Prospective assessment of inter-rater reliability of a neonatal adverse event severity scale.

Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005-1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS.

Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications.

BACKGROUND: Recombinant human (rh)IGF-1/IGFBP-3 protein complex, administered as a continuous intravenous infusion in preterm infants, is being studied for the prevention of complications of prematurity. METHODS: We conducted in vitro studies to evaluate the physical and chemical compatibility of rhIGF-1/IGFBP-3 with medications routinely administered to preterm neonates. In vitro mixing of rhIGF-1/IGFBP-3 drug product with small-molecule test medications plus corresponding controls was performed. Physical compatibility was defined as no color change, precipitation, turbidity, gas evolution, no clinically relevant change in pH/osmolality or loss in medication content. Chemical compatibility of small molecules was assessed using liquid chromatography (e.g., reverse-phase HPLC and ion chromatography), with incompatibility defined as loss of concentration of ≥ 10%. A risk evaluation was conducted for each medication based on in vitro compatibility data and potential for chemical modification. RESULTS: In vitro physical compatibility was established for 11/19 medications: caffeine citrate, fentanyl, fluconazole, gentamicin, insulin, intravenous fat emulsion, midazolam, morphine sulfate, custom-mixed parenteral nutrition solution (with/without electrolytes), parenteral nutrition solution + intravenous fat emulsion, and vancomycin (dosed from a 5 mg/mL solution), but not for 8/19 medications: amikacin, ampicillin, dopamine, dobutamine, furosemide, meropenem, norepinephrine, and penicillin G, largely owing to changes in pH after mixing. Small-molecule compatibility was unaffected post-mixing, with no loss of small-molecule content. For physically compatible medications, risk analyses confirmed low probability and severity of a risk event. CONCLUSION: Co-administration of rhIGF-1/rhIGFBP-3 drug product with various medications was assessed by in vitro studies using case-by-case risk analyses to determine the suitability of the products for co-administration.

The neonatal adverse event severity scale: current status, a stakeholders' assessment, and future perspectives.

To support informed decisions on drug registration and prescription, clinical trials need tools to assess the efficacy and safety signals related to a given therapeutic intervention. Standardized assessment facilitates reproducibility of results. Furthermore, it enables weighted comparison between different interventions, instrumental to facilitate shared decisions. When focused on adverse events in clinical trials, tools are needed to assess seriousness, causality and severity. As part of such a toolbox, the international Neonatal Consortium (INC) developed a first version of the neonatal adverse event severity scale (NAESS). This version underwent subsequent validation in retro-and prospective trials to assess its applicability and impact on the inter-observer variability. Regulators, sponsors and academic researchers also reported on the use of the NAESS in regulatory documents, trial protocols and study reports. In this paper, we aim to report on the trajectory, current status and impact of the NAESS score, on how stakeholders within INC assess its relevance, and on perspectives to further develop this tool.

Development and evaluation of an assessment of the age-appropriateness/inappropriateness of formulations used in children.

BACKGROUND: Medicines designed for adults may be inappropriate for use in children in terms of strength, dosage form and/or excipient content. There is currently no standardised method of assessing the age-appropriateness of a medicine for paediatric use. AIM: To develop and test a tool to assess whether a dosage form (formulation) is appropriate for children and estimate the proportion of formulations considered 'inappropriate' in a cohort of hospitalised paediatric patients with a chronic illness. METHOD: A multi-phase study: patient data collection, tool development, case assessments and tool validation. Inpatients aged 0-17 years at two UK paediatric/neonatal hospitals during data collection periods between January 2015 and March 2016. Written informed consent/assent was obtained. Medicines assessed were new or regularly prescribed to inpatients as part of their routine clinical care. All medicine administration episodes recorded were assessed using the Age-appropriate Formulation tool. The tool was developed by a consensus approach, as a one-page flowchart. Independent case assessments were evaluated in 2019. RESULTS: In 427 eligible children; 2,199 medicine administration episodes were recorded. Two assessors reviewed 220 episodes in parallel: percentage exact agreement was found to be 91.7% (99/108) and 93.1% (95/102). In total, 259/2,199 (11.8%) medicine administration episodes involved a dosage form categorised as 'age-inappropriate'. CONCLUSION: A novel tool has been developed and internally validated. The tool can identify which medicines would benefit from development of an improved paediatric formulation. It has shown high inter-rater reliability between users. External validation is needed to further assess the tool's utility in different settings.

