug-related harm and their motivation to report it (110).

Reporting ADEs by HCPs is mandatory only in certain cases. This method is usually the main source of ADE, especially serious ADE, in post-marketing phases (111,112). It has the advantages to provide exhaustive information, including narrative sections of the context and causative factors. This information is necessary to analyse the causes and the contributing factors of ADEs. However, ADEs were found under-detected and under-reported through this method. This leads to limits our knowledge about drug safety in children. In daily practice, the difficulty encountered in detecting ADEs in the hospital environment can still be observed due to factors such as a lack of the ability to suspect it, a false belief that an observed ADE is an 'expected' reaction, which results in only reporting 'unexpected' severe and serious ADEs (112), and a lack of knowledge concerning ADRs (113).

Direct observation

Direct observation is an active method that refers to a wide range of direct, real-time observation techniques of all aspects of the medication use process (114,115). The main advantage of this method is that a higher number of ADEs can be detected in real time, which allows a better and faster ADE management. Nevertheless, it consumes a considerable amount of time and human and financial resources.

Medical chart review

Medical chart review is an active method and includes both concurrent and retrospective reviews of medical records, discharge summaries, pharmacy databases, and laboratory data (116,117). Despite providing high-quality information regarding ADEs, this method has showed serious practical limitations, including the need of trained experts, considerable period of time and significant amount of human and financial resources.(118).

Trigger tools

A trigger tool is an active method defined as a targeted medical record review, either manually or automatically (80,117). A trigger is a data element (alert) within a health record identifying the presence of an ADE that has occurred or is about to occur (80). The ability of automatization is the major advantage provided by this tool. The main limitation is its long planning process before use, including training, evaluation and automatisation. Many paediatric trigger tools exist, and each one of them represents a unique set of triggers, with many of them are shared by different tools.

A complete comparison between the four methods is provided in (Table 1)

Trigger tools -

The number of refers to the positive results reported of the method compared to other methods. -: data are not reported.

Key strategies to promote drug safety in children 4.1. Generating and collecting more data on paediatric drug safety

Increasing data on paediatric drug safety is essential for the improvement of childcare.

Promoting this collection is important in both pre-marketing and post-marketing stages.

Facilitating the conduction of clinical trials in children

In suggesting that more efforts are still needed (69).

Improving post-marketing paediatric pharmacovigilance methods

Given the significant rates of ADRs reported in hospitalised children, many of which are serious and preventable, better detection methods and interventions are required to improve children's safety (125). Each of the existing detection methods has advantages and limitations.

Until now, there has been no gold standard for detecting ADEs in clinical practice (126).

Combining two or more methods appears to be the best pragmatic approach to collect more safety data on drugs and to conclude to a clearer ADR assessment (127). However, the use of each of the existing methods could be improved for paediatric use. The improvement may target signal identification techniques, paediatric-specific detection roles or reporting systems.

Among the available detection methods, we focus in the present document on the trigger tool method and its possible improvement. This method has been recently developed and is a promising practical method used in paediatric inpatients (118).

Trigger tools have shown numerous advantages and are compatible with the growing generation and use of Electronic health records (EHRs). Yet, their use to detect ADEs in paediatric daily practice in many developed countries, including France, is still limited.

The performance of this method varies between the different trigger tools and depends directly on the triggers included in each tool (118). An optimised use of such a method in daily practice requires selecting triggers effective and pertinent to the targeted population, the settings and the commonly used drugs. Therefore, updated information on available triggers and the description of their performances are needed. It is well known that using irrelevant or ineffective triggers can result in high false positive rates, and consequently over-alerting, a loss of trust in the detection system and increased costs, especially when used in a real-time detection mode.

Promoting safe practices

Optimizing dosage form choice in children

While waiting for the marketing of novel child-friendly dosage forms, prescribers need to deal with available dosage forms. For many drugs, many liquid and solid dosage forms are often available for oral administration in the paediatric populations. Choosing between them should consider the advantages and the disadvantages of each one of them for the patient age group (65). Prescribers also have to consider the compliance to the child and the family preference, which could differ from the prescriber primary choice, in order to reach the best drug acceptability and adherence (128,129). Studies show that liquid dosage forms were the most frequently oral forms used in practice in all child age groups (130) despite the advantages provided by solid dosage forms for certain paediatric age groups (65). Factors influencing dosage form choice by paediatricians are not well reported. Yet, the properties of dosage forms do not appear to be considered in physicians' prescribing decisions (131)

In order to make the most appropriate dosage form choice for their patients, prescribers need to be informed of the other safe dosage form alternatives available; including information on labelling status, possible dosages, patient acceptability and cost.

Harmonizing dosing recommendations

The different dosage regimens available of a drug in children are based on different levels of evidence and different efficacy and safety results. Recommending one dosage regimen is a complicated process due to the low comparability between studies and the absence of a validated selection strategy considering high variability in terms of population, design, parameters, outcomes, and results. However, providing unique updated dosing guidelines based on the best available evidence for paediatric prescribers for many drugs is a real need that must be addressed. Drug prescriptions in children as in adults should be based on the best available evidence, including data from peer-reviewed scientific studies (132). For that, harmonisation projects need to be initiated with the objective of identifying the most appropriate dosage regimen of drugs and define the type of study(ies) needed to validate it with a higher level of evidence. The harmonization initiatives should target at first the off-label and unlicensed used medicines that are associated with serious potential ADRs, especially those used in neonates.

The provided dosage recommendations should be kept up-to-date and consider all new information. All harmonization projects need to collect literature data on the dosage regimens of the drugs in question.

Chapter B: My articles

Summary

Aims. -To identify all available trigger tools applicable to the pediatric population in hospital settings to detect adverse drug events (ADEs) and to describe their performances by positive predictive value (PPV).

Methods. -PubMed ® was searched until December 2021. The reference sections were also consulted for new articles. Studies were selected when they used one or more triggers to identify AEs and used data on pediatric inpatient settings. Studies mentioning triggers relatedto AEs that were only caused by care procedures were excluded. Only triggers related to ADEs were included. PPVs of triggers were reported. Mean PPVs were calculated for multi-study triggers. The interest of each trigger in a real-time detection system was assessed.

Results. -Thirty studies were included. A total of 271 unique triggers were -induced harms. Among them, reporting. Nineteen triggers (11%) had a mean PPV between 50% and 100%, including 5 that had a 100% PPV. Despite their numerous therapeutic benefits, the use of medications may cause adverse drug events (ADEs) and morbidity [1] . These aspects have to be considered by clinicians in order to optimize drugs' benefits and minimize or better prevent ADEs.

Conclusion

An ADE is an injury resulting from clinical intervention related to a drug [2] . This includes adverse drug reactions (ADRs) and medication errors (MEs). An ADR is defined as any response to a drug that is noxious and unintended which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modifications of physiological function [3] . An ME is defined as any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer [4] .

Traditionally, clinical trials and spontaneous reporting systems are the main sources of reported ADEs in post-marketing phases. However, due to a lack of time and motivation, ADEs are underreported by healthcare professionals in their day-to-day practice which results in underestimating the actual rate of ADEs, especially in children [5], [6] . Three other proactive medication safety assessment techniques have been proposed: direct observation, chart review and trigger tools [7][8][9] . A systematic review of the literature comparing these methods showed that the trigger tool method is the most effective and labor-efficient method to detect ADEs [9] , even though it is time-consuming, especially the thorough review of the electronic records [10] .

When computerized, triggers are able to identify 45% of ADEs, chart review 65% and voluntary report 4% while it requires 80% less human-time resources than chart review and twice as many as voluntary report [11] .

A trigger is defined as a data element within a health record that identifies the presence of an ADE that has occurred or is about to occur [12] . A trigger is called positive when it has been identified in a patient's health records [7] . Typically, these triggers are derived from clinical, medication or laboratory tests [6,14] .

A trigger tool is a targeted medical record review that is carried out either manually or automatically [7] . The manual review of triggers is a sampling method based on the evaluation of a limited number of health records. The medical team decides which trigger tool they will use for chart analysis and defines the procedure by which the charts will be analyzed, which ideally are selected randomly. Each selected chart is screened, only through triggers. By contrast, the automated detection is based on the identification of specific triggers in all electronic health records (EHRs) for any given period and is considered as a more time-efficient approach. Once a trigger is detected using any of the methods, a more in-depth review is undertaken to examine the potential for an ADE [5,[7][8][9]14,15] . Trigger performance is usually evaluated using PPV, which is the percentage of patients with a positive trigger who actually have an ADE (true positive [TP]), whereas negative predictive value (NPV) is the percentage of patients with a negative trigger who do not have an ADE (true negative [TN]) [16,17] . The risk analyses through trigger tools can be computerized and systematized through algorithms. These charts have to be further manually analyzed by an experienced professional.

In 1999, the Institute for Healthcare Improvement (IHI) developed the Trigger Tool for Measuring Adverse Drug Events, which was improved in 2009 with a second edition called Global Trigger Tool for Measuring Adverse Events (GTT) [7] . Classen et al. demonstrated that the GTT may identify ten times more serious ADEs than voluntary reports and other tested indicators [18] . The IHI has successfully advocated the use of this approach in adult hospitals [7] .

Research on trigger tools applied to children started in Canada in 2005 based on the IHI's methodology [19] . Kirkendall et al. tried to apply the GTT to the pediatric population and found that 25.8% of children had at least one ADE during their hospital stay [20] . To date, this innovative ADE detection tool has been proved to be efficient in the detection of ADEs in adults but its use is still limited in hospitalized children [17,[20][21][22][23][24][25] . The method could be more effective in detecting ADEs when relevant and adapted triggers for daily practice are selected [23] . To select the most clinically relevant triggers to detect ADEs in children, a review of the literature is necessary to identify the possible triggers and describe their properties.

Objective

The aim of this systematic review is to identify all available trigger tools applicable to the pediatric population in inpatient settings to detect ADEs and to describe their performances by PPV, if available. To identify other relevant articles, the reference sections of all included articles were consulted.

After screening and removing duplicates, all article titles, abstracts and full texts were independently reviewed for inclusion by two authors of this article. In case of discordance, another author was consulted in order to confirm or reject the inclusion. Articles meeting all of the following criteria were eligible for inclusion: research using one or more triggers to identify AEs and research using data on pediatric inpatient settings. Exclusion criteria were pieces of research using data from only non-hospital or outpatient settings, mentioning triggers related to AEs caused only by care procedures, research with unavailable or unpublished full texts and research with triggers not provided.

Data Extraction

Extracted data contained information on: first author, country, year of publication, number of After extraction, similar or repeated triggers were standardized using one term: types of triggers were also reviewed and standardized using a classification mode based on the potential source of information. Classifications were: medication, laboratory, clinical intervention, clinical sign, administration or combination (when two triggers of two types were combined) (e.g. the trigger "drug level out of range" is classified as a laboratory type trigger because this piece of information would be found in laboratory data). The new terms and classifications of triggers were verified by another author of this article. We also classified triggers if they identify an AE potentially related to a medication (ADE) or only to care procedures. Only triggers that could identify ADEs were considered.

Synthesis of Results

A narrative synthesis of the data was completed by reporting the findings related to the study characteristics, trigger tools and individual triggers (qualitative methods). The PPV was chosen as the main parameter to describe the performances of the individual triggers, because it was the most commonly available in articles reviewed while designing this work. For each trigger, all available PPVs were reported and the mean PPV was calculated. Due to the heterogeneity of triggers between the different trigger tools and the unavailibility of adequate performance data on individual triggers, no further statistical analysis or meta-analysis was performed.

Trigger Assessment

The included triggers were assessed according to their potential clinical use in a real-time detection system by two pediatricians. They were then classified into three categories: Warning triggers, Validation triggers and Reporting triggers. Warning triggers include triggers that are potentially usable for early-detection such as the administration of a high-risk medication, a risk factor or an early abnormal laboratory value. Validation triggers include triggers that are detectable after the occurrence of the ADE but enable the validation of a relationship with a drug. Reporting triggers include late-detection triggers of which the ADE has occurred and has been managed and the suspected medication was identified.

The interest of using warning triggers in a real-time detection system is to warn for a potential ADE in order to prevent it. Using validation triggers allows detecting ADEs and optimizing their management by identifying a potential relationship between the drug and the condition.

The interest of using reporting triggers is to report and notify ADEs in a more efficient way than spontaneous reporting. So, all triggers would help improve the quality of care and hospital organization.

Quality Assessment

Two reviewers independently conducted the quality assessment of each of the included studies using the method of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool [26] . The time interval between the index test and the reference standard was not considered for the evaluation. The risk of bias was judged "high" when one or more signalling questions were answered negatively.

