Debbie Avant

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.

Pediatric information in drug product labeling.

To the Editor: The dearth of information on drugs for children led to children being called “therapeutic orphans.” In 1975, Wilson determined that 78% of drug labeling had inadequate pediatric information. In 1999, Wilson summarized 25 years of efforts to get pediatric information into labeling and extended his analysis. In the decade after Wilson’s review, regulations and legislation have led to more pediatric studies and labeling. We hypothesized that a higher percentage of labeling has information on use in children compared with the analyses by Wilson in 1975 and in 1999. Methods. We evaluated labeling in the June 2009 electronic Physicians’ Desk Reference (ePDR) using methods established by Wilson in analyzing the 1973 print PDR. Labeling was categorized as adequate if it stated that the drug was approved for pediatric use, had been studied, or had safety, efficacy, or dosing information for all appropriate pediatric populations; and inadequate if labeling lacked data on dosing, safety, or efficacy in at least 1 pediatric subpopulation. Partially labeled was a subgroup of inadequately labeled and defined as adequate labeling for at least 1 but not all appropriate pediatric subpopulations. Labeling in the ePDR was reviewed by 3 people (A.N.S., D.A., W.R.). Differences were reviewed by a fourth person who made final assignments (M.D.M.). The was 0.91. Topicals, nasal sprays and most over-the-counter products were excluded per the methods of Wilson. In products with multiple formulations, only 1 likely to be used in children (ie, oral formulation) was analyzed. Because limitations in the ePDR may lead to an underestimate of pediatric labeling, 2 subanalyses were performed. First we excluded products on the US Food and Drug Administration’s (FDA’s) list of Products Deemed Not Relevant to Pediatrics. Second, we compared the ePDR list with the FDA’s Pediatric Labeling Changes Table (February 1998-June 2009), which reflects only pediatric legislative initiatives and is not comprehensive, to determine whether most new pediatric labeling changes were included in the ePDR. Similar to Wilson, we also assessed the labeling for all new molecular entities (NMEs) approved between 2002 and 2008 to determine if the product might be used in pediatrics and the adequacy of the pediatric information. Results. There were 1264 trade name products in the ePDR. After excluding 510 products (consistent with the approach by Wilson) and 194 multiple formulation products, 560 products in the ePDR were analyzed. Of these, 231 (41%; 95% CI, 37%-45%) were adequately labeled and 29 (5%; 95% CI, 3%-7%) were partially labeled for pediatric use. Therefore, 260 (46%; 95% CI, 42%-51%) products had some information on pediatric use in labeling. If products deemed not relevant to pediatrics were removed, 231 of 461 (50%; 95% CI, 46%-55%) were adequately labeled for pediatric use, 29 (6%; 95% CI, 4%-9%) were partially labeled; and 260 (56%; 95% CI, 52%-61%) had some pediatric labeling. If 72 products with pediatric labeling from the Pediatric Labeling Changes Table that were not in the ePDR were added, 303 (57%; 95% CI, 53%-61%) products were adequately labeled, 29 (5%; 95% CI, 4%7%) were partially labeled, and 332 (62%; 95% CI, 58%66%) had some pediatric information. Between 2002 and 2008, the FDA approved 142 NMEs; 105 (74%) were deemed to have potential pediatric use and 43 (41%) had pediatric information in the labeling (TABLE). Comment. In 2009, only 46% of products in the ePDR had some information on pediatric use in labeling. Progress has been made since 1975, when only 22% were labeled. Of NMEs with pediatric labeling, the increase from 20% in 1999 to 41% in 2009 is also an improvement. Our estimate of the true percentage of products with pediatric labeling information is probably an underestimate because many commonly used products were excluded from the analysis and not all products are listed in the ePDR. Labeling with pediatric information in only 46% of products is still insufficient. Legislation to increase pediatric clinical trials and require the resulting information be added to labeling is necessary. The current legislation expires in 2012 without reauthorization.