Health Equity in Pediatric Drug Development: Translating Aspiration into Operation.

The concept of health equity-the attainment of the highest possible level of health for all members of society-requires equitable access to all aspects of healthcare, including pediatric drug development. However, many communities are under-represented in pediatric drug development programs. Barriers to participation include geographic, economic, racial/ethnic bias, legal, cultural, linguistic, and other factors. While there is no "one size fits all" approach to addressing these barriers, community engagement and collaboration is recognized by the Centers for Disease Control, the World Health Organization, and other global health organizations as a cornerstone for building a more equitable healthcare system. In this article, we will present case studies of stakeholder and community engagement in clinical research for rare diseases and other areas of healthcare, as examples of strategies and practices for actively involving under-represented communities and fostering their participation in pediatric drug development programs. These studies may serve as templates for facilitating equity in pediatric drug development from aspiration into operation.

Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial.

BACKGROUND: Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. METHODS: NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996). FINDINGS: Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). INTERPRETATION: In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. FUNDING: EU Seventh Framework Programme for research, technological development and demonstration.

The conect4children (c4c) Consortium: Potential for Improving European Clinical Research into Medicines for Children.

The need for information about new and existing drugs used in children was recognized in the European Union (EU) with the implementation of the Paediatric Regulation in 2007. In 2017, the 10-year review of the Paediatric Regulation identified barriers to the conduct of clinical trials, including delays in setting up and completing paediatric trials. Across Europe, the difficulties with clinical research are compounded by variation within countries and between countries. Ethics and regulatory review have national specificities. This paper describes the Collaborative Network for European Clinical Trials for Children (conect4children, c4c), which addresses selected difficulties in the design and conduct of paediatric clinical trials. c4c is a time-limited public-private consortium funded by the Innovative Medicines Initiative (IMI2). The elements of c4c are as follows: expert advice providing input on study design and/or paediatric development programmes (including patient involvement activities); a network of sites following harmonised procedures coordinated by National Hubs and a single point of contact for Europe; a facility for education and training for sites and trial teams; and support for managing data used by the network and a common paediatric data dictionary. c4c does not sponsor trials. c4c is taking a phased approach with careful piloting through industry and non-industry studies intended to demonstrate the viability of the network (proof-of-viability studies). c4c uses a co-design approach involving industry and academics within a clearly defined scope. A sustainable, successor organization open to all potential service users will be open for business before the end of IMI2 funding in 2024.

Big Data in the Assessment of Pediatric Medication Safety.

Big data (BD) in pediatric medication safety research provides many opportunities to improve the safety and health of children. The number of pediatric medication and device trials has increased in part because of the past 20 years of US legislation requiring and incentivizing study of the effects of medical products in children (Food and Drug Administration Modernization Act of 1997, Pediatric Rule in 1998, Best Pharmaceuticals for Children Act of 2002, and Pediatric Research Equity Act of 2003). There are some limitations of traditional approaches to studying medication safety in children. Randomized clinical trials within the regulatory context may not enroll patients who are representative of the general pediatric population, provide the power to detect rare safety signals, or provide long-term safety data. BD sources may have these capabilities. In recent years, medical records have become digitized, and cell phones and personal devices have proliferated. In this process, the field of biomedical science has progressively used BD from those records coupled with other data sources, both digital and traditional. Additionally, large distributed databases that include pediatric-specific outcome variables are available. A workshop entitled "Advancing the Development of Pediatric Therapeutics: Application of 'Big Data' to Pediatric Safety Studies" held September 18 to 19, 2017, in Silver Spring, Maryland, formed the basis of many of the ideas outlined in this article, which are intended to identify key examples, critical issues, and future directions in this early phase of an anticipated dramatic change in the availability and use of BD.

Inequalities and stillbirth in the UK: a meta-narrative review.