3. Results

Description of the included studies

We identified 83 articles. After a review of titles and abstracts, we assessed 34 full-text articles of which 24 fulfilled the inclusion and exclusion criteria and were included in the review. A review of the reference sections of the included articles identified six additional articles. In total, 30 articles were included [14,17,[20][21][22][23][24][25] (Figure 1 -Table 1). The studies were published between 2006 and 2020.

The most commonly used method to detect triggers was chart review with 20 studies using it while10 used automated trigger tools.

In 23 studies, triggers were applied on a general pediatric population, 2 on acutely ill inpatients, 2 in pediatric intensive care units (PICUs), 1 in a neonatal intensive care unit (NICU), 1 in a pediatric otolaryngology service (ORL) and 1 in a psychiatric ward.

The number of triggers used in the studies varied between 3 and 88. Twenty-four studies provided information about the overall PPV of trigger tools. Overall PPVs varied from 2% to 49%. Twenty-one included studies provided information regarding individual PPVs. Studies were undertaken in 10 countries. Twenty studies were located in North America, four in Europe, two in South America, three in Asia and one in Africa. Fifteen studies focused on AEs in general, thirteen on ADEs, one on MEs and one on any type of harm (Table 1).

Description of the included triggers

Nine hundred and sixty-six non-unique triggers were extracted. After the standardization process, 271 unique triggers were identified and 179 were included. respectively show the warning triggers, the verification triggers and the reporting triggers for which a PPV is available and > 0 (a complete list of the triggers is presented in appendix A).

Forty-six of the included triggers were created to detect an undefined ADE (e.g. anesthesiarelated harm and medication reaction), while 133 triggers were designed to detect one or more defined ADEs (e.g. the 10 triggers related to bleeding that are presented in Figure 5: 8 of them are classed for warning and 2 are classed for verification).

Quality assessment

Table 2 presents the methodological quality assessment (risk of bias) of the included studies.

Two types of risk of bias were commonly found across the included studies. The first one concerned the reference standard (in 28 studies). The reference standard was usually a physician review, which was only performed when the index test (trigger test) was positive by reviewers aware of this positivity. The second risk of bias concerned patients' flow and timing (in 27 studies). Records with a negative trigger test did not receive a reference standard and were not considered for the performance analysis of triggers. The quality results regarding patient selection and index test as well as the applicability results were generally satisfactory (three or fewer high risks for each).

4. Discussion

About 38% of the identified triggers (i.e., warning triggers) could be used in the prevention of ADEs, although the studies do not particularly specify this utilisation. Some of the included triggers, which were well-studied and had a high mean PPV, were undefined (e.g., occurrence of a complication and abrupt medication stop).

The use of trigger tools in pediatrics is limited. Laboratory data provide the richest information source of triggers. The majority of identified triggers were employed in more than one study.

The performance indicated by the PPVs of the majority of included trigger was quite poor (PPV < 50). Generally, reporting triggers tend to perform better than verification triggers and verification triggers better than warning triggers. However, there are no specifically defined thresholds for the interpretation of a PPV. The seriousness and the severity of the related ADE have to be considered when selecting clinically relevant triggers. To be selected, a trigger for serious ADEs (e.g., death) may have a low PPV, whereas, for ADEs with a non-significant level of harm, the probability of affirming the presence of the ADE must be high. In order to refine triggers in some of the included studies, various limits were defined: Landrigan et al. [41] while Matlow, A. G. et al. eliminated triggers with a low PPV and a ratio of false-positive to true positive predictors > 0.7 [22] .

Bleeding, hypoglycemia, allergic reactions and drug intoxications were the most frequent ADEs identified when using triggers.

All mean PPVs of 100% reported in this study were related to 1 single study [31,34] . Selection of the best performing triggers needs to integrate the number of studies where the trigger was used and their sample sizes.

PPVs depend on the trigger, the type of population, and how the study was designed and conducted. The use of triggers in specific pediatric population looks promising; the overall PPVs of 4 specific-population studies (PICU, NICU, ORL, acutely ill patients) [24,29,45,47] were higher than the overall PPVs of 18 general population studies. Furthermore, Stockwell et al.

showed that a notable increase of PPV is observed when triggers are well combined. The hypoglycemia trigger defined as "all serum glucose values less than 50 mg/dL" has a PPV between 0% and 38% [20,22,25,27,28] while the combined trigger "serum glucose values less than 50 mg/dL and insulin administration" has a PPV of 61% and 100% [29,30] . The adoption of a lower threshold of glucose level of 40mg/dL for the definition of hypoglycemia did not significantly improve the PPVs, which were of 28% and 56% [14,27] .

The combination of certain triggers enables to consider time and clinical context. For instance, the administration of an antihistamine as prophylaxis treatment to the hypersensitivity effect of certain drugs would not be associated with any ADE whereas the administration of an antihistamine in the existence of a drug-induced allergic reaction generates a valid ADE.

Lemon et al. assessed a trigger for anticoagulation-related ADEs through a combination of an

International Normalized Ratio (INR) >4, an activated partial thromboplastin time (aPTT)>100 seconds, Anti-Factor Xa Activity (anti-Xa)>1.5 IU/mL or administration of protamine. It has led to the restructuring and standardization of anticoagulation therapy protocols as well as the modification of thresholds [14] .

Some trigger PPVs differed largely across studies. The PPVs of 8 triggers ranged from 0 to 100%. This could be explained by the type of hospital units involved, whether a manual or automated tool was used, the duration of the study and the type of patients. For example, naloxone administration had a PPV ranging from 0% to 78% [14,[20][21][22]27,29,[31][32][33][34] and flumazenil administration a PPV ranging from 0% to 100% [14,17,20,29,[31][32][33] . It seems that in these situations PPVs were higher when using an automated trigger tool. These findings suggest that the triggers need to be tested more in pediatrics in order to get better estimations of their performances in this context.

A complete examination of patient records is an essential step to validate the existence of an ADE when a positive trigger is identified. It also allows us to determine the nature of the ADE (ADR or ME), the severity, the drug causality and the preventability using specific evaluation methods. For example, reviewing data on drug administrations, calculations, prescriptions and patient characteristics is necessary to determine whether the bleeding event associated with a vitamin K administration trigger resulted from a dose calculation error, an administration error, a preparation error, a prescription error, a drug interaction or happened during a standard anticoagulant dosing adjustment. Since medication errors are common in pediatric patients [49,50] ,

triggers could be used in order to detect harmful medication errors and take corrective actions.

However, the examination of ADEs through trigger tools has a tendency to concentrate on patient harm rather than errors [33] .

In this paper, in addition to identifying triggers, they were also classified considering the clinical relevance for their use in daily practice. However, selecting clinically relevant triggers for internal use and defining each trigger is recommended before implementing the method in daily practice detection. After selecting triggers, an internal feasibility evaluation considering detectability of selected triggers from the internal electronic data records, expected number of positive triggers, estimated time needed per trigger, available human resources and the possibility of an automated transmission could be necessary. Proper training of in-depth reviewing of patient's records would be probably needed.

Our study has several limitations. The interpretation of the mean PPVs of triggers could be biased since it does not consider the sample sizes of the studies. However, the recommended meta-analysis methods for such diagnostic test should combine either specificity and sensitivity parameters or PPV and NPV. The information provided on individual triggers by the included studies does not allow performing any of these methods. Indeed, the sensitivity and specificity provided in some studies concerned only the entire trigger tool used.

Another potential limitation is that we grouped biological triggers that were employed with various definitions across the studies as part of the standardization of term process. This point may have influenced the mean PPV since a trigger with narrower limits is expected to have a higher PPV. For example, the category "high serum partial thromboplastin time (PTT) trigger" gathered 13 PTT >100 seconds, 1 PTT >140 seconds and 1 PTT with no threshold mentioned.

However, the integration of the PTT >140 seconds trigger did not appear to highly influence the total PPV in this example (from 24% to 28%).

The included studies were mainly performed in the United States of America where the population and settings differ from other countries, which limits the applicability of these studies' findings in other countries. We suggest considering the clinical relevance of triggers in the first place in any selection of triggers to be tested or applied in a hospital.

The search for studies was carried out on one single database (Medline), which could restrict the number of publications. However, Halladay et al. suggested that it may have little impact [51] .

The physician's judgment is considered as a reference standard for the determination of the causative relation of an adverse event [52] . The quality of determination varied between studies.

For example: Mouton et al. used a multidisciplinary experienced team [36] , Stockwell et al. used a multi-phase assessment by physician-reviewers [27] while Kilbridge et al. used a single-stage assessment performed by pharmacists only [29] .

The detection process of triggers with a high PPV has the potential of being fully automated in practice [52] . The automation of trigger tools could enable a continuous and more exhaustive detection of ADEs and offers additional advantages like saving time, allowing real-time intervention when facing ADE, better understanding ADEs and improving their outcome [8,15], [9,14] . In three of the included studies, a near real-time detection system was established based on automated triggers and daily review of positive triggers by a specialist [14,32,44] .

Further research would focus on diagnostic and prognostic models for semi-automatic or automatic detection and prevention of clinically significant ADEs. Diagnostic models using combinations of triggers and considering the clinical context of hospitalized children may increase the performance of ADE detection, help identify new risk factors of ADE, and contribute to early detection and prevention of severe ADE. The prognostic models would be useful for the proactive prevention of ADE.

Our aim for further research is to develop a model combining a selection of triggers relevant to clinical practice to detect related ADEs, and to implement a tool in the hospital information system to screen electronic patient data on a continuous basis. In summary, ADEs would be reported in a time-efficient manner, reducing the burden of filling in voluntary reports.

Corrective actions will be implemented to improve the model, in case of false positive results.

Care delivery could be performed earlier and ADE impact may be mitigated. Underreporting may also be investigated leading to a better estimate of ADE incidence and to the implementation of preventative actions to reduce their rate. The clinical utility of such models should then be assessed in clinical trials.

Conclusion

We found articles identifying many triggers, with very varying performances across studies;

further studies are needed in children to assess precisely triggers' performances. As diagnostic test performances are measured primarily using their sensitivity, specificity, PPV and NPV;

similarly, the use of these parameters should be generalized to evaluate triggers' performances in future studies. The detection of ADEs through computerized triggers and/or real-time detection systems remains an emerging field, very much needed in children especially, due to frequent off-label use. This study proposes the use of three types of triggers for ADE earlydetection and prevention, validation and reporting. We suggest that significant PPV thresholds based on the severity of the ADEs could be defined.

Flow and timing

Patient selection

Index test

Reference standard

Stockwell et al. [31] Fortenberry et al. [38] Ivashchenko et al. [37] Ferranti et al. [32] Patregnani et al. [42] Kilbridge et al. [29] Long et al. [30] Call et al. [23] Lemon et al. [14] Kirkendall et al. [44] ? Solevag et al. [43] Landrigan et al. [41] Stockwell et al. [27] Kirkendall et al. [20] Larsen et al. [46] Ji et al. [25] Maaskant et al. [39] Mouton et al. [36] Lander et al. [45] Stroupe et al. [40] Davenport et al. [28] Unbeck et al. [34] Matlow et al. [22] Sharek et al. [47] Nydert et al. [35] Agarwal et al. [24] Takata et al. [21] Chapman et al. [33] Takata et al. [17] Liu et al [48] Low Risk High Risk ? Unclear Risk *Quality Assessment of Diagnostic Accuracy

Introduction

The need for age-appropriate dosage forms in pediatric patients has been a major concern for the pediatric community since the Paediatric Regulation (EC) No. 1901/2006 [1] was adopted.

The development of age-appropriate formulations has constituted a challenge for pharmaceutical scientists [2,3] , since such forms must be easily produced, cost-effective, and commercially viable [1] .

The ideal dosage form for pediatric use should permit accurate dose administration, minimize dosing frequency, limit impact on lifestyle, reduce the risk of medication errors, and contain only safe excipients [1,2,4] . Dosage forms available in pediatric doses are scant, and many formulations are therefore used off-label in children [5] .

Due to their dosing flexibility and high swallowability, liquid dosage forms (i.e. solutions, syrups, suspensions, and emulsions) are usually recommended for young children unable to swallow [6] . However, liquid dosage forms exhibit some major disadvantages in comparison to solid dosage forms, such as poor stability, taste masking difficulties, low transportability, and excipients inappropriate for children [1,2,7,8] . Dosing errors are more likely when using liquid dosage forms (i.e., inhomogeneous distribution in suspensions, errors in counting drops, incorrect calculation or measurement of liquid volume) [9] .

Oral solid dosage forms are considered more suitable for children's everyday life (i.e., easy to transport and store), do not usually require using a dosing tool, and allow low dosing frequency, which can enhance drug compliance [9,10] .