Drug Labeling and Exposure in Neonates

IMPORTANCE Federal legislation has led to a notable increase in pediatric studies submitted to the Food and Drug Administration (FDA), resulting in new pediatric information in product labeling. However, approximately 50% of drug labels still have insufficient information on safety, efficacy, or dosing in children. Neonatal information in labeling is even scarcer because neonates comprise a vulnerable subpopulation for which end-point development is lagging and studies are more challenging. OBJECTIVE To quantify progress made in neonatal studies and neonatal information in product labeling as a result of recent legislation. DESIGN, SETTING, AND PARTICIPANTS We identified a cohort of drug studies between 1997 and 2010 that included neonates as a result of pediatric legislation using information available on the FDA website. We determined what studies were published in the medical literature, the legislation responsible for the studies, and the resulting neonatal labeling changes. We then examined the use of these drugs in a cohort of neonates admitted to 290 neonatal intensive care units (NICUs) (the Pediatrix Data Warehouse) in the United States from 2005 to 2010. EXPOSURE Infants exposed to a drug studied in neonates as identified by the FDA website. MAIN OUTCOMES AND MEASURES Number of drug studies with neonates and rate of exposure per 1000 admissions among infants admitted to an NICU. RESULTS In a review of the FDA databases, we identified 28 drugs studied in neonates and 24 related labeling changes. Forty-one studies encompassed the 28 drugs, and 31 (76%) of these were published. Eleven (46%) of the 24 neonatal labeling changes established safety and effectiveness. In a review of a cohort of 446,335 hospitalized infants, we identified 399 drugs used and 1,525,739 drug exposures in the first 28 postnatal days. Thirteen (46%) of the 28 drugs studied in neonates were not used in NICUs; 8 (29%) were used in fewer than 60 neonates. Of the drugs studied, ranitidine was used most often (15,627 neonates, 35 exposures per 1000 admissions). CONCLUSIONS AND RELEVANCE Few drug labeling changes made under pediatric legislation include neonates. Most drugs studied are either not used or rarely used in US NICUs. Strategies to increase the study of safe and effective drugs for neonates are needed.

Safety and Transparency of Pediatric Drug Trials

OBJECTIVES To quantify the frequency and type of new safety information arising from studies performed under the auspices of the Pediatric Exclusivity Program, to describe the dissemination of these findings in the peer-reviewed literature and compare this with the US Food and Drug Administration (FDA) review, and to describe their effect on pediatric labeling. DESIGN Cohort study of the 365 trials performed for 153 drugs. SETTING The Pediatric Exclusivity incentive from December 1997 through September 2007. PARTICIPANTS Food and Drug Administration publicly available records and peer-reviewed literature retrievable by MEDLINE search. Main Exposures New safety findings obtained from the trials completed for exclusivity. OUTCOME MEASURES Concordance of the information highlighted in the peer-reviewed article abstracts with the information in the FDA labeling and drug reviews. RESULTS There were 137 labeling changes; we evaluated 129 of these (the 8 selective serotonin reuptake inhibitors were excluded from review). Thirty-three products (26%) had pediatric safety information added to the labeling. Of these, 12 products had neuropsychiatric safety findings and 21 had other important safety findings. Only 16 of 33 of these trials (48%) were reported in the peer-reviewed literature; however, 7 of 16 focused on findings substantively different from those highlighted in the FDA reviews and labeling changes. CONCLUSIONS Medication adverse events in children often differ from those in adults, particularly those that are neuropsychiatric in nature. Labeling changes for pediatric use demonstrate that pediatric drug studies provide valuable and unique safety data that can guide the use of these drugs in children. Unfortunately, most of these articles are not published, and almost half of the published articles focus their attention away from the crucial safety data.

Impact of Pediatric Exclusivity on Drug Labeling and Demonstrations of Efficacy

BACKGROUND: Besides vaccines and otitis media medicines, most products prescribed for children have not been studied in the pediatric population. To remedy this, Congress enacted legislation in 1997, known as pediatric exclusivity (PE), which provides 6 months of additional market protection to drug sponsors in exchange for studying their products in children. METHODS: We reviewed requests for pediatric studies and subsequent labeling for drugs granted PE from 1998 through 2012. Regression analysis estimates the probability of demonstrating efficacy in PE trials. Variables include therapeutic group, year of exclusivity, product sales, initiation process, and small disease population. RESULTS: From 1998 through 2012, the US Food and Drug Administration issued 401 pediatric study requests. For 189 drugs, studies were completed and granted exclusivity. A total of 173 drugs (92%) received new pediatric labeling, with 108 (57%) receiving a new or expanded pediatric indication. Three drugs had non-efficacy trials. Efficacy was not established for 78 drugs. Oncology, cardiovascular, and endocrine drugs were less likely to demonstrate efficacy (P < .01) compared with gastrointestinal and pain/anesthesia drugs. Drugs studied later in the program were less likely to demonstrate efficacy (P < .05). Sales, initiation process, and small disease population were not significant predictors. CONCLUSIONS: Most drugs (173; 92%) granted exclusivity added pediatric information to their labeling as a result of PE, with 108 (57%) receiving a new or expanded pediatric indication. Therapeutic area and year of exclusivity influenced the likelihood of obtaining a pediatric indication. Positive and negative outcomes continue to inform the construct of future pediatric trials.

