Combined Pediatric and Adult Trials Submitted to the US Food and Drug Administration 2012-2018.

Despite legislation incentivizing and requiring drug companies to conduct pediatric clinical trials, there still is a 9-year delay in drug approval for pediatric labeling after the initial adult drug approval. The aim of this study was to review the experience of the US Food and Drug Administration (FDA) with combined pediatric and adult trials as a means for expediting pediatric approval and labeling. Combined pediatric and adult trials submitted to the FDA from 2012 to 2018 were reviewed. Only the publicly available labels and reviews were utilized for this analysis. Combined trials were identified for 72 products, with a total of 156 combined adult and pediatric trials. The therapeutic areas with the largest number of combined trials were in pulmonology for products reviewed under the Best Pharmaceuticals for Children Act (BPCA) and/or the Pediatric Research Equity Act (PREA), and hematology reviewed under the Orphan Drug Act (ODA). All drugs that utilized combined pediatric and adult clinical trials were approved simultaneously for both the adults and that part of the pediatric population. A separate pediatric subgroup efficacy analysis was reported in 57% and 48% of products under BPCA/PREA and the ODA, respectively, with a separate safety analysis in 48% and 38% of these products. When considering both BPCA/PREA and orphan drug studies, all the combined pediatric and adult trials allowed concurrent approval and labeling for part of the pediatric population at the time of the adult approval.

Beyond the Randomized Clinical Trial: Innovative Data Science to Close the Pediatric Evidence Gap.

Despite the application of advanced statistical and pharmacometric approaches to pediatric trial data, a large pediatric evidence gap still remains. Here, we discuss how to collect more data from children by using real-world data from electronic health records, mobile applications, wearables, and social media. The large datasets collected with these approaches enable and may demand the use of artificial intelligence and machine learning to allow the data to be analyzed for decision making. Applications of this approach are presented, which include the prediction of future clinical complications, medical image analysis, identification of new pediatric end points and biomarkers, the prediction of treatment nonresponders, and the prediction of placebo-responders for trial enrichment. Finally, we discuss how to bring machine learning from science to pediatric clinical practice. We conclude that advantage should be taken of the current opportunities offered by innovations in data science and machine learning to close the pediatric evidence gap.

Prescription Drug Shortages: Implications for Ambulatory Pediatrics.

OBJECTIVE: To describe contemporary drug shortages affecting general ambulatory pediatrics. STUDY DESIGN: Data from January 2001 to December 2015 were obtained from the University of Utah Drug Information Service. Two pediatricians reviewed drug shortages and identified agents used in ambulatory pediatrics. Shortage data were analyzed by the type of drug, formulation, reason for shortage, duration, marketing status, if a pediatric friendly-formulation was available, or if it was a single-source product. The availability of an alternative, and whether that alternative was affected by a shortage, also was noted. RESULTS: Of 1883 products in shortage during the study period, 314 were determined to be used in ambulatory pediatrics. The annual number of new pediatric shortages decreased initially but then increased to a high of 38 in 2011. Of the 314 pediatric shortages, 3.8% were unresolved at the end of the study. The median duration of resolved shortages was 7.6 months. The longest shortage was for ciprofloxacin 500-mg tablets. The most common class involved was infectious disease drugs. Pediatric-friendly dosage forms were affected in 19.1% of shortages. An alternative agent was available for 86% drugs; however, 29% of these also were affected. The most common reason for shortage was manufacturing problems. CONCLUSIONS: Drug shortages affected a substantial number of agents used in general ambulatory pediatrics. Shortages for single-source products are a concern if a suitable alternative is unavailable. Providers working in the ambulatory setting must be aware of current shortages and implement mitigation strategies to optimize patient care.

Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms.

The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints forEnterobacteriaceaein 2014, and MICs of 4 and 8 µg/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 µg/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, ≥30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 µg/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 µg/ml. Prolonged i.v. infusions may be useful for this population.

Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates.

OBJECTIVES: In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates. METHODS: Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines. RESULTS: Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age. CONCLUSIONS: The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatment.

Meropenem pharmacokinetics in the newborn.