Liquid dosage forms remain the most frequently administered oral forms in children, even for ages 6 years and older [11] . The inadaptability of solid dosage forms for pediatric use [3,12] and the inability of some children to swallow a tablet or a capsule are presented by healthcare professionals as the main limitations to the use of solid dosage forms in children under 6 years [5,13] , and even under 7.3 years according to nurses [10] . Many studies, however, have reported good acceptability of mini-tablets for these age ranges [14] . Single-unit dosage forms for reconstitution (i.e., dispersible tablets, powders, granules, pellets, or sprinkles) are effective delivery strategies, as they maximize the advantages of the conventional solid dosage forms while providing better swallowability and greater dosing flexibility [1,9] .

A recent study, using prescription data over a one-week period in a hospital in England, showed that two-thirds of the liquid dosage forms administered in children over 2 years old could have been substituted with suitable solid dosage forms [15] .

In a previous study, we reported a low use of solid dosage forms in our hospital and a need for more research on the acceptability of oral solid dosage forms in children [11] .

The first objective of this study was to identify the 10 drugs most frequently administered to children in liquid dosage forms eligible for replacement with suitable authorized solid dosage forms (i.e., easy to swallow and available in the proper dosage). The second objective was to assess the expected economic impact of this potential substitution.

Materials and methods

Data sources

This study was conducted on data collected over a 3-year period (February 6, 2013 -February

Drug selection

The criteria for identifying oral liquid dosage drugs which could be potentially substituted with solid forms were: containing a single active ingredient, industrially manufactured, available in at least one solid dosage form in the hospital pharmacy.

Data concerning children who could not even receive the minimal dosage of a given solid form (i.e. younger than the authorized age, lighter than the authorized weight, unable to swallow the smallest tablet) were discarded from the drug selection analysis. We then selected the 10 most frequently administered drugs which were eligible for a thorough substitution assessment.

The Summary of Product Characteristics (SmPC) was used to identify authorized age groups and the Clinical Investigation of Medicinal Products in the Pediatric Population guidance was used to identify the age range for each category (newborns, infants, etc.) [16] . The Committee for Medicinal Products for Human Use (CHMP) guideline was used to identify at what age children could swallow the minimum dose tablets [9] . Of note, when the minimum dose was achieved by tablet division, half of the diameter was considered.

Substitution assessment

In order to determine the age/weight categories of eligible patients for each drug and administration substitution, the dosage acceptability and then the size suitability of the available solid dosage forms for the patients receiving the liquid dosage forms were assessed (figure 1B).

The substitution analysis aimed to determine, for each of the 10 drugs identified as most frequently administered to children and eligible for substitution with authorized suitable alternative solid forms, the number of administrations for which a suitable solid form was possible referred to herein as substitution frequency.

Dosage acceptability

First, all daily doses achievable using the available solid dosage form(s) were identified. During this step, the recommended dosing frequency was followed, the division of breakable tablets (when accepted in the SmPC) was allowed, but the combination of two different solid dosage forms was not. The weight and age ranges of patients who could receive these daily doses were then determined according to the recommended posology provided by the SmPC.

Secondly, the number of administrations using liquid dosage forms performed in these weight/age ranges was determined.

When more than one daily dose was possible for a patient, the minimum dose was considered for the substitution analysis. It was decided that all solid dosage forms should be taken without further manipulation (e.g., no tablet crushing or capsule opening). Missing data concerning body weight were replaced using the Last Observation Carried Forward technique during the same hospital stay for a given patient. When age or weight could not be replaced, administrations were not assessed.

Size suitability

For every substitution that was possible in terms of dosage, the size suitability of the alternative solid form or, in other words, the children's ability to swallow it, was assessed. The age of the children at the time of administration was confronted with the size of the suggested solid dosage form. The standards from the Pharmaceutical Development of Medicines for Paediatric Use [9] guidelines were then used to determine if the solid dosage form was suitable (i.e., 3-5 mm diameter tablets are acceptable above 2 years , 5-10 mm diameter tablets are acceptable above 6 years, 10-15 mm diameter tablets are acceptable above 12 years, and tablets larger than 15 mm diameter are not acceptable for the entire pediatric population under 18 years of age).

Economic impact

For each drug, the cost of every suggested daily dose using the solid dosage form was compared with the cost of the same daily dose using the liquid dosage form. The cost difference of the substitution was then calculated. Potential cost savings for the hospital were also calculated, assuming that this substitution was performed at every opportunity of substitution identified.

This calculation was done by multiplying the cost difference of every daily dose by the number of real treatment days of the concerned patients. The sum of these values represents the potential cost difference for the hospital over the 3-year analysis period.

It was assumed that no medication waste occurred (all tablet sections were administered when a tablet division was needed and that the total amount of liquid in the bottles was administered in liquid dosage forms).

Results

Data on 488,762 administrations were recorded between February 6, 2013 and February 5, 2016. As shown in figure 2, a total of 121,274 oral administrations using liquid dosage forms (female: 58,737 and male: 62,538) from 129 different industrially manufactured drugs were identified over 3 years. They were given to 3,402 inpatients during 4,769 hospital stays. The mean age of children at admission was 3.9 years (SD 4.6 years). The mean duration of stay was 132 days (appendix A).

Drugs selected for substitution

Among the 129 drugs, 90 drugs were available in solid dosage forms, corresponding to 98,741 administrations in liquid dosage forms given to 3,127 inpatients. Of the 90 drugs, the 10 drugs identified as most frequently administered to children and eligible for substitution with authorized suitable alternative solid form were, in decreasing order of substitution frequency: paracetamol, cyamemazine, valproic acid, clonazepam, furosemide, prazepam, hydroxyzine, alfacalcidol, amitriptyline, and levetiracetam. Table 1 shows the categories of patients eligible for the substitution, the alternative solid form, and the number of liquid form administrations for each drug that could be performed using suitable solid dosage forms. The 10 most frequently administered drugs represent 58% (56,924/98,741) of the total drug administrations in liquid dosage forms available in solid dosage forms. Among these, 34.6% (19,671/56, 924) could be delivered using suitable solid dosage forms (the summary of the substitution assessment of the 10 drugs is presented in appendix B). There were 6 alternative solid dosage forms suitable for children aged at least 6 years old, 1 for children aged 10 to 12 years, and only 2 for younger children aged 28 days or more.

(Table 1)

Economic impact

Overall, 74.5 % (14,657/19,671) of the substitutions could be achieved with a less expensive suitable solid form. For 7 of the 10 drugs (i.e., cyamemazine, clonazepam, furosemide, prazepam, hydroxyzine, amitriptyline, and levetiracetam), all the substitutions were associated with potential savings for the hospital. Regarding paracetamol, the suggested substitutions were associated with a positive economic impact for 72% (5,066/7,045) of the administrations.

The computed potential cost savings for the hospital over 3 years was €145.6 for paracetamol, €10,537.80 for cyamemazine, €2.20 for clonazepam, €247.54 for furosemide, €18.59 for prazepam, €31.69 for hydroxyzine, €19.88 for amitriptyline, and €18.56 for levetiracetam.

For valproic acid and alfacalcidol, all suggested substitutions were associated with a negative economic impact. The potential loss for the hospital over 3 years would be €173.19 for valproic acid and €79.89 for alfacalcidol.

The cost differences of daily doses and the potential cost savings for the hospital for each of the 10 drugs are detailed in appendix C.

Discussion

This study found that about one third of the administrations of 10 drugs, frequently administered using liquid dosage forms in a pediatric population, could be substituted with at least one active, safe, and easy-to-swallow suitable solid dosage form. Notably, almost all liquid dosage forms of prazepam and cyamemazine used could be replaced with solid dosage forms (>97%).

The suggested substitutions were not found to be associated with substantial economic savings for the hospital. A large difference in costs between liquid and solid forms was observed only for cyamemazine but not for the other drugs (mean cost difference per daily dose: €6.90 for cyamemazine versus €0.2 for all the other drugs). These findings differ from those of a study in a British pediatric hospital [15] which found significant savings from drug substitution. The disparities in drug prices between various European countries and the difference in sets of studied drugs between both studies may explain this inconsistency. However, the calculation made herein did not account for the potential cost savings in terms of transportation and storage of solid dosage forms which present with decreased weights and volumes.

Unexpectedly, some highly used drugs in pediatric settings that are generally available in solid dosage forms, such as antibiotics, were not identified as appropriate for direct substitution with solid dosage forms in the present study. For example, during the 3-year period, 4,295 administrations of amoxicillin in liquid dosage forms were performed, 1,624 for rifampicin, and 1,049 for ciprofloxacin. The lack of possible substitution observed for these drugs can be explained by the fact that: the alternative solid form for amoxicillin was authorized only for children weighing 40 kg or more and no administration of amoxicillin was recorded for this category of patients; the available capsule of rifampicin was authorized only for children aged 6 years and older and only 38 administrations of rifampicin were recorded for this category of patients; ciprofloxacin was only available in large tablets (18 mm diameter for a 500 g tablet) and was not considered acceptable for the pediatric population [9] . This underlines that alternative solid forms available for very young children are still scarce, confirming the need to develop formulations specific to this group [17] .

In the present study, tablet division was considered acceptable as long as it remained in accordance with the instructions of the SmPC. Division increases the dosing flexibility of tablets. Additionally, scored tablets could provide ease in swallowing and may reduce costs.

However, they could cause inaccurate dosing depending on the manufacturing quality [18] .

The main limitation of this study is that all drug prescriptions were considered as compliant with the SmPC, as no information about the indication was available in the database, despite the frequency of off-label drug prescriptions in pediatrics. The use of a theoretical daily dose instead of the observed administered dosages of oral liquid dosage forms potentially overlooked administrations of hard-to-substitute low dosages to very young children and may have provided overestimated substitution rates. Inversely, liquid dosage forms can demonstrate different pharmacokinetic properties compared to solid dosage forms and necessitate more frequent administrations of lower dosages, which could yield artificially lower substitution rate findings. Interestingly, the substitution findings herein were lower than the 41% reported in a study based on the observed dosages in a pediatric hospital [15] . Although the criteria used were comparable to those of the present study, the sample was smaller with only 440 administrations analyzed. The use of real health data in the present study had the benefit of providing meaningful substitution assessments in an inpatient setting. It should be noted that other solid dosage forms not available in the hospital's pharmacy could be available on the market, meaning additional substitutions could be possible for outpatients or inpatients in other hospitals.

A major strength of this study lies in the fact that all suggested substitutions were completely in accordance with the drug marketing authorizations. Converting current inpatients from liquid to solid dosage forms according to the suggestions described herein is encouraged in our hospital as well as in other hospitals. Pediatricians should be informed and sensitized to the benefits of using solid forms when possible [19] . However, improvement is needed regarding the availability of mini-tablets and other flexible solid oral dosage forms of the most commonly prescribed drugs in pediatrics. Producing more tablets and capsules available in different dosages is also encouraged. This study could guide all parties involved in the development and manufacture of medicinal products to improve the availability of suitable pediatric forms by defining the real and important needs in pediatric practice. In future research, we intend to develop an algorithm which could help practitioners chose a suitable alternative solid form when possible.

Conclusion

Despite the current limited use of oral solid dosage forms in pediatric practice in the HFME in Lyon, substitution from liquid to solid forms appears feasible. The 10 drugs identified as most appropriate for substitution were: paracetamol, cyamemazine, valproic acid, clonazepam, furosemide, prazepam, hydroxyzine, alfacalcidol, amitriptyline, and levetiracetam. Solid dosage forms for these drugs could have been used in about 35% of the total administrations that occurred using liquid dosage forms. Suitable alternative solid forms are generally available for children aged 6 years and older, while more flexible oral dosage forms are still needed for younger children. We intend to develop an intelligent algorithm that could suggest the prescription of a suitable alternative solid form to practitioners, when appropriate. A number of administrations that could not be performed with an available solid dosage form was discarded from the drug selection analysis and the remaining was determined after a detailed substitution assessment. a The total drug administrations using liquid dosage forms = administrations that could be performed using suitable solid dosage forms + administrations that could not be performed with an available solid dosage form because of unappropriate age or weight.

(Article III) Efficacy and safety outcomes of dosage regimens of amikacin in neonates: a systematic review

Rama Arab

Summary

Aim of the study. -To identify amikacin dosage regimens evaluated in neonates and to describe their efficacy and safety results. Methods. -a systematic review carried out following PRISMA guidelines. A bibliographic search was conducted until March 2021 on PubMed and until April 2021 on Cochrane. All studies evaluating efficacy and safety of amikacin in neonates were considered for inclusion.

