Dianne Murphy

Trends of Outpatient Prescription Drug Utilization in US Children, 2002–2010

OBJECTIVE: To describe trends in outpatient prescription drug utilization in US children and the changes in major areas of pediatric therapeutic use for the years 2002 through 2010. METHODS: Large prescription databases (the IMS Vector One: National and Total Patient Tracker) were used to examine national drug utilization patterns for the US pediatric population (ages 0–17 years) from 2002 through 2010. RESULTS: In 2010, a total of 263.6 million prescriptions were dispensed to the US pediatric population, 7% lower than in 2002, while prescriptions dispensed to the adult population increased 22% during the same time. Analysis of pediatric drug utilization trends for the top 12 therapeutic areas in 2010 compared with 2002 showed decreases in systemic antibiotics (–14%), allergies (–61%), pain (–14%), depression (–5%), and cough/cold without expectorant (–42%) prescriptions, whereas asthma (14%), attention-deficit/hyperactivity disorder (46%), and contraceptive (93%) prescriptions increased. In 2010, amoxicillin was the most frequently dispensed prescription in infants (aged 0–23 months) and children (aged 2–11 years). Methylphenidate was the top prescription dispensed to adolescents (aged 12–17 years). Off-label use was identified, particularly for lansoprazole; ∼358 000 prescriptions were dispensed in 2010 for infants <1 year old. CONCLUSIONS: Changes in the patterns of pediatric drug utilization were observed from 2002 to 2010. Changes include a decrease in antibiotic use and an increase in attention-deficit/hyperactivity disorder medication use during the examined time. This article provides an overview of pediatric outpatient drug utilization, which could set the stage for further in-depth analyses.

Improving Pediatric Dosing Through Pediatric Initiatives: What We Have Learned

OBJECTIVE. The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling. METHODS. We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing. RESULTS. The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had ≥1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics. CONCLUSIONS. Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.

Age and Risks of FDA-Approved Long-Acting β2-Adrenergic Receptor Agonists

OBJECTIVE: To determine the risk, by age group, of serious asthma-related events with long-acting β2-adrenergic receptor agonists marketed in the United States for asthma. METHODS: The US Food and Drug Administration performed a meta-analysis of controlled clinical trials comparing the risk of LABA use with no LABA use for patients 4 to 11, 12 to 17, 18 to 64, and older than 64 years old. The effects of age on a composite of asthma-related deaths, intubations, and hospitalizations (asthma composite index) and the effects of concomitant inhaled corticosteroid (ICS) use were analyzed. RESULTS: One hundred ten trials with 60 954 patients were included in the meta-analysis. The composite event incidence difference for all ages was 6.3 events per 1000 patient-years (95% confidence interval [CI]: 2.2–10.3) for using LABAs compared with not using LABAs. The largest incidence difference was observed for the 4- to 11-year age group (30.4 events per 1000 patient-years [95% CI: 5.7–55.1]). Differences according to age were statistically significant (P = .020). Results for the subgroup of patients with concomitant ICS use (n = 36 210) were similar to the overall results; with assigned ICSs (n = 15 192), the incidence difference was 0.4 events per 1000 patient-years (95% CI: −3.8 to 4.6), and there was no statistically significant difference according to age group. CONCLUSIONS: The excess of serious asthma-related events attributable to LABAs was greatest among children. Additional data are needed to assess risks of LABA use for children with simultaneous ICS use.

Paediatric Labelling Requirements

SummaryThe US Food and Drug Administration (FDA) has proposed new labelling regulations that describe alternative approaches for providing additional information to support labelling a drug, already approved for use in adults, for use in children. Therefore, the study of drugs in paediatric populations may now be encouraged. Paediatric pharmacokinetic studies are an important part of these trials. This action by the FDA may help resolve the ethical and technological concerns about the performance of clinical trials in children, and may render paediatric clinical trials more feasible. Most investigations in children are opportunistic in nature and their design is often constrained by a requisite noninvasive approach.Appropriately applied population-based techniques for both pharmacokinetic and pharmacodynamic data analysis may represent the most robust approach for generating a sufficiently large and accurate database for the use of new or old drugs in paediatric patients. Accordingly, this information, which is crucial for paediatric labelling of any drug product, must be obtained in infants and children if we are to truly individualise therapy for paediatric patients.The funding of 6 Pediatric Pharmacology Research Units by the US National Institutes of Health, and guidelines for application of pharmacokinetic methods to children may further contribute to the performance of paediatric clinical trials.