OBJECTIVE: To review what is known about the relationship between stillbirth and inequalities from different disciplinary perspectives to inform stillbirth prevention strategies. DESIGN: Systematic review using the meta-narrative method. SETTING: Studies undertaken in the UK. DATA SOURCES: Scoping phase: experts in field, exploratory electronic searches and handsearching. Systematic searches phase: Nine databases with no geographical or date restrictions. Non-English language studies were excluded. STUDY SELECTION: Any investigation of stillbirth and inequalities with a UK component. DATA EXTRACTION AND SYNTHESIS: Three authors extracted data and assessed study quality. Data were summarised, tabulated and presented graphically before synthesis of the unfolding storyline by research tradition; and then of the commonalities, differences and interplays between narratives into resultant summary meta-themes. RESULTS: Fifty-four sources from nine distinctive research traditions were included. The evidence of associations between social inequalities and stillbirth spanned 70 years. Across research traditions, there was recurrent evidence of the social gradient remaining constant or increasing, fuelling repeated calls for action (meta-theme 1: something must be done). There was less evidence of an effective response to these calls. Data pertaining to socioeconomic, area and ethnic disparities were routinely collected, but not consistently recorded, monitored or reported in relation to stillbirth (meta-theme 2: problems of precision). Many studies stressed the interplay of socioeconomic status, deprivation or ethnicity with aggregated factors including heritable, structural, environmental and lifestyle factors (meta-theme 3: moving from associations towards intersectionality and intervention(s)). No intervention studies were identified. CONCLUSION: Research investigating inequalities and stillbirth in the UK is underdeveloped. This is despite repeated evidence of an association between stillbirth risk and poverty, and stillbirth risk, poverty and ethnicity. A specific research forum is required to lead the development of research and policy in this area, which can harness the multiple relevant research perspectives and address the intersections between different policy areas. PROSPERO REGISTRATION NUMBER: CRD42017079228.

Assessment of long-term neurodevelopmental outcome following trials of medicinal products in newborn infants.

There is significant uncertainty over the role of assessment of long-term neurodevelopmental outcome (LTO) in neonatal clinical trials. A multidisciplinary working group was established to identify key issues in this area and to make recommendations about optimal approaches to evaluate LTO in therapeutic trials in newborns, which can be developed by sponsors and investigators with other key stakeholders. A key consideration for neonatal trials is the potential for the investigational product to cause widespread effects and drives the need to assess outcome in multiple organs. Thus investigators must assess whether the product has an impact on the brain and the potential for it to cause potential effects on LTO. Critically, is assessment of LTO an important direct therapeutic target or a safety outcome? Such decisions and outcomes need to be specific to the product being studied and use published data, only considering expert opinion when prior evidence does not exist. In designing the trial, the balance of benefits, costs, and burdens of assessments to the researcher and families need to be considered. Families and parent advocates should be involved in design and execution of the study. A framework is presented for use by all key stakeholders to determine the need, nature, and duration of LTO assessments in regulatory trials involving newborn infants.

Industry and Patient Perspectives on Child Participation in Clinical Trials: The Pediatric Assent Initiative Survey Report.

BACKGROUND: Obtaining assent from children participating in clinical trials acknowledges autonomy and developmental ability to contribute to the consent process. This critical step in pediatric drug development remains poorly understood, with significant room for improving the clarity, efficiency, and implementation of the assent process. Beyond ethical necessity of informing children about their treatment, the assent process provides the advantages of including children in discussions about their diagnosis and treatment-allowing greater understanding of interventions included in the study. A formalized assent process acknowledges the child as a volunteer and provides a forum for questions and feedback. Legal, cultural, and social differences have historically prevented the development of clear, concise, and accessible materials to ensure children understand the clinical trial design. Published guidelines on obtaining pediatric assent are vague, with many decisions left to local institutional review boards and ethics committees, underscoring the need for collaboratively designed standards. To address this need, 2 surveys were conducted to quantify perspectives on assent in pediatric clinical trials. METHODS: Two digital surveys were circulated in the United States and internationally (October 2014 to January 2015). The first survey targeted children, parents, and/or caregivers. The second polled clinical trial professionals on their organizations' experience and policies regarding pediatric assent. RESULTS: Forty-five respondents completed the child and parent/caregiver survey; 57 respondents completed the industry survey. Respondents from both surveys detailed experiences with clinical trials and the impediments to securing assent, offering potential solutions to attaining assent in pediatric patients. CONCLUSIONS: An important opportunity exists for standardized practices and tools to ensure pediatric patients make well-informed decisions regarding their participation in clinical trials, using materials appropriate to their level of understanding. These tools would establish a baseline standard for the assent process and be made available to researchers, improving their ability to secure assent from young patients.