Results. -This review included 59 studies involving 7,681 neonates. Among these studies, 12 were randomized controlled trials. One included data on clinical efficacy, eight on nephrotoxicity and six on ototoxicity. Thirty-seven studies provided data on amikacin serum concentrations and nineteen provided data on achievement of target serum concentrations. Serum concentration targets were variable between studies; 15 different target ranges of peak concentrations and 13 of trough concentrations were identified. From these publications, 37 different amikacin dosage regimens were proposed, most frequently based on post-natal age and/or on body weight. Rates of reported renal function impairment varied between 0 and 70%. Rates of reported ototoxicity varied between 0 and 20%. Mean peak concentrations ranged between 9.5 and 46.7 mg/L. Mean trough concentrations ranged between 1.2 and 14.4 mg/L. Rates of target achievement ranged between 14% and 100%. Conclusion. -Numerous dosage regimens of amikacin were proposed for use in neonates. The next stage of our work will be to select the most appropriate dosage regimen based on the reported data in this systematic review.

KEYWORDS

Drug safety, Amikacin, Neonates, Optimal dosage regimen, Pharmacokinetic

Introduction:

Unlicensed or off-label drug prescriptions concern almost every infant in neonatology and can be more frequently observed as the gestational age (GA) decreases 1,2 . This is due to the lack of clinical studies in neonatology, which are difficult to conduct in new-borns for a variety of reasons, including ethics, parental permission, recruitment and lack of industrial investment 3 .

Identifying the optimal dosage regimen of a drug for a new-born is complicated in the absence of clinical evidence-based data. This should not result from a simple adjustment of adult dosing according to the new-born weight or body surface area 4,5 .

At birth, some body organs are not yet mature, especially in preterm infants. High interindividual variability in drug pharmacokinetics is observed, due to ongoing changes in neonates' organ functions 6 .

The lack of evidence-based data on drug dosage regimens in neonates results in significant discrepancies between existing guidelines and recommendations. These discrepancies have been observed in practice at both national 7 and international levels 8 . Leroux et al. observed 1 to 32 different dosage regimens per antibiotic in a survey conducted in 44-French neonatal intensive care units. For every drug used in new-borns, the optimal dosage regimen is ideally established by means of pharmacokinetic studies (PK) in neonates and validated in clinical safety and efficacy studies. A pragmatic approach to obtain acceptable data was proposed by the US Food and Drug Administration (FDA) in 1994 9,10 . This approach was based on the extrapolation of efficacy findings from adults to the paediatric population in order to maximise the use of adult data.

Amikacin is an aminoglycoside bactericidal antibiotic. It was identified as the most commonly off-label antibiotic used in the neonatal intensive care units of our hospital 2 and as 1 of the 20 drugs most frequently related to neonatal serious Adverse Drug Reactions (ADRs) reported over 26 years in the French Pharmacovigilance Database 11 . Ototoxicity and nephrotoxicity are the two major adverse events associated with amikacin therapy. These events are more likely to occur in premature new-borns. 12,13 Despite the frequent use of amikacin in neonatology to treat suspected neonatal sepsis and its serious side effects, numerous different dosage regimens are used for neonates in practice. Since amikacin has a narrow therapeutic window 14 , inaccurate dosage regimens can cause a lack of efficacy or conversely, reach toxic ranges 15 . Both efficacy and safety of amikacin depend directly on its plasma concentrations [16][17][18][19] . These concentrations depend on physiological factors in neonates, mainly on body water volume and renal function since amikacin diffuses in the extracellular space and is eliminated by glomerular filtration 14,8 . These factors are continuously changing in new-borns according to age and weight. The percentage of extracellular water to total body weight in neonates is high at birth, it then decreases then with age, influencing the amikacin volume of distribution [20][21][22] . The renal function development occurs in the gestational period and continues after birth. It is observed day-to-day in neonates and impacts amikacin clearance 23,24 . Therefore, there is a need to consider these maturational changes when establishing a dosage regimen of amikacin.

The aim of this study was to identify all dosage regimens of amikacin that have been proposed for administration in neonates in the literature and to report the relationship between the different dosage regimens and their clinical or pharmacokinetic outcomes.

Methods:

Study identification

This systematic review was conducted following the Preferred Reporting for Systematic

Results

Bibliographic search:

A total of 1658 records were identified, of which 1551 were obtained from PubMed and 107 from Cochrane databases. After eliminating duplicates as well as checking titles and abstracts, 180 records were kept for a full text review. A total of 59 articles fulfilled the inclusion criteria and were included in our review (Figure 1).

Characteristic and findings of the included studies

Objectives, designs and population

A total of 7,681 neonates received amikacin in the 59 included studies. Eighteen studies included only preterm infants, 7 included term infants and 34 included both term and preterm infants. There were 28 studies that evaluated efficacy and/or toxicity of a given dosage regimen, 22 that focused on investigating the covariables affecting amikacin serum concentrations, 10 that evaluated amikacin toxicity, 6 that investigated amikacin concentrations in extravascular compartments and 1 that evaluated treatment duration. Twenty-five studies were prospective studies 23, , 25 were retrospective studies 13,15, , 4 used a mixed methodology [73][74][75][76] , 1 was a cross-sectional study 77 and 4 had unclear designs 69,[78][79][80] . Among the prospective studies, 12

were randomised controlled trials (RCTs) [28][29][30][31][33][34][35][36][37][38][39]81 . Among the RCTs, 6 studies compared once-daily doses with multiple-daily doses, 4 compared amikacin with another antibiotic agent, 1 compared 2 durations of treatment and 1 compared the intravenous (IV) administration route with the intramuscular (IM) administration route.

Amikacin was administered intravenously in 44 studies, intramuscularly in 6 studies, intracerebroventricularly in 1 study and using different parenteral routes in 6 studies and there was no information provided regarding the route of administration in 2 studies. In 41 studies used IV route, the duration of administration was provided, 20 studies used IV infusion (>30min) and 31 studies used IV bolus (<30min), 4 of them used rapid IV bolus (< 5min) (Table 1).

Target serum concentrations

As shown in

Outcomes

Twelve studies, including four RCTs 31,35,37,81 , provided results on clinical outcomes regarding safety and efficacy, one study evaluated clinical efficacy 35 , eight reported data on renal toxicity of amikacin (measured by biological parameters) 13,28,29,31,36,37,42,68,80 , six reported data on ototoxicity 13,31,40,47,68,81 and three provided information on overall mortality 25,78,80 Other pharmaceutical outcomes were also provided by the studies: 12 studies provided results on covariables influencing amikacin pharmacokinetics, 3 studies measured amikacin concentrations in the cerebrospinal fluid and 1 in the epithelial lining fluid (Table 2).

Discussion

This systematic review confirms that limited high-quality evidence data are available regarding the efficacy and safety of amikacin dosage regimens in neonates. This explains the absence of a unique recommended dosage regimen for neonates. Only one study dealt with the clinical efficacy of amikacin to evaluate the treatment duration of a given dosage regimen. The study carried out by Pasha et al. used the treatment failure, defined as the reappearance of symptoms confirmed by laboratory findings as a primary outcome. It concluded that there is no evidence to support a duration of a five-day treatment instead of three 35 . However, since this RCT allowed excluded patients with treatment failure at the 3th day of treatment before randomization and associated amikacin with other antibiotics, it does not provide information on the efficacy of the specific dosage regimen that was used.

Rates of ototoxicity varied between 0 and 20% for 7 different dosage regimens 27,31,40,47,68,81 .

Both highest and smallest rates were reported for the same dosage regimen (15 mg/kg/24h) indicating the need for studies including larger sample sizes. Because of the small sample sizes of the studies investigating ototoxicity, it is neither possible to conclude on any relation between a dosage and ototoxicity, nor to establish a frequency level of this adverse drug reaction. The low number of studies investigating this side effect could be attributed to the fact that ototoxicity takes long time to be diagnosed, is difficult to demonstrate in neonates and is reversible in around one out of two cases 79,82 . Demonstrating ototoxicity prospectively requires patients to be followed-up for several years and a high number of participants 83 . The unique RCT investigating ototoxicity followed-up patients only until the 10 th day of treatment 81 .

However, available data seem to point that hearing alterations could be induced by a long 13 77 . These high levels of trough concentrations are more likely to be reached with short dosage intervals 37 .

Rates of renal function impairment caused by amikacin varied between 0 and 70% 13,31,37,80 .

The dosage regimen of 7.5 mg/kg/12h was the most frequently associated with reported cases of renal toxicity. 29,31,36,68,80 . The RCTs conducted by Kotze, Abdel Hady and Vasquez-Mendoza compared one-daily doses to twice-daily doses, and failed to demonstrate a significant difference in renal toxicity between both treatment groups because of their small sample sizes 28,31,37 . The frequency of the nephrotoxicity cases was associated with high levels of serum trough concentrations (>8 mg/L) in two RCTs 29,37 . Different markers were employed to detect renal toxicity of amikacin across studies, such as levels of serum creatinine and Nacetylglucosaminidase (NAG). The sensitivities of these markers were different: NAG was a sensitive marker of tubular injury, but it was not sufficient alone to predict clinical impact 31 .

On the contrary, the use of serum creatinine could underestimate the nephrotoxicity of amikacin in neonates because the increase in creatinine clearance by maturation could affect the results 84 .

Multiple cofactors could interfere with the evaluation of amikacin tolerance. Assessing nephrotoxicity could be biased by hypoxia, septic status and the specificity of markers.

Assessing ototoxicity could be difficult to highlight because of the rarity of cases, sensitivity of the tests, and time to onset. Assessing both ototoxicity and nephrotoxicity caused by the different dosage regimens of amikacin could also be biased since amikacin was also associated with other antibiotics, suggesting that trough concentrations of amikacin should always be considered.

Regarding the pharmacokinetic results, 6 dosage regimens employed in 6 studies succeeded to reach target serum concentrations established by the authors in 70% of patients for both Cpeak and Ctrough 31,45,50,[73][74][75] while 16 dosage regimens used in 13 studies 26,28,30,31,45,46,48,50,51,57,[73][74][75][76] succeeded to reach target serum concentrations in 50% of patients. The majority of these 16 dosage regimens considered one or more covariables (8 dosage regimens considered 2 covariables, 6 others considered 1 covariable). This is supported by the fact that preterm infants were expected to reach toxic concentrations more frequently compared to term infants when using the same dosage 53 . Two other dosage regimens were used in three studies 38,80,85 and achieved mean serum concentrations in the therapeutic targets defined by the authors.

Serum concentration targets were widely different across studies. The target peak concentrations of amikacin progressed over time: it was defined between 15-30 mg/L in the 80s 70,76,80 , then between 20-30 mg/L for several years 25,38,45,74 and between 24-35 mg/L in more recent studies 15,49,51,85 . Labaune et al. proposed an adaptation of the target Cmax with GA 75 .

The adoptions of these targets were not justified in the studies. It is agreed that peak concentrations of amikacin should ideally reach eight to ten times the minimum inhibitory concentration (MIC). The MIC depends on the pathogen and local bacterial resistance 86 optimal target with a target less than 10 mg/L being considered to be safe 30 . Later, another author considered a target between 4 and 10 mg/L in 1991 45 . Target trough concentrations were also adapted with GA in 2001 75 . Vucicevic et al. defined different targets according to the number of administrations per day 81 . Two strict targets less than 3 mg/L were proposed in 3 recent studies 15,46,49 .

Many covariates were found to correlate with the serum concentrations of amikacin in neonates.

These covariates reflect the changes in amikacin distribution and elimination during maturation and explain interindividual variability. The anthropometric covariates identified were weight 15,27,56,63,64,69,87 , GA 27,39,63,66,69,72 , PNA 15,66,70 , PMA and PCA 45,54,57,65,73,76 . Although PMA and PCA indirectly reflect both PNA and GA, their use could be less accurate in reflecting maturation changes before and after birth compared to the use of GA and PNA separately. Other medical conditions were also found to influence pharmacokinetic values of amikacin in neonates such as hypoxemia 27,69 , respiratory distress syndrome 67 , clinical state of the patient 88 , renal function 51,54 and the coadministration of ibuprofen, indomethacin or acetylsalicylic acid 44,58,60,62,89 . These medical conditions associated with amikacin prescriptions were considered for adjusting the dosage regimen in very few studies. De Cock et al. mentioned that the time interval between doses should be extended from 6 to 10 hours in case of asphyxia or co-administration of ibuprofen 15,46 . Illamola et al. proposed an adapted dosage regimen for neonates with renal failure 51 .

Our systematic review showed the wide range of dosage regimens of amikacin in neonates. The results could be used to select the dosage regimen of interest for clinical evaluation.