Migraine Therapeutics in Adolescents A Systematic Analysis and Historic Perspectives of Triptan Trials in Adolescents

OBJECTIVES To conduct a systematic review and analysis of trial data submitted to the US Food and Drug Administration (FDA) to identify possible causes for the failure of pediatric trials of triptans for treatment of migraines. DATA SOURCE The FDA website for drug information and published literature. STUDY SELECTION All pediatric efficacy and pharmacokinetics trial data of drugs used for abortive treatment of migraine submitted to the FDA from January 1, 1999, through December 31, 2011. MAIN OUTCOME MEASURES Patient demographic baseline characteristics, inclusion and exclusion criteria, trial designs, efficacy end points, and pharmacokinetic profiles were analyzed and compared across drug products. RESULTS We analyzed data for sumatriptan succinate nasal spray and zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate tablets. Seven efficacy trials had a randomized, double-blinded, placebo-controlled, parallel-group trial design. In 4 trials, patients were required to have a history of migraine attacks lasting at least 4 hours. High response rates for placebo were observed in all trials, with pain relief at 2 hours ranging from 53% to 57.5%. Nonrandomization of patients with an early placebo response design was used in the rizatriptan trial in 2011. Compared with the rizatriptan trial conducted in 1999, the 2011 rizatriptan trial reduced the placebo response rate by 6% for headache freedom at the 2-hour posttreatment end point owing to study design. The pharmacokinetic profiles between adolescents and adults were statistically similar. CONCLUSIONS High placebo response rates are consistent across all trials and may represent the principal challenge in pediatric trials of drugs for abortive treatment of migraine. Enrichment with selection of subjects with long-lasting migraine attacks is not sufficient to overcome high placebo response rates. Another enrichment strategy, the nonrandomization of patients with an early placebo response, successfully reduces the high placebo response rate for rizatriptan and is a trial design that should be considered for future pediatric trials of abortive migraine therapeutics.

US Food and Drug Administration Approval of Ciprofloxacin Hydrochloride for Management of Postexposure Inhalational Anthrax

In August 2000, the US Food and Drug Administration (FDA) approved ciprofloxacin hydrochloride (Cipro; Bayer) for management of postexposure inhalational anthrax. This was the first antimicrobial drug approved by the FDA for use in treating an infection due to a biological agent used intentionally. The terrorist attacks of 2001 involving anthrax underscore the imperative that safe and effective drugs to manage such infections be readily available in the United States. The approval of ciprofloxacin hydrochloride, which was made on the basis of a surrogate human marker of efficacy, made extensive use of data from an animal model of disease. This represents a new direction in the development of efficacy data in support of drug approval and facilitates the availability of those drugs for which there is an urgent need. This article presents the scientific data and regulatory mechanism that supported the approval of ciprofloxacin hydrochloride for management of postexposure of inhalational anthrax.

Current regulatory policies regarding pediatric indications and exclusivity.

Pediatric studies have resulted in changes in the dose of many medications given to children and an increased awareness of safety issues. An additional 6 months of pediatric exclusivity legislated under the Food and Drug Administration (FDA) Modernization Act of 1997 for pediatric studies undertaken in response to written requests from the FDA have stimulated the conduct of a large number of studies.

Pediatric Medicine Development: An Overview and Comparison of Regulatory Processes in the European Union and United States

Pediatric legislation in the US and the EU is driving pediatric product development on an international scale. To facilitate harmonization and global development of pediatric medicines, it is important to understand the legislative requirements that must be met along with incentives that exist in the US and the EU to include pediatric patients in therapeutic clinical trials. Although there are many similarities, differences exist. This review is an effort to enhance understanding of the pediatric legislation in both regions. It is intended as an overview to supplement the region-specific legislation and guidance documents that are available on the websites of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite differences, the goal of the legislation in both the EU and the US is to incentivize and require timely, ethical, and sound scientific development of pharmaceutical products for the pediatric population and to provide information for their safe and effective use.

FDA Safety Reviews on Drugs, Biologics, and Vaccines: 2007–2013

BACKGROUND AND OBJECTIVES: In 2002, Congress mandated that the US Food and Drug Administration (FDA) monitor postmarketing pediatric adverse events and present safety reports to the FDA’s Pediatric Advisory Committee (PAC). These safety reviews play a critical role in the postmarketing surveillance and identification of pediatric safety issues. This article follows a previous review ending in 2007 and summarizes 6 years of recent pediatric safety reporting, recommendations by the PAC, and actions by the FDA, including labeling changes. METHODS: An analysis of the FDA’s PAC safety reviews performed from November 2007 through September 2013 was conducted. PAC recommendations for subsequent labeling changes, future studies, or other safety issues were reviewed. RESULTS: There were 6930 serious adverse event reports in 181 reviews. These findings resulted in 33 (18%) recommended labeling changes, and 21 (64%) of these changes were adopted. For 10 products, information was added to the Warning and Precautions section of the label. The PAC also discussed or recommended additional studies for certain products. CONCLUSIONS: This article highlights the importance of the FDA’s ongoing pediatric postmarketing safety reviews of regulated products, advice from the PAC, and FDA actions in the best interest of pediatric patients. This mandated process facilitates detection of safety concerns that may not be identified in prelicensure clinical trials. It continues to identify critical safety concerns, including unlabeled adverse events, frequent off-label use, product misuse, and secondary exposures in children.

Pediatric registries at the Food and Drug Administration: design aspects that increase their likelihood of success.

To determine aspects of the design of pediatric registries that contribute to the success of registries conducted as a postmarketing study following approval of drugs or biological products by the US Food and Drug Administration.