M. Dianne Murphy

Extrapolation of Adult Data and Other Data in Pediatric Drug-Development Programs

OBJECTIVES: In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time. METHODS: We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling. RESULTS: Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and partial for 68% of them (113 of 166). Approaches to extrapolation changed over time for 19% of the therapeutic indications studied (13 of 67). When extrapolation was used, 61% of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group; this number decreased to 34% (10 of 29) when there was no extrapolation. CONCLUSIONS: Extrapolating efficacy from adult data or other data to the pediatric population can streamline pediatric drug development and help to increase the number of approvals for pediatric use.

Pediatric Antihypertensive Trial Failures. Analysis of End Points and Dose Range

Historically, drugs prescribed for children have not been studied in pediatric populations. Since 1997, however, a 6-month extension of marketing rights is granted if manufacturers conduct Food and Drug Administration–defined pediatric trials. In nearly half of the drugs studied, there were unexpected results in dosing, safety, or efficacy compared with adult studies, including failure of half of the antihypertensive dose-response trials, which are pivotal for deriving dosing recommendations. We sought to define design elements that might have contributed to these trial failures by combining patient-level data from 6 dose-ranging antihypertensive efficacy trials completed for pediatric exclusivity and submitted to the Food and Drug Administration from 1998 to 2005. We evaluated dosing, primary end point, and other components to assess underlying reasons for failure to show efficacy in children. Of 6 trials examined, 3 showed a dose response; 3 did not. Eligibility criteria were similar across studies, as were subject demographics. Successful studies showed large differences in doses, with little or no overlap between low, medium, and high doses; failed trials used narrow dose ranges with considerable overlap. Successful trials also provided pediatric formulations and used reduction in diastolic, not systolic, blood pressure as the primary end point. Careful attention to pediatric pharmacology and selection of primary end points can improve trial performance. We found poor dose selection, lack of acknowledgement of differences between adult and pediatric populations, and lack of pediatric formulations to be associated with failures. More importantly, our ability to combine data across trials allowed us to evaluate and potentially improve trial design.

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.

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.

Safety Monitoring of Drugs Receiving Pediatric Marketing Exclusivity

OBJECTIVES. The Food and Drug Administration Modernization Act provided for an additional 6-month period of marketing exclusivity to companies that perform pediatric drug trials in response to a Food and Drug Administration–issued written request. Because many safety concerns cannot be detected until after the introduction of a product to a larger and more diverse market, the Best Pharmaceuticals for Children Act required the Food and Drug Administration to report to the Pediatric Advisory Committee on adverse events occurring during the 1-year period after granting pediatric exclusivity. We sought to describe the Pediatric Advisory Committees recommendations made in response to safety reviews informed by data from the Food and Drug Administration Adverse Event Reporting System in 67 drugs granted exclusivity. PATIENTS AND METHODS. Pediatric Advisory Committee meetings and data presented by the Food and Drug Administration for all drugs were reviewed from June 2003 through April 2007. We divided the drugs into 2 groups: those that were returned to routine adverse event monitoring and those that had specific Pediatric Advisory Committee recommendations. RESULTS. Forty-four (65.7%) drugs were returned to routine monitoring for adverse events. The Pediatric Advisory Committee, sometimes working with other advisory committees, recommended label changes for 12 (17.9%) drugs, continued monitoring for 10 (14.9%), production of MedGuides for 9 (13.4%), and an update on label changes resulting from discussions with the sponsor for 1 (1.5%) drug. Some drugs had >1 action. Several of the adverse events revealed during this process were rare and life-threatening. CONCLUSIONS. Safety monitoring during the early postmarketing period is crucial to detect rare, serious, or pediatric-specific adverse events. Fortunately, the majority of drugs given exclusivity had no adverse events of a frequency or severity that prevented a return to routine adverse event monitoring.

The economic returns of pediatric clinical trials of antihypertensive drugs.

BACKGROUND Congress has authorized the United States Food and Drug Administration (FDA) to provide industry sponsors with a 6-month extension of drug marketing rights under the Pediatric Exclusivity Provision if FDA-requested pediatric drug trials are conducted. The cost and economic return of pediatric exclusivity to industry sponsors has been shown to be highly variable. We sought to determine the cost of performing pediatric exclusivity trials within a single therapeutic area and the subsequent economic return to industry sponsors. METHODS We evaluated 9 orally administered antihypertensive drugs submitted to the FDA under the Pediatric Exclusivity Provision from 1997 to 2004 and obtained key elements of the clinical trial designs and operations. Estimates of the costs of performing the studies were generated and converted into after-tax cash outflow. Market sales were obtained and converted into after-tax inflows based on 6 months of additional patent protection. Net economic return and net return-to-cost ratios were determined for each drug. RESULTS Of the 9 antihypertensive agents studied, an average of 2 studies per drug was performed, including at least 1 pharmacokinetic study and a safety and efficacy study. The median cost of completing a pharmacokinetic trial was

The Globalization of Pediatric Clinical Trials

862,000 (range

Safety of Placebo Controls in Pediatric Hypertension Trials

556,000 to 1.8 million). The median cost of performing safety and efficacy trials for these agents was

Globalization Facilitates Pediatric Drug Development in the 21 st Century

4.3 million (range