This review has several limitations. The majority of studies had a small number of participants as only 12 of the 59 studies included more than 200 patients. The small sample sizes are an obstacle to detect the impact of amikacin on organic functions. Many studies therefore did not detect toxicity. Others did but could not conclude on the onset frequency of the adverse effects for the same raison. There were only 12 RCTs included in this review, 7 of which were published before 2000, and their randomization method was not clearly reported. A total of 28 included studies were published before 2000, which means that they may not reflect the current practice. Reported duration of administration, sampling time and assay methods of serum concentrations differed between studies.

In a further step, we intend to select the most appropriate dosage regimen for term and preterm infants through a critical reading of the available data and propose to use it in our neonatal services. This selection is challenging due to the variability of their level of evidence, target ranges and types of outcomes. We did not identify a selection method that considers all these variabilities. Furthermore, no acceptable thresholds were identified for both clinical and pharmacokinetic outcomes. The definition of these thresholds by experts appears to be essential for the selection. The Delphi technique could be used for this step. Once done, we will select the most appropriate dosage regimen based on three main items: the level of evidence of the study, the consideration of specific covariables for dosing in neonates (i.e., age, weight) and the results of efficacy and safety of the drug. This proposition could be done as follows: first, by classifying the included studies according to their level of evidence as presented in Figure 2, then, by critically examining the data from the studies with the highest level of evidence to determine if it is possible to recommend a dosage regimen. This examination could be performed by a panel of two persons or with the help of the three following questions: does the dosage regimen consider specific covariable(s) for dosing in neonates? Are the results on the efficacy and safety of the drug satisfying? Is the number of patients sufficient? Each examination of a set of studies should finish either by recommending a dosage regimen or considering that it is not possible to recommend a dosage regimen from the available data. As a second option, some dosage regimens could be eliminated and other considered for further examination: the studies classified in the next lower level of quality of evidence could be included in this case. This strategy allows us to select dosage regimens with different level of evidence from published data. An assessment of the quality of the included studies will be carried out to facilitate this selection. Given the different types of included studies, the use of different assessment tools will be necessary.

Conclusion

Numerous dosage regimens of amikacin for neonates were identified. The designs, dose regimens, therapeutic targets, and types of outcomes were highly variable between studies.

Most of the studies evaluated amikacin in both term and preterm neonates. Clinical efficacy and safety of amikacin in neonates are not well studied. Our knowledge regarding the majority of dosage regimens is based on their pharmacokinetics results. High variability in target serum concentration ranges of amikacin was detected. In the next step, we intend to select the most appropriate dosage regimen among available ones based on a pre-established selection method considering the level of evidence of the study, the consideration of covariables in the dosage regimen, and the efficacy and safety results. Defining acceptable safety results of different types of outcomes by experts is recommended. Future studies would be needed to investigate the TD: 20) Group1: PNA: 0.67(0-4.3) GA: 39.9 (37-41) Group1: PNA: 0.64(0-2.8) GA: 39.9(37-41)

Group1
- 2000g 2) 3) >7d+1200-2000g 4) >7d+>2000g

Improve reporting systems

Even the best detection method becomes ineffective if it is not paired with an effective reporting system. For this reason, measures to increase current reporting rates should accompany the development of the existing pharmacovigilance detection methods. Improving ADR reporting is more important in the paediatric population because of its small population size. Many methods could be used to achieve this, such as using automated report production, continuously encouraging health-care workers to report ADRs, as well as putting in place educational interventions (e.g., training programmes, reminders, meetings, etc.), in parallel with implementing an appropriate trigger tool. These methods were shown to be effective in increasing the quality and quantity of safety reports. Educational interventions were found to be helpful in raising awareness on the necessity of reporting and in acquiring knowledge about ADRs, the reporting techniques, and the assessment methods, resulting in higher reporting rates (10-13) . A study showed that ADR reporting increased 14-fold after putting in place educational interventions including pharmacovigilance talks, pharmacists participating in patient visits, reminders, improvement of ADR-reporting format accessibility, in addition to the performance of feedback activities (14). It is noteworthy that repeating these kind of interventions is essential to keep improving reporting rates (15). It may be important as well to address all health-care professionals by these interventions. Until now, physicians have accounted for the highest number of reporters in the national pharmacovigilance databases (16).

Efforts to improve reporting require the ongoing awareness raising of healthcare professionals about the importance of drug safety monitoring in children. It also requires to take into account the existing fundamental factors influencing reporting decisions, such as the time since the medicine has been launched , the pharmacovigilance-related regulatory activity, the media attention and the indication(s) for use of the medicine (17-19).

Include triggers in prognostic and diagnostic models (article I)

The development of a tool to automatically detect ADRs using well-known multivariate ADRs. The inadequate number of reported ADRs in this dataset, the heterogeneity of their nature and the non-concordance with the identified triggers did not allow us to develop the predictive and diagnostic models using any of the strategies mentioned above (Appendix A).

We found that generating and collecting triggers then examining which of them are useful for a detection model development using already collected data may not be the most efficient way.

Moreover, the sufficiency of existing positive training for modelling or validating models should have been investigated from the beginning.

This experience suggests that one local database of collected-ADRs in hospitalised children could never be enough for such a modelling approach. Resorting to the biggest national or international pharmacovigilance databases (e.g., the WHO database [VigiBase] and the FDA Adverse Event Reporting System [FAERS]) could be necessary to identify an adequate number of ADRs of interest (e.g., serious or high-impact ADRs). Given that these big pharmacovigilance databases do not usually contain the types of data regarding patients and hospitalization as local EHRs do, the use of EHRs of patients who presented ADRs and other patients who did not may be more effective. Combining and standardising EHRs could provide a high powerful database for this type of modelling, thus improving drug safety monitoring in children (20,21).

On the ground, some expert-designed harmonisation frameworks have been recently proposed in order to harmonise dosing recommendations and consequently improve safety and efficacy of drugs prescribed to children (29,30). For example, a national database has been recently initiated in Switzerland to provide paediatric healthcare professionals with harmonised dosing recommendations on the most commonly used drugs in children. For that, an advanced standardised process was built considering both the real-life information collected on currently applied dosages and the literature data. In this initiative, recommendation decisions were made by a group of experts based on data with the highest level of evidence and the practical aspects of dosages (e.g. administration modalities and dosage frequencies in order to achieve the best possible compliance) (28). Similar initiatives are needed worldwide for all concerned drugs, ideally at the international level. Including multi-countries collected data and international clinical experiences will raise the level of evidence of recommendations.

Despite the positive impact expected from using a well-selected appropriate dosage regimen, there are clearly more studies needed to find the optimal dosage regimen of these drugs.

Adopting a complete electronic medication system (EMS) (articles I, II, III)

The adoption of a complete electronic medication system (EMS) or computerised medication, as part of an electronic health system, in hospitals is important for improving drug safety efforts in hospitalised children (31). This system is required for the use of almost all new developed methods aiming to improve the safety of medicines and the quality of care in general (e.g., implementing the method of trigger tools and implementing clinical decision support tools to select an appropriate dosage form or to recommend a dosage regimen) (32). While this system has become reality in daily practice in many hospitals in developed countries, it is not yet the case in other countries. A systematic review, published in 2018, showed that most studies requiring EHRs were performed in developed countries, referring to large differences in the adoption of the electronic health systems between countries (33). Compared to non-electronic systems, EMS offers the benefit of allowing different sources of patient data to be easily inserted and analysed, such as administrative data, clinical and laboratory information, prescription delivery, and administration (34,35). The use of EMS has already made significant contributions in promoting drug safety in hospitalised patients, including reducing the rates of prescribing errors by 1.8% (p<0.001) and administration errors by 2.7% (p=0.005) (36,37).

However, some usability challenges of such a system could contribute to medication events in hospitalised children (32). Systematic reviews covering published pharmacovigilance studies in children between 1999 and 2010 confirmed the increasing utility of routine electronic healthcare datasets for the application of pharmacovigilance methods in children (31).

Conclusion

Optimising a safer and more appropriate use of medicines in hospitalised children needs to be based on several strategies, to be implemented concomitantly, including:

Optimizing the use of the trigger tool method allowing an earlier and proactive detection of ADRs. This could be reached using pertinent, performant and computerised paediatric triggers, and implementing them in a real-time detection system. Certain triggers could be used for early detection of ADRs including prevention.

Favoring dosage forms that expose to less medication errors; solid dosage forms should be favored whenever they are available and suitable to patients.

Identifying the most appropriate dosage regimen of drugs using a pragmatic approach, especially for neonates.

(5)

  Universitaire de Bâle, Suisse Dr. Catherine Cornu, Praticien Hospitalier, Hospices Civils de Lyon, France (Président du jury)

Faculté

  Sciences et Techniques des Activités Physiques et Sportives Observatoire des Sciences de l'Univers de Lyon Polytech Lyon Ecole Supérieure de Chimie Physique Electronique Institut Universitaire de Technologie de Lyon 1 Ecole Supérieure du Professorat et de l'Education Institut de Science Financière et d'Assurances Directeur : M. F. DE MARCHI Directeur : M. le Professeur F. THEVENARD Directeur : Mme C. FELIX Directeur : M. Hassan HAMMOURI Directeur : M. le Professeur S. AKKOUCHE Directeur : M. le Professeur G. TOMANOV Directeur : M. le Professeur H. BEN HADID Directeur : M. le Professeur J-C PLENET Directeur : M. Y.VANPOULLE Directeur : M. B. GUIDERDONI Directeur : M. le Professeur E.PERRIN Directeur : M. G. PIGNAULT Directeur : M. le Professeur C. VITON Directeur : M. le Professeur A. MOUGNIOTTE Directeur : M. N. LEBOISNE

Figure 1 :

 1 Figure 1: List of the most common challenges that can be encountered during the conduct of a paediatric clinical trial proposed by Chiaruttini et al.

Figure 2 :Figure 3 :Figure 4 :Figures of the article IFigure 1 :Figure 2 :Figure 3 :Figure 4 :Figure 5 :Figures of the article IIFigure 1 :

 234123451 Figure 2: Summary of advantages and disadvantages of existing liquid and solid oral dosage forms for child use (established by Lajoinie et al.) Figure 3: Venn diagram showing the relationship between adverse events, adverse drug reactions and medication errors Figure 4: Timeline of pharmacovigilance for a drug from development (pre-market) to postmarketing use

Figure 2 :

 2 Figure 2: Flow chart of data analysis.

Figure 1 :Figure 2 :Chapter

 12 Figure 1: Flow diagram for selection of articles 111 Figure 2: Proposition of a selection method 123

Figure 3 :

 3 Figure 3: List of the most common challenges that can be encountered during the conduct

Figure 4 :

 4 Figure 4: Summary of advantages and disadvantages of existing liquid and solid oral

1 -Figure 3 :

 13 Figure 3 : Venn diagram showing the relationship between adverse events, adverse drug

Figure 4 : 3 . 2 . 1 .

 4321 Figure 4: Timeline of pharmacovigilance for a drug from development (pre-market) to

  the recent years, legal efforts have been made by regulatory agencies worldwide (119-122), aiming to encourage and facilitate conducting more RCTs in children and to reinforce the requirements to obtain safety information on drugs during these trials. Positive but not enough impacts were reported for these legalisations; The Best Pharmaceuticals for Children Act in 2002 and the Pediatric Research Equity Act in 2003 resulted in an increase in rational prescribing for children, with over 800 labelling changes registered until 2014 (123). However, the European governmental initiatives, taken until 2007, to promote the conduction of paediatric clinical research had only a limited impact on decreasing the rates of unlicensed and off-label drug use in children (124). Another recent study reviewing all currently available medicines in Germany have concluded that the new EU Paediatric regulation did not succeed in stimulating the conduction of clinical studies for medicines of which the patent had already expired,

  This chapter includes the three axes of my thesis work. This work meets the three subobjectives. It is presented in a form of scientific articles. The first two articles are already published. The third is in the process of submission. Article I meets the first sub-objective. It presents a description of available paediatric triggers and provides suggestions aiming to optimise the performance of this tool in the detection of ADRs in hospitalised children. Article II meets the second sub-objective. It identifies 10 drugs frequently administered to children in liquid dosage forms and eligible for replacement with suitable authorized solid dosage forms. Applying these replacements could contribute in reducing the rate of MEs in hospitalised children.Article III meets the third sub-objective. It provides a description of the efficacy and safety of amikacin using the different dosage regimens in neonates. These data are currently used to select the dosage regimen with the best risk-benefit balance in neonates. The adoption of the selected dosage regimen could help reduce the rate of ADRs related to the administration of amikacin in neonates.