Foley catheterisation versus oral misoprostol for induction of labour in hypertensive women in India (INFORM): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Between 62 000 and 77 000 women die annually from pre-eclampsia and eclampsia. Prompt delivery, preferably by the vaginal route, is vital for good maternal and neonatal outcomes. Two low-cost interventions-low-dose oral misoprostol tablets and transcervical Foley catheterisation-are already used in low-resource settings. We aimed to compare the relative risks and benefits of these interventions. METHODS: We undertook this multicentre, open-label, randomised controlled trial in two public hospitals in Nagpur, India. Women (aged ≥18 years) who were at 20 weeks' gestation or later with a live fetus and required delivery as a result of pre-eclampsia or hypertension were randomly assigned (1:1), via computer-generated block randomisation (block sizes of four, six, and eight) with concealment by use of opaque, sequentially numbered, sealed envelopes, to receive labour induction with either oral misoprostol 25 µg every 2 h (maximum of 12 doses) or a transcervical Foley catheter (silicone, size 18 F with 30 mL balloon). Randomisation was stratified by study centre. The catheter remained in place until active labour started, the catheter fell out, or 12 h had elapsed. If the catheter did not fall out within 12 h, induction continued with artificial membrane rupture and oxytocin, administered through a micro-drip gravity infusion set. Fetal monitoring was by intermittent auscultation. The primary outcome was vaginal birth within 24 h. Due to the nature of the interventions, masking of participants, study investigators, and care providers to group allocation was not possible. We analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01801410. FINDINGS: Between Dec 20, 2013, and June 29, 2015, we randomly assigned 602 women to induction with misoprostol (n=302) or the Foley catheter (n=300; intention-to-treat population). Vaginal birth within 24 h was more common in women in the misoprostol group than in the Foley catheter group (172 [57·0%] vs 141 [47·0%] women; absolute risk difference 10·0%, 95% CI 2·0-17·9; p=0·0136). Rates of uterine hyperstimulation were low in both the misoprostol and Foley catheter groups (two [0·7%] vs one [0·3%] cases; absolute risk difference 0·3%, 95% CI -0·8 to 1·5; p=0·566) and neonatal deaths did not differ significantly between groups (six [2·0%] vs three [1·0%] neonatal deaths; 1·0, -1·04 to 2·97; p=0·322). 17 serious adverse events (3%) were reported during the study: one case of intrapartum convulsion and one case of disseminated intravascular coagulation (both in the Foley group); ten perinatal deaths, including two stillbirths (both in the Foley catheter group) and eight neonatal deaths (n=5 in the misoprostol group and n=3 in the Foley catheter group); and five of neonatal morbidity, comprising birth asphyxia (n=3), septicaemia (n=1), and neonatal convulsion (n=1). INTERPRETATION: Oral misoprostol was more effective than transcervical Foley catheterisation for induction of labour in women with pre-eclampsia or hypertension. Future studies are required to assess whether oxytocin augmentation following misoprostol can be replaced by regular doses of oral misoprostol tablets. FUNDING: Medical Research Council, Department for International Development, and Wellcome Trust Joint Global Health Trials Scheme.

Development of the Liverpool Adverse Drug Reaction Avoidability Assessment Tool.

AIM: To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings. METHODS: The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the 'gold standard' (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist). MAIN OUTCOME MEASURES: Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories. RESULTS: Preliminary work-Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52-90%. Phase 3: Percentage exact agreement ranged from 35-70%. Overall, individuals had better agreement with the 'gold standard'. CONCLUSION: Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups.

Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design.

BACKGROUND AND OBJECTIVE: The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. METHODS: Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. RESULTS: Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. CONCLUSION: Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.

Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age.

Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

Comparison of two alternative study designs in assessment of medicines utilisation in neonates.