We studied meropenem in 23 pre-term (gestational age, 29 to 36 weeks) and 15 full-term (gestational age, 37 to 42 weeks) neonates. Meropenem doses of 10, 20, and 40 mg/kg were administered as single doses (30-min intravenous infusion) on a random basis. Blood was obtained for determining the meropenem concentration nine times. Each child required other antimicrobials for proven/suspected bacterial infections. Samples were assayed by high-performance liquid chromatography analysis. Population pharmacokinetic parameter values were obtained by employing the BigNPAG program. Model building was performed by the likelihood ratio test. The final model included estimated creatinine clearance (CLcr) (Schwartz formula) and weight (Wt) in the calculation of clearance (meropenem clearance = 0.00112 x CLcr + 0.0925 x Wt + 0.156 liter/hr). The overall fit of the model to the data was good (observed = 1.037 x predicted - 0.096; r2 = 0.977). Given the distributions of estimated creatinine clearance and weight between pre-term and full-term neonates, meropenem clearance was substantially higher in the full-term group. A Monte Carlo simulation was performed using the creatinine clearance and weight distributions for pre-term and full-term populations separately, examining 20- and 40-mg/kg doses, 8- and 12-h dosing intervals, and 0.5-h and 4-h infusion times. The 8-h interval produced robust target attainments (both populations). If more resistant organisms were to be treated (MIC of 4 to 8 mg/liter), the 40-mg/kg dose and a prolonged infusion was favored. Treating clinicians need to balance dose choices for optimizing target attainment against potential toxicity. These findings require validation in clinical circumstances.

Managing drugs safely.

There is hard data to show that newborn infants are more likely than adults to experience adverse reactions to drugs. Paradoxically, drug-related legislation to ensure safe and effective drug use in humans neglected neonates until 2002, when the Best Pharmaceuticals Act for Children was signed into law in the USA. The situation for neonates should now catch up with that for adults and neonates will be prescribed more licensed drugs in the near future. If we are to be able to analyze the underlying system errors to improve the safe use of drugs in the studied patient population, reporting of adverse drug events and reactions needs to happen in a blame free environment. In addition, computerized physician order entry will certainly further improve the current situation by preventing errors in ordering, transcribing, verifying, and transmitting medication orders.

Therapeutic drug monitoring of antiretroviral therapy.

The concept of managing pharmacotherapy based on plasma drug concentrations has been used for decades in a variety of clinical settings. The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. A primary characteristic of TDM of antiretroviral drugs is that multiple agents are concomitantly used in HAART regimens. Inadequate drug concentrations may lead to evolution of drug resistance mutations and endanger present and future treatment options. A number of clinical trials have demonstrated that drug serum concentrations are an important factor in response to therapy for HIV, but whether TDM will become a tool for the routine management of HIV infection remains to be determined. This review includes an illustrative case report of measuring concentrations of antiretroviral drugs in a pediatric patient.

Determinants for drug prescribing to children below the minimum licensed age.

OBJECTIVES: In the light of the undesired effects that unlicensed and off-label drug use might have, it is necessary to study the determinants affecting the prescribing of such drugs. Prescription of drugs to children younger than the minimum licensed age may carry the highest risk of adverse reactions. To obtain insight into the factors that affect prescription of drugs to children below the minimum licensed age, we conducted a population-based case-control study. METHODS: The case-control study was nested in a cohort of 13,426 children aged 0-16 years, who were registered in the Integrated Primary Care Information (IPCI) project, a longitudinal observational general practitioners' database in the Netherlands. "Cases" were children who received a drug prescription for which they were below the minimum licensed age. To each case we matched up to four controls based on GP practice and patient age. As potential risk factors we evaluated the use of health care resources, and acute and chronic morbidity. RESULTS: We identified 447 cases who were matched to 1355 controls. The cases consulted their GPs significantly more often during the preceding half year, had more drug prescriptions, and had more specialist referrals than the controls. Respiratory diseases were the most important determinants for the prescription of drugs to children below the minimum licensed age. In adolescents, migraine and other headaches were the most important reasons. CONCLUSIONS: This study showed that children suffering from respiratory disease or migraine have the highest risk of receiving a drug prescription for which the patient is below the minimum licensed age. Regulatory authorities and the pharmaceutical industry should be stimulated to improve the evaluation of drug efficacy and safety in children.