  . -The performances of individual triggers need to be more adequately studied. The detection of ADEs through computerized triggers and/or real-time detection systems remains an emerging needed in children especially, due to frequent off-label use. © 2022 Socie ´te ´française de pharmacologie et de the ´rapeutique. Published by Elsevier Masson SAS. All rights reserved.

2 2 .

 2 MethodsSearch Strategy and Study SelectionThis systematic review was conducted by following the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The research was carried out on PubMed on June 16 th , 2019 and updated on February 27 th , 2020 and on December 07 th , 2021 using 3 search strategies to identify relevant studies. Main keywords were combined as follows: trigger tool AND (pediatric OR pediatrics OR paediatric OR paediatrics OR child OR children OR infant OR infants) AND (adverse drug event OR adverse drug events OR adverse drug reaction OR adverse drug reactions OR harm OR harms).

  triggers used, overall PPV, the PPV of the set of triggers used in the study (%), total positive triggers in the study, total positive AEs in the study, manual or automated triggers, range of individual PPVs [min, max] (an individual PPV is a PPV of one trigger in one study), list of all triggers used, and for each trigger: type, PPV, positive trigger alerts and positive AEs. Data were independently extracted by two authors of this study. When the PPV was not provided, it was calculated by dividing the number of validated AEs by the number of positive triggers.

Figure 1 :

 1 Figure 1: Flow diagram for selection of articles

Figure 2 :Figure 3 :Figure 4 :Figure 5 :

 2345 Figure 2: Warning triggers of available PPV, and PPV > 0

5 ,

 5 2016) within the pediatric unit of the teaching hospitals in Lyon, France (Hôpital Femme Mère Enfant, HFME). Information on oral drugs administered to hospitalized children was provided by the EREMI study database. EREMI is a prospective cohort of children staying at the hospital for more than 3 days, which assesses the relationship between adverse drug reactions and unlicensed or off-label drug use in hospitalized children. The EREMI database automatically and prospectively collects data on drugs administered to children between the ages of 0 and 15 years and receiving at least one drug during their hospital stay. For all children included solutions, syrups, suspensions, and emulsions. The general stages of data processing are presented in figure 1A.

Figure 1 .

 1 Figure 1. A. The general stages of data processing. B. Stages of data processing in the substitution assessment and the economic impact assessment for every identi ed drug.

Figure 2 :

 2 Figure 2: Flow chart of data analysis.

  . Safe trough concentrations less than 5 or 10 mg/L were the most frequently used for years. Target trough concentrations between 3-8 mg/L were clearly defined for the first time by Cookson et al. in 1980. Deramoudt-Dutrus et al. defined a stricter target from 2 to 5 mg/L in 1989 as an

Figure 1 :Table 1 : 1 Group1

 111 Figure 1: Flow diagram for selection of articles

5 Table 1 :

 51 Design and target population of each of the identified studies (continued)

Figure 5

 5 Figure 5

Figure 2 :

 2 Figure 2: Proposition of a selection method

  diagnostic and prognostic models is a promising strategy to reach more effective detection. The original purpose of the work, which consists in identifying triggers used in children, was to create prognostic and diagnostic models in order to predict and detect ADRs in hospitalised children, involving selected automated triggers, 'preventing' triggers for prognostic models and 'validating and reporting' triggers for diagnostic models. Two possible strategies were proposed for consideration. The first strategy consisted in targeting ADR(s), retrieving related triggers, combining the triggers with factors identified by a panel of experts based on the available knowledge about the disease, drugs, child physiology and ADRs, examining the availability of the triggers and the factors in the EREMI database, developing a model based on these triggers and testing it the EREMI database. The second strategy consisted in targeting ADR(s), identifying new prognostic and diagnostic factors (as new triggers) related to the targeted ADRs (e.g., concomitant treatments) through modelling techniques using the EREMI database, building a model combining the most performant related triggers from the literature and the new triggers, then testing, developing, and validating the model using an external database. The EREMI database was considered because it gathers hospital-based computerised data of 5127 children aged below 15 years-old, hospitalised in two hospitals located in Lyon and Paris, totalling 388 ADRs validated by an independent committee. The available dataset for use during the period of this thesis concerned Lyon inpatients only and consisted of 198 validated

  dosage regimen proposed by Hughes. et al. 2017 (not validated prospectively)

1 .

 1 Arab R, Cornu C, Kilo R, Portefaix A, Fretes-Bonett B, Hergibo F, et al.

Trigger tools to identify adverse drug events in hospitalised children: a systematic review.

  Kassai B, Kilo R, Cornu C, Gomes E, Dagonneau T.

	Therapies	[Internet].	2022	Jan	31;	Available	from:
	https://www.sciencedirect.com/science/article/pii/S0040595722000269
	2. Arab R,

Replacing liquid with solid dosage forms in pediatric practice: Feasibility and economic impact from a hospital

-based study. Therapies [Internet]. 2021 décembre ; Available from: https://www.sciencedirect.com/science/article/pii/S0040595721002651 3. Kilo R, Laporte S, Arab R, Mainbourg S, Provencher S, Grenet G, et al. Metaregression of randomized control trials with antithrombotics: weak correlation between net clinical benefit and all cause-mortality. Sci Rep. 2021 Jul 19;11(1):14728.

Table 1 :

 1 Summary of the studies included in the systematic review

Table 2 :

 2 Risk of bias summary of the included studies according to the QUADAS-2*

tool Tables of the article IITable 1 :

 1 The 10 drugs in liquid dosage forms most frequently administered to children eligible for substitution with authorized suitable alternative solid dosage

forms 96 Tables of the article IIITable 1 :

 1 Design and target population of each of the identified studies. 112

Table 2 :

 2 Dosage regimens and main findings of the included studies 117

3.1.2. Prevalence of AEs in hospitalised children 3.1.2.1. Prevalence of ADRs/ADEs

	A systematic review published in 2021 including 18 studies indicated that paediatric patients
	are easily affected by ADRs even though the majority of ADRs were preventable, and their
	severity is mostly considered minor and moderate (64).
	A recent systematic review included 26 studies, based in the UK, reported a median prevalence
	equal to 25.6% of patients (IQR 21.8-29.9) experiencing ADRs during hospitalisation; 79.2%
	of the reactions warranted withdrawal of medication (88).
	Another systematic review of studies regarding ADRs in children, published in 2001 and
	including 17 prospective studies, showed that the overall incidence of ADRs in hospitalised
	children was 9.53% (95% CI, 6.81, 12.26), with severe reactions accounting for 12.29% (95%
	CI, 8.43,16.17) of the total number of ADRs (89).
	One prospective study, which enrolled 703 patients admitted to 2 general child wards and 1
	paediatric intensive care unit at a teaching hospital in Germany, observed that 14.1% of children
	experienced an ADR during hospitalisation (90).
	The main known risk factors of the occurrence of ADRs in children are young age,
	polypharmacy, prolonged hospitalisation, being critically ill, the use of unlicensed and off-label
	medications and dosing problems.(47,64)

Table 3 : Comparison between the four detection methods according to the results of the systematic review conducted by Meyer-Massetti et al. (118)

 3

	Methods	Quantification	Resource	Time	Specificity	Sensitivity
			saving
	/advantages	of ADE		saving
	Incident	report
	review
	Direct observation				-
	Medical	chart		-		-
	review

  Two triggers were tested in more than 20 studies, 17 triggers were tested in 10 to 20 studies and 160 in fewer than 10 studies, of which 93 triggers were tested in one single study. Elevated anti-epileptic drug level, naloxone administration, early readmission and romazicon administration were the most frequently triggers studied (in 27, 23, 19 and 19 studies,

	respectively).
	For 61 triggers (34%), no PPV was available in the included studies. The mean PPV for 26
	triggers (14%) was 0. The mean PPV for 73 triggers (41%) was between 0 and 50. Only 19
	triggers (11%) had a mean PPV of 50% or more, 5 of which had a PPV of 100% (i.e., anesthesia-
	related harm, medication reaction, hallucinations/delirium/ICU syndrome, phentolamine
	administration and urinary retention).

The most common type of included triggers was laboratory abnormalities (51 triggers), 45 were related to medications, 42 to clinical signs, 18 to clinical interventions, 14 were combinations of triggers of 2 different types, and 9 were administrative data. Sixty-eight triggers were classified as warning triggers. Eighty triggers were classified as verification triggers and 31 triggers were classified as reporting triggers. Figures 2,3 and 4

Table 4 : Risk of bias summary of the included studies according to the QUADAS-2* tool

 4

	Study	Risk of bias		Applicability concerns
		Patient	Index	Reference
		selection	test	standard

Table 1 : The 10 drugs in liquid dosage forms most frequently administered to children eligible for substitution with authorized suitable alternative solid dosage forms.

 1

	Drug (NNT)	Eligible patients for the substitution	Alternative	Number of	Administrations in
				solid dosage	drug	liquid dosage forms
				form	administration	which could be
					using liquid	performed using
					dosage forms a	suitable solid dosage
						forms
		Appropriate	Appropriate			(n)	(% of total
		age range for	weight range				drug
		substitution	for				administration
			substitution				using liquid
		(kg)					dosage forms)
	Paracetamol	> = 28 days	> = 6	Powder for	12,452	7045	56.6
				reconstitution
				and
				effervescent
				tablet.
	Cyamemazine	> = 6 years	> = 6.25	Tablet	3784	3672	97
	Valproic acid	> = 28 days	(> = 3.33 and	Granule in	2792	2460	88.1
			< = 5) or	sachets
		> = 6.67
	Clonazepam	> = 6 years	>= 10	Tablet	4318	1798	41.6
	Furosemide	> = 6 years	>= 10	Tablet	21,106	1303	6.2
	Prazepam	> = 6 years	-	Tablet	1276	1276	100
	Hydroxyzine	> = 6 years > = 12.5 kg and <25 kg	Tablet	3003	1019	34
		> = 12 years and >25 kg
	Alfacalcidol	> = 6 years	> 20	Tablet	3742	575	15.4
	Amitriptyline	> = 10 years	-	Tablet	1367	437	32
	Levetiracetam	> = 12 years	> = 25 and < 50	Tablet	3084	86	2.8
	Total				56,924	19,671	35

1 , Laurent Lafarge 2 , Lilia Chiheb 1 , Catherine Cornu 1, 3 , Franck Plaisant 4, Michel Tod 1 , Behrouz Kassai 5,6 , Xavier Dode 7 , Kim-An Nguyen

  Department of Clinical Epidemiology, Hospices Civils de Lyon, 69008 Lyon, France.7 Pharmacy Department, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France.

	1
	1
	Evolutive biometry and biology laboratory, CNRS, UMR 5558, Claude Bernard Lyon 1 University,
	69008 Lyon, France.
	2
	Pharmacy Department, Condrieu Hospital, 69420 Condrieu, France
	3
	Clinical investigation centre, INSERM CIC1407, EPICIME, Department of Clinical Epidemiology
	Hospices Civils de Lyon, 69500 Bron, France.
	4
	Hôpital Femme Mère Enfant, Hospices Civils de Lyon, NICU, F-69677, Bron, France.
	5
	Public Health Pole, Hospices Civils de Lyon, 69008 Lyon, France.
	6

  Reviews and Meta-Analyses (PRISMA) Guidelines. PubMed was searched until March 2021 and Cochrane was searched until April 2021. The search formulas used to define studies on

	("Amikacin"[Mesh] Data extraction and synthesis AND	"Drug	Administration	Schedule"[Mesh])	OR
	"Amikacin/administration and dosage"[Mesh] OR "Amikacin/pharmacokinetics"[Mesh]) AND Data were extracted independently by two authors. The following information was collected
	("Neonatology"[Mesh] OR "Infant, Newborn"[Mesh] OR newborn*[Title/Abstract] OR for each eligible article: first author's name, year of publication, route of administration,
	neonat*[Title/Abstract]). The formula was simplified for Cochrane as follow: Amikacin AND number of patients, main characteristics of studied population (weight, age), study design,
	(infant OR neonate OR newborn). therapeutic target if defined in the study, amikacin dosage regimen and variables considered for
	Study selection efficacy and toxicity results: mean peak concentrations, mean trough concentrations, rate of
	Inclusion criteria were defined according to the Population, Intervention, Comparison, patients in and out of therapeutic range and other relevant findings.
	Outcome and Study (PICOS) design process, as follows:
	Participants: neonatal infants (from birth to 28 days of age), term or preterm.
	Study design: interventional studies, observational studies, prospective, retrospective, or cross-
	sectional.
	Case reports, review articles, comments or letters to editors were excluded. Meta-analyses were
	consulted to identify relevant included studies. We excluded bacteriological and
	epidemiological studies, fundamental studies, biochemical studies, infectious disease or clinical
	pathophysiological studies, studies focused on medication errors, quality, good clinical
	practices or cost-effectiveness analyses, articles that did not provide any data on dosage
	regimens of amikacin, non-human studies, articles written in languages other than English or
	French, and registered trials with no published articles.
	After screening and removing duplicates, all article titles and abstracts, and full texts were
	PubMed	were:	(aminoglycos*[title/abstract]	OR	amika*[Title/Abstract]	OR

Interventions: studies focusing on amikacin alone or associated with other drugs.