BACKGROUND: Estimates of prevalence are known to be affected by the design of cross-sectional studies. A pan-European study provided an opportunity to compare the effect of two cross-sectional study designs on estimates of medicines use. METHODS: A Service evaluation survey (SES) and a web-based point-prevalence study (PPS) were conducted as part of a European study of neonatal exposure to excipients. Neonatal units from all European Union countries plus Iceland, Norway, Switzerland and Serbia were invited to participate. All medicines prescribed to neonates were recorded during three-day and one-day study periods in the SES and PPS, respectively. In the PPS individual demographic and prescription data were also collected.To compare the probabilities that a particular medicine would be reported by each study multilevel mixed effects logistic regression models with crossed random effects were applied. The relationship between medicines exposure at the unit and individual levels in the PPS data was assessed using polynomial regression with square root transformation. RESULTS: Of 31 invited countries 20 and 21 with 115 and 89 units joined the SES and PPS, respectively. Out of 5,572,859 live births in invited countries in 2010 a higher proportion was covered by units participating in the SES compared to the PPS (11% vs 6%, respectively; OR 1.89; 95% CI 1.87-1.89). A greater number of active pharmaceutical ingredients (API), manufacturers and trade names were registered in the SES compared to the PPS. High correlation between the two studies in frequency of use for each specified API was seen (R2 = 0.86). The average probability of a department to use a given API was greater in the SES compared to the PPS (OR 2.36; 95% CI 2.05-2.73) with higher frequency of use and longer average duration of prescription further increasing the difference. The polynomial regression model described the correlation between APIs exposure on unit and individual level well (R2 = 0.93). CONCLUSION: The simple data structure and longer study period of the SES resulted in improved recruitment and higher likelihood of capture for a given API. The frequency of use at the unit level appears a good surrogate of individual exposure rates.

Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence.

BACKGROUND: A lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice. METHOD: A structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses' experiences and views. RESULTS: The observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance. CONCLUSION: Manipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence-based guidance for manipulations of medicines in children.

The manipulation of drugs to obtain the required dose: systematic review.

AIM: To describe the development of a systematic review protocol that maps the evidence relating to drug manipulations conducted to obtain the required dose. This process included defining a search strategy and methods to assess the quality and to synthesize the evidence retrieved. BACKGROUND: Economic constraints mean that marketed formulations may not meet the needs of all patients. Consequently, it is sometimes necessary to manipulate marketed products with the aim of obtaining the required dose. Most clinical practice appears to be guided by ad hoc approaches and informal literature reviews. METHODS: This systematic review protocol has been designed to identify the evidence available on drug manipulation. The review aims to identify what evidence is available and where the gaps appear in the current evidence. This report describes the challenges of developing a systematic review in an area that potentially involves many drugs and considers outcomes other than effectiveness. In particular, searches required the use of non-specific terms and the iterative development of a complex search strategy. The development of quality assessment criteria is also described. Funding commenced in April 2009. DISCUSSION: The systematic review described here will capture a broad selection of research about drug manipulations and may also be of interest to those conducting reviews in broad remit subject areas that are not easy to define using accepted terminology.

Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool.

AIM: To develop and test a new adverse drug reaction (ADR) causality assessment tool (CAT). METHODS: A comparison between seven assessors of a new CAT, formulated by an expert focus group, compared with the Naranjo CAT in 80 cases from a prospective observational study and 37 published ADR case reports (819 causality assessments in total). MAIN OUTCOME MEASURES: Utilisation of causality categories, measure of disagreements, inter-rater reliability (IRR). RESULTS: The Liverpool ADR CAT, using 40 cases from an observational study, showed causality categories of 1 unlikely, 62 possible, 92 probable and 125 definite (1, 62, 92, 125) and 'moderate' IRR (kappa 0.48), compared to Naranjo (0, 100, 172, 8) with 'moderate' IRR (kappa 0.45). In a further 40 cases, the Liverpool tool (0, 66, 81, 133) showed 'good' IRR (kappa 0.6) while Naranjo (1, 90, 185, 4) remained 'moderate'. CONCLUSION: The Liverpool tool assigns the full range of causality categories and shows good IRR. Further assessment by different investigators in different settings is needed to fully assess the utility of this tool.

Neonatal drug development.

Drug development is crucial to improving the care given to neonates through new and existing medicines. Pressure from regulatory agencies has improved the way in which pharmaceutical companies work with neonates. This provides new opportunities for the neonatal community. This paper describes the issues that arise during the development of new drugs and considers how the contemporary approach to new drugs can inform research on existing drugs.