Predicting neonatal pharmacokinetics from prior data using population pharmacokinetic modeling

Selection of the first dose for neonates in clinical trials is very challenging. The objective of this analysis was to assess if a population pharmacokinetic (PK) model developed with data from infants to adults is predictive of neonatal clearance and to evaluate what age range of prior PK data is needed for informative modeling to predict neonate exposure. Two sources of pharmacokinetic data from 8 drugs were used to develop population models: (1) data from all patients > 2 years of age, and (2) data from all nonneonatal patients aged > 28 days. The prediction error based on the models using data from subjects > 2 years of age showed bias toward overprediction, with median average fold error (AFE) for CL predicted/CLobserved greater than 1.5. The bias for predicting neonatal PK was improved when using all prior PK data including infants as opposed to an assessment without infant PK data, with the median AFE 0.91. As an increased number of pediatric trials are conducted in neonates under the Food and Drug Administration Safety and Innovation Act, dose selection should be based on the best estimates of neonatal pharmacokinetics and pharmacodynamics prior to conducting efficacy and safety studies in neonates.

The impact of the written request process on drug development in childhood cancer

The Food and Drug Administration (FDA) Modernization Act, enacted in 1997, created a pediatric exclusivity incentive allowing sponsors to qualify for an additional 6 months of marketing exclusivity after satisfying the requirements outlined in the Written Request (WR). This review evaluates the impact of the WR mechanism on the development of oncology drugs in children.

Globalization Facilitates Pediatric Drug Development in the 21 st Century

Introduction: US legislation, supported by strengthened ethical frameworks and improved trial design, has produced significant increases in the number of pediatric clinical trials. This has global implications. Method: We reviewed all submissions of pediatric data received by the US FDA from 2002 to 2007 in response to new FDA pediatric initiatives. Results: Although 54% of the trials were multinational, the US dominated as a trial location. The European Union and Latin America followed. Few trials specifically studied neonates, infants, and toddlers. Conclusion: Although most pediatric drug programs are global, the United States remains the dominant location for pediatric trials. This distribution differs for adult trials. The balance may change in the future. EU and FDA regulators should continue to discuss coordinated approaches to minimize unnecessary pediatric trials and to optimize trial design, safety, and conduct so that the limited pediatric populations available are enrolled only in ethically implemented, scientifically important trials.

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.

Neonatal Safety Information Reported to the FDA During Drug Development Studies

Background: Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015. Methods: FDA databases were searched for BPCA and/or PREA studies that enrolled neonates. Studies that enrolled a minimum of 3 neonates were analyzed for the presence and content of neonatal safety data. Results: The analysis identified 40 drugs that were studied in 3 or more neonates. Of the 40 drugs, 36 drugs received a pediatric labeling change as a result of studies between 1998 and 2015, that included information from studies including neonates. Fourteen drugs were approved for use in neonates. Clinical trials for 20 of the drugs reported serious adverse events (SAEs) in neonates. The SAEs primarily involved cardiovascular events such as bradycardia and/or hypotension or laboratory abnormalities such as anemia, neutropenia, and electrolyte disturbances. Deaths were reported during studies of 9 drugs. Conclusions: Our analysis revealed that SAEs were reported in studies involving 20 of the 40 drugs evaluated in neonates, with deaths identified in 9 of those studies. Patients enrolled in studies were often critically ill, which complicated determination of whether an adverse event was drug-related. We conclude that the traditional means for collecting safety information in drug development trials needs to be adjusted for neonates and will require the collaboration of regulators, industry, and the clinical and research communities to establish appropriate definitions and reporting strategies for the neonatal population.