Comparison: with or without comparator.

Outcomes: mean serum concentrations, or mean extravascular concentrations, or target achievement, or other outcomes on safety and efficacy of amikacin defined by the study. independently reviewed for inclusion by two authors of this article. In case of discordance, one other author was consulted to confirm or reject the inclusion.

Table 2

 2

	Dosage regimen used
	As shown in Table 2, 37 different dosage regimens (including 2 dosing charts) were identified
	from the included studies. The dosing schedule used in most cases was 7.5 mg/kg/12h (15
	studies), while most of the remaining dosage regimens were mentioned in single studies.
	Twelve dosage regimens involved 1 covariable, 14 involved two covariables or more and 11
	did not involve any covariables. The covariables identified were patient age (GA, postnatal age
	[PNA], post-conceptional age [PCA] and post-menstrual age [PMA]) patient weight and

, 25 studies predefined target serum concentrations of amikacin, 23 predefined both target peak concentrations and target trough concentrations, and 2 predefined only target peak concentrations. We identified 15 target ranges for peak concentration and 13 for trough concentration. Target peak concentrations ranged from 15 to 40 mg/L, measured typically 30 min after the end of administration. Target trough concentrations ranged from 0 to 10 mg/L measured typically 30 min before the next administration. creatinine clearance levels. Patient weight and PNA were the most frequent covariables considered since PNA was involved in 17 dosage regimens and patient weight in 16 dosage regimens (alone or with other factors). Patient weight and PNA were involved together in 9 dosage regimens.

  .

	Most of the included studies analysed serum concentrations: 31 studies, involving 23 different
	dosage regimens measured both peak and trough concentrations of patients, 3 studies involving
	4 dosage regimens measured peak concentrations alone and 3 studies involving 2 dosage

regimens measured trough concentrations alone. Mean peak concentrations ranged between 9.5 and 46.7 mg/L. Mean trough concentrations ranged between 1.2 and 14.4 mg/L. Concerning achievement of target serum concentrations, 15 studies, involving 19 different dosage regimens, revealed rates of patients who achieved target serum concentrations, 4 studies, involving 3 different dosage regimens, showed rate of patients who did not achieve target serum concentrations. Rates of neonates who reached the target serum concentrations, defined by the authors, ranged between 14% and 100%.

Table 1 : Design and target population of each of the identified studies (continued) Design Articles Year Main objective Route and Duration of Admini- stration Target Population Nb. of Subjects and Characteristics

 1

	Group1: 1.052±0.287 Group2:	1.733±0.22 Group3: 2.311 ±0.42	Group4: 3.157 ±0.585	2.1±1 (0.6-5.4)		N.D		1.32 (0.76-2.43)	3.058 (1.500-4.080)
	Group1: GA: 27.7±1.12 Group2: GA:	32.0±0.69 Group3: GA: 35.5±0.32 Group4:	GA: 38.7±1.32	PNA: 4.1±6.8(1.0-21.0) GA: 33.1±4.4(25.0-	40.0)	PNA: 30.6(7-70)		GA: 30(26-34)	PNA : 3.8 (1-7)
	114 near-term (3 age groups: group1 GA< 31:14	group2 GA 31-34: 24 group3 GA 34 -37: 38	group4 37 -41: 38)	38 term and preterm infants		8 a Term and preterm infants with meningitis		22 preterm infants	5 term and preterm infants
	IV (30 min)			IV (30 min)		ICV		IM	IM
	DRE			DRE		EXV		DRE	DRE
	1993			1991		1981		1979	1976
				Petersen et	al 45	Wright et	al 41	Want et al	43	Sardeman	n et al. 27

Table 1 : Design and target population of each of the identified studies (continued) Design Articles Year Main objective Route and Duration of Admini- stration Target Population Nb. of Subjects and Characteristics

 1

	Birth weight (kg) Mean ± SD (min-	max)
	Observed Age:	GA (w) PNA (d) PMA (w)	Mean ± SD (min-max)

Table 1 : Design and target population of each of the identified studies (continued) Design Articles Year Main objective Route and Duration of Admini- stration Target Population Nb. of Subjects and Characteristics

 1

	Birth weight (kg) Mean ± SD	(min-max)
	Observed Age:	GA (w) PNA (d) PMA (w) Mean ± SD	(min-max)

Table 2 : Dosage regimens and main findings of the included studies

 2

	Dosage Regimen Used
	Target Serum	Concentrations (mg/L)
	Year
	First author

Table A2 : dosage regimes proposed by Illamola SM et al 2016 (not validated

 A2

	Age (PMA)	PNA	Group 1		Group 2
				Neofax2014
			0-7	18 mg/kg every 48 hr	14 mg/kg every 48 hr
			8-28	15 mg/kg every 36 hr	12 mg/kg every 36 hr
				15 mg/kg every 24 hr	12 mg/kg every 24 hr
	30-40	0-7	18 mg/kg every 36 hr	12 mg/kg every 36 hr
				15 mg/kg every 24 hr	12 mg/kg every 24 hr
			ALL	15 mg/kg every 24 hr	12 mg/kg every 24 hr
	prospectively)
	Weight (g)		Clcr (Schwartz, mL/min)
			<15	15-30	30-60	60-90	90-120
	1)	5000	80 mg/54h	80 mg/30h	85 mg/18h	80 mg/12h	90 mg/12h
	2)	4500	70 mg/54h	75 mg/30h	70 mg/18h	75 mg/12h	90 mg/12h
	3)	4000	65 mg/54h	65 mg/30h	70 mg/18h	70 mg/12h	75 mg/12h
	4)	3500	50 mg/48h	55 mg/24h	55 mg/18h	65 mg/12h	65 mg/12h
	5)	3000	45 mg/48h	45 mg/24h	50 mg/18h	55 mg/12h	60 mg/12h
	6)	2500	35 mg/48h	40 mg/24h	45 mg/18h	45 mg/12h	50 mg/12h
	7)	2000	30 mg/48h	35 mg/24h	35 mg/18h	35 mg/12h	40 mg/12h
	8)	1500	25 mg/48h	25 mg/18h	25 mg/12h	30 mg/12h	30 mg/6h
	9)	1000	15 mg/36h	20 mg/18h	20 mg/12h	20 mg/12h	20 mg/6h
	10) 500	10 mg/30h	10 mg/18h	10 mg/12h	10 mg/6h	15 mg/6h
	Weight (g)			PNA
			<7	7-14	14-21	21-28	28-80
	1)	5000	80 mg/30h	80 mg/24h	80 mg/18h	85 mg/18h	85 mg/18h
	2)	4500	75 mg/30h	75 mg/24h	75 mg/18h	75 mg/18h	80 mg/18h
	3)	4000	65 mg/30h	65 mg/24h	65 mg/18h	65 mg/18h	70 mg/18h
	4)	3500	55 mg/30h	60 mg/24h	60 mg/18h	60 mg/18h	65 mg/18h
	5)	3000	50 mg/30h	50 mg/24h	55 mg/24h	50 mg/18h	55 mg/18h
	6)	2500	40 mg/30h	40 mg/24h	45 mg/24h	45 mg/18h	45 mg/18h
	7)	2000	30 mg/36h	35 mg/24h	35 mg/24h	35 mg/18h	35 mg/18h
	8)	1500	25 mg/38h	25 mg/24h	30 mg/24h	30 mg/24h	30 mg/18h
	9)	1000	20 mg/36h	20 mg/30h	20 mg/24h	20 mg/24h	20 mg/18h
	10)	500	10 mg/36h	10 mg/24h	10 mg/24h	10 mg/18h	10 mg/12h

Table A10 : proposed dosing regimen of Labaune et al. 2001 (validated prospectively on 57 newborns)

 A10 THE FIGURES IN PARENTHESES CORRESPOND TO THE SECOND (24 H LATER) DOSE. TIME INTERVAL FIXE : 24H, FOR NEWBORNS OF PNA < 2D

BW (G)

Table A13 : Dosing regimen proposed and validated by Rozé et al. 1989 (validated prospectively on 63 patients)

 A13

	PCA (week)	Dosage regimen
	< 28	10 mg/kg/24h
	28	10 mg/kg/21h
	30	10 mg/kg/18h
	32	10 mg/kg/16h
	36	10 mg/kg/14h
	40	10 mg/kg/12h
	47	10 mg/kg/8h

Table A14 : Dosage regimen of Sardemann H et al 1976 (Validated prospectively on 5 patients)

 A14

	PNA (D)	Loading dose	maintenance
	1	7,2 mg/kg	4 mg/kg/8h
	5	9 mg/kg	5 mg/kg/8h
	10	10,7 mg/kg	6 mg/kg/8h
	15	12,5 mg/kg	7 mg/kg/8h
	20	14,3 mg/kg	8 mg/kg/8h
	25	16,1 mg/kg	9 mg/kg/8h
	30	17,9 mg/kg	10 mg/kg/8h

Table A .

 A 1: most frequent ADRs in EREMI database-Lyon and the corresponding triggers in the literature The processes of classification of the type of data and the availability in EREMI database of triggers

	Figure A.2: Medication-related Medication-related		EHR usually EHR usually	Is it a structured Is it a structured	Availability of the Availability of the
	triggers triggers			available? available?		data data	trigger in EREMI trigger in EREMI
						database database
	Angioedema or lip swelling yes Hypoglycaemia or glucose yes		no yes	No Yes
	Most frequent ADR in (EREMI-Lyon) Anti Xa >1,5 mg/dL N. cases administration Anti-allergic or Adrenaline Correspon ding trigger from the yes yes Hypokalemia yes adminstration Hypomagnesemia yes literature Anti-emetic adminstration yes Hyponatremia yes	Availability of yes the trigger (as information) in EREMI yes yes yes database yes yes	Yes Yes Yes Comments of pediatricians Yes Yes Yes
	Anticoagulant Hypotension			yes yes		yes yes	Yes No
	Antidiarrheal administration yes Hypoxia yes		yes yes	1-Low detectability: undetectable Yes No
	Antihistamine admistration yes In hospital stroke yes		yes ?	from EREMI using the trigger Yes No
	Elevated digoxine level Induced delivery		yes yes		yes ?	(information doesn't exist in the Yes No
	Withdrawal syndrome Any Insulin administration 20 laboratory withdrawal syndrome yes yes Benadryl yes Hypoglycaemia abnormalities Insulin administration and yes	no	yes yes yes yes	database), data of the mother should Yes Yes be associated. 2-this event is usually monitoring; so not interesting to Yes predictable, and there's systematic Yes
	Hypokalemia (diphenhydramine) 18 Interactions administration Laxative adminstration kidney, or liver adminstration Biopsy of bone marrow, Hypokalemi yes yes a potassium (low yes Laxative or stool softener yes	yes	yes yes no yes	build a model for that Yes Yes Usually detected in practice No Yes
	level) Biperiden, promethazine or yes Leucopenia yes		yes yes	Yes Yes
	diazepam administration Any antidote administration yes		yes	Yes
	Somnolence Calcium Magnesium level >3,5 15 non gluconate yes yes	-	yes yes	Usually not a serious event Yes Yes
	administration mEq/l
	Hypotension Abrupt medication stop 16 complication Calcium ionised >1,5 mg/dl yes hypotension no yes Mechanical ventilation yes	No yes no	interesting for the prediction, event No Undetectable in EREMI, trigger not Yes No
	Emergent C-section delivery Readmission within 30 days yes yes		no yes	usually detected No Yes
	(Neonate Only) Meperidine administraion	yes		yes	Yes
	Chloride level <80 mEq/l and rising serum creatinine	yes		yes	Yes
	Chlorphenamine Metabolic acidosis: anion	yes yes		yes yes	Yes Yes
	adminstration gap > 11 with drug cause
	Chlorphenamine Methadone administration	or	yes yes		yes yes	Yes Yes
	antihistamine adminstration Mucositis or mucosal	yes		no	No
	Constipation ulceration			yes		no	No
	Naloxone	(Narcan)	yes yes		yes yes	Yes Yes
	(treatment)\ administration
	(transplantation of organ) Narcotic admistration or	yes		yes	Yes
	Decrease in hemoglobin or benzodiazepine	yes		yes	Yes
	hematocrit > 25% adminstration
	Decreased Nausea, vomiting level	of	yes yes		no no	No No
	consciousness or pressure sores Necrotizing enterocolitis	yes		no	No

It has no marketing authorisation in the paediatric population.

Remerciements Acknowledgements:

We thank Dr Muriel Rabilloud for her support and her contribution in editing and reviewing the final manuscript as well as Linh Phuong for her participation in assessing the quality of the included studies. We would like to thank Gaëlle Siméon (LBBE-UMR5558 CNRS) for her suport in English writing and editing.

This study was supported by the Programme PAUSE (Collège de France) and the Open Health Institute. Both sponsors had no role in the study design and conduct.

ACKNOWLEDGEMENTS

Data on drug administration in hospitalized children were provided by the EREMI study database. The EREMI study was funded by the ANSM (2012 ANSM Call for Proposal Grant -Analysis of unlicensed drug use). We would like to thank the EREMI research group for their collaborative support: Corinne Alberti (Clinical Epidemiology, Inserm-U1123, APHP), Kim An Nguyen (Clinical Investigation Center, HCL), Alexis Arzimanoglou (Epilepsy, Sleep, Pediatric Neurophysiology, Inserm-U1028, CNRS-UMR5292, HCL/UCBL-Lyon 1), Yannick Aujard (Neonatology, APHP), Odile Boespflug-Tanguy (Pediatric Neurology and Metabolic Diseases, Inserm-U931, CNRS-UMR6247, APHP), Nadine Bossard (Biostatistics, CNRS UMR5558, HCL/UCBL-Lyon 1), Valentine Bréant (Pharmacy Department, HCL), Corrine Carcel (Lyon Pharmacovigilance Center, HCL), Jean-Claude Carel (Pediatric Endocrinology, Inserm-U1141, APHP), Charlotte Castellan (Clinical Investigation Center, HCL), Olivier Claris (Neonatology, EAM4128, HCL/UCBL-Lyon1), Pierre Cochat (Pediatric Nephrology/Rheumatology, IBCP-UMR 5305 CNRS, HCL/UCBL-Lyon 1), Georges Deschênes (Pediatric Nephrology, CNRS-UMR7134, APHP), Vincent Des Portes (Pediatric Neurology, CNRS-UMR5230, HCL/UCBL-Lyon 1), Sylvie Di Filippo (Cardiology, EA4173, HCL/UCBL-Lyon 1), Xavier Dode (Pharmacy Department, HCL) and the CNIHM (Drug Information National Hospital Centre, Thériaque ® ), Lamia El Amrani (Clinical Investigation Center, HCL), Pierre Fourneret (Child Psychiatry, CNRS-UMR5304, HCL/UCBL-Lyon 1), Laure Guittard (Clinical Investigation Centre, Medical Informatics, Evaluation, Research EPICIME, HCL) Emilie Henin (CNRS UMR5558, UCBL-Lyon1), Evelyne Jacqz-Aigrain (Pediatric Pharmacology and Pharmacogenetics, Clinical Investigation Center, Inserm-U1426, APHP), Etienne Javouhey (Pediatric Intensive Care Unit, UMRESTTE, HCL/UCBL-Lyon 1), Behrouz Kassai (Clinical Investigation Center, HCL), Alain Lachaux (Pediatric Hepatogastroenterology, Inserm-U1111, CNRS UMR5308, HCL/UCBL-Lyon 1), Salma Malik (Clinical Investigation Center, HCL), Catherine Michel (Computer and Information System Management, HCL), Yanis Minouni (Clinical Investigation Center, HCL), Marie-Christine Mouren-Siméoni (Child Psychiatry, APHP), Marc Nicolino (Pediatric Endocrinology and Metabolic Diseases, Inserm-U1060, HCL/UCBL-Lyon 1), Nathalie Paret (Lyon Pharmacovigilance Center, HCL), Benjamin Riche (CNRS UMR5558, HCL/UCBL-Lyon 1), Aurélie Portefaix (Clinical Investigation Center, HCL), Corinne Pulce (Toxicovigilance and Poison Control Center, HCL), Jean-Marc Sapori (Toxicovigilance and Poison Control Center, HCL), Anne-Marie Schott (Medical Informatics, Evaluation, Research EPICIME, Inserm-U1033, HCL/UCBL-Lyon1), Thierry Vial (Lyon Pharmacovigilance Center, HCL).We would also like to thank Gaëlle Siméon, Jane Corwin (LBBE-UMR5558 CNRS), and Véréna Landel (Direction de la Recherche en Santé, HCL) for their proofreading assistance.

Abbreviations

List of Figures

Aim of Thesis

The overall objective of the thesis is to present data supporting the progression toward safe prescribing and safety monitoring of medicines in hospitalised children.

This thesis has three independent sub-objectives, each of them addresses a specific problem related to the safety of medicine in paediatric inpatients and has been the subject of a scientific article.

The first sub-objective is to review all trigger tools proposed to detect ADRs in paediatric inpatients, describe their performances and propose approaches aiming to optimise their use in daily practice.

The second sub-objective is to identify the best relevant practical circumstances for the substitution from liquid to solid dosage forms in hospitalised children based on hospital database analysis and to assess the expected economic impact of this potential substitution.

The third sub-objective to provide updated literature data on the efficacy and the safety of amikacin using different dosage regimes in neonates, as a drug concerned by the need of a unique recommended dosage regimen for neonates, in the purpose to select the most appropriate dosage regimen for use.

CLINICAL PHARMACOLOGY (Article I) Trigger tools to identify adverse drug events in hospitalised children: A systematic review

Disclosure of interests:

The authors declare that they have no competing interest to 27 used in the study, the entire list of triggers was considered for this review. i 36 triggers were j only 2 triggers were k 29 triggers selected in the nal trigger tool. l 35 triggers selected in the nal trigger tool. m Sensitivity = 0.88 (% of trigger-positive charts that physicians judged to have an ADE) and = 0.44 (% trigger-negative charts that had no ADE according to physicians' review). AE: adverse event. ADE: adverse drug event.

included, our Hospital Information System (HIS) provides data on every drug and on the children's characteristics (i.e., age, weight, height) at every administration. Labile blood products, investigational drugs, and electrolyte solutions are not included in the EREMI study.

All study data are coded using untraceable anonymized numbers to respect the confidentiality The information on administration extracted concerned (i) quantity administered, (ii) measurement unit, (iii) time of administration, and (iv) route of administration. The patient information collected was sex, age, height, and weight at each administration.

Data analysis

The data recorded over 3 years were analyzed in terms of route of administration, dosage form (i.e., solid, liquid, dispersible solid form, and others), number of active ingredients, and type of preparation (i.e., industrial manufacture and extemporaneous preparation). Liquid dosage forms

Disclosure of interests:

The authors declare that they have no competing interest clinical safety or/and safety of one or more selected dosage regimens. A large number of participants would be required for these studies. providing adapted definitions and thresholds could also be considered for this method to be more effective. (1).

First author

Year

Towards earlier ADR detection (article I)

From a clinical perspective, ADRs may be detected too late with the existing ADE-detection methods. There is great interest to increase the use of earlier and proactive detection methods (including prediction), allowing prevention or faster management of occurring ADRs in present and future patients (2-5). The classification of triggers through their potential clinical use, as presented in this work, supports this orientation. Even though the use of triggers for ADR prevention needs to be validated and depends on the quality of the application of the (near) realtime detection system, numerous triggers are usable for early detection, allowing a better potential management of ADRs. However, the optimal methodology for an effective prediction of ADRs have not been identified yet (6,7). As in their retrospective use (8), the applicability and effectiveness of using triggers for early detection purposes need to be tested and validated.

Nevertheless, this real-time mode may require a reviewing of trigger definitions (decision

Informed choice of oral dosage form in children (article II)

When it comes to oral drug administration in children, most paediatric prescribers choose liquid formulations, almost automatically and without considering the other existing options (22,23).

This work encourages paediatric prescribers to switch from a preferred and generalised oral dosage form to the most appropriate dosage form for each patient among the available dosage forms. Most of the previous researches focused (24-26) on the lack of child-friendly dosage forms and the development of new forms while only a few ( 27) offered practical solutions based on available resources. From our point of view, both approaches are necessary to improve medicine safety in children. Beyond the fact that we encourage to choose solid dosage forms in children whenever it is suitable, feasible, authorised and available, we point out how important is to make better informed choices regarding oral dosage forms in children. Conducting similar studies aiming to optimise dosage form choices in children is encouraged. We admit that making the best dosage form choice for a child could be very complex since there is a lot of information to consider (e.g., the patient characteristics, the patient preferences, the swallowing capacity, the properties of the available dosage forms of the needed drug, the advantages and disadvantages of each one with regards to the patient, the disease, the clinical and psychological state of the patient and the duration of treatment). This choice needs to be made for each drug prescription. Therefore, developing an algorithm and integrating it in a clinical decision support tool to help prescribers make the best dosage form choice appears to be a very promising solution. Such an algorithm facilitates the treatment of the high amount of information.

However, establishing decision-making rules needs to be done first. The acceptability of the suggested dosage forms (of our study or those proposed by a developed algorithm) could be validated prospectively in hospitalised children. The effect of the replacement on safety (comparison between the proposed dosage forms and those chosen spontaneously by prescribers), including the probability of dosing errors, could be tested as well. Parallel to all this, investing in the development of new flexible solid oral dosage forms adapted for children use, especially for younger ones, is needed.

Projects to harmonise dosing recommendations (article III)

Despite that there is continuous advancement in understanding medicine dosage in new-borns, the journey to use the most appropriate dosage regimen in practice is slow and complicated.

Accepting the value of satisfactory regimens is a key step towards harmonising dosing recommendations and consequently practices when adequate data with high-level of evidence are unavailable. The main purpose of the data collected on the dosage regimens of amikacin was to facilitate recommending a unique dosage regimen in neonates. We continue working to reach this objective. Presently, a strategy was established to select the 'good enough' regimen of amikacin.

Ideally, projects determining the most appropriate dosage regimen in all off-label and unlicensed drugs and aiming to harmonise dosing recommendations and practices should be launched first for neonates and later for older children. Creating more sophisticated selection and harmonization processes to cover numerous drugs is possible.

Based on our ongoing experience, recommending such a dosage regimen could be very challenging. A selection process needs to be well studied and well described to avoid confusion yielded by the variability and the complexity of the available data. Implication of experts is also important when selecting a dosage regimen to recommend. The requirements of the needed experts are ideally predefined. Experiences in clinical pharmacology, methodology, the different specialties of paediatrics (infectious diseases, neonatology for the dosage regimen of amikacin) are often needed (28).

Appendices Appendices of the article (I)

Appendix A: Complete list of included triggers The suggested daily doses are the minimal acceptable doses reachable using the available solid form dosage(s). Weight ranges are calculated according to the recommended dosage provided in the summaries of product characteristics (SmPC) of the drugs, the recommended administration frequencies are respected. * proportion of the number of administrations could be performed with suitable solid form for size and dosage on the number of administrations that could be performed with acceptable solid form in terms of dosage.

Appendix

(2)

(2)

(2) 700

(3)

(3)

(3)

(3)

Appendices related to the discussion

Appendix A:

Arguments about the experience of building a model to predict/detect ADRs using

EREMI database and pediatric triggers

The work was started by identifying triggers applicable on pediatric population, in order to use them as indicators in our model. The triggers were collected (article submitted on trigger tools in pediatric). The next phase of the work was to select target ADRs to work on, feasibility difficulties have been shown in this step. The main difficulties were:

1. There is no concordance between the detected ADRs in the EREMI database and the identified triggers the literature (the indicators). (The high frequent ADRs and corresponding triggers are presented in table A and the list of ADEs presented in the available EREMI database table B) 2. The number of reported and validated events in the available EREMI database is limited (only 198 validated events in EREMI-lyon) and the fact that they do not correspond to the triggers identified in the literature increases the difficulty. 3. The nature of EIMs is very heterogeneous (in average 2,2 cases/event) (As seen in table B) which leads to insufficient positive training events for identifying new triggers when considering specific ADRs. 4. Table A presents the most frequent ADR in EREMI database, the corresponding triggers and the comments of the pediatricians. As seen, the 4 most frequent ADRs are Withdrawal syndrome (n=20), Hypokalaemia (n=18), Hypotension(n=16), and Somnolence (n=15), but we have identified from the literature only 1 trigger/by event for 3 of them, and non for somnolence (low detectability). For these events, the interest would be to predict them but three triggers don't allow to predict the events. In addition, according to the opinion of two pediatricians at the hospital, the events are not the most clinically interesting ADEs to make a diagnostic model (raisons in the table C)