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.
- pediatric exclusivity
- blockbuster drug
- labeling changes
- negative studies
- clinical trials
- drug safety
- drug sales
- FDA —
- US Food and Drug Administration
- PE —
- pediatric exclusivity
- WR —
- Written Request
What’s Known on This Subject:
Most therapeutic products used in children have not been studied in that population. There is a need for special incentives and market protection (pediatric exclusivity) to compensate drug sponsors for studying these products in children.
What This Study Adds:
Of 189 products studied under pediatric exclusivity, 173 (92%) received new labeling information. Pediatric efficacy was not established for 78 (42%), including 81% of oncology drugs. Probability of demonstrating efficacy was related to therapeutic area and year exclusivity was granted.
Apart from vaccines and products for common pediatric diseases such as otitis media, most products prescribed for children historically have not been studied in the pediatric population. By the end of the 20th century, three-fourths of drugs used in children remained unstudied in pediatric patients despite decades of advocacy to remedy this situation.1,2 In 1997, the US Congress established the pediatric exclusivity (PE) program to provide financial incentives to drug sponsors in exchange for studying products used in pediatric populations.3 PE offers 6 months of additional market exclusivity to companies for the moiety (active molecule), rather than a specific drug product, in exchange for conducting pediatric studies requested by the US Food and Drug Administration (FDA). Studies do not need to prove efficacy to obtain PE. However, they must adhere to the pediatric trial protocols designated in a document called a Written Request (WR) that is issued by the FDA.
Since 2007, studies conducted under pediatric legislation must include pediatric study information in the product’s labeling even if the trial failed to demonstrate efficacy.4 This is in contrast to negative adult studies, which are not usually noted in product labeling.
Our objectives in the current study are to describe the types of products studied under the PE program, the resulting pediatric labeling information, and the factors influencing demonstration of pediatric efficacy. Factors analyzed include therapeutic group, year PE was granted, indications affecting a small disease population, and annual drug sales in the year granted exclusivity.
This study analyzed all WRs (N = 401) and all drugs with completed requested studies, which subsequently were granted PE (n = 189), from July 1, 1998 to December 31, 2012. Drugs granted PE are listed publicly online.5 Four products receiving a “second exclusivity” for additional studies, in which the exclusivity is more limited and applies only to the resulting new patent, were not included in the dataset. Three products were evaluated for safety or pharmacokinetics only. These 3 are omitted in our regression analysis, which looked at factors impacting obtaining a pediatric indication, but are retained in the rest of the study. The FDA’s Institutional Review Board granted a waiver of review for this study.
By using internal FDA data, we collected all WRs issued under the exclusivity provision from 1998 to 2012. These were organized by therapeutic group of the indication requested and whether the sponsoring company accepted or declined the WR. In some cases the WR was rescinded or the sponsor did not respond to the request.
We identified pediatric labeling changes resulting from clinical trials performed in exchange for exclusivity. These labeling changes are available publicly.6 For those studies that did not result in a labeling change (n = 16), we reviewed a combination of non-public and public clinical trial data submitted to the FDA to determine trial outcomes.7,8
Drugs in the present analysis that did not establish or expand a pediatric indication from requested efficacy studies are considered “negative” studies. A negative designation applies to (1) studies that failed to demonstrate efficacy in all indications in all subpopulations requested by the FDA, (2) where the sponsor withdrew the studies, or (3) where there was no pediatric labeling change. Studies for the same product for the same indication could demonstrate efficacy in 1 subpopulation but fail in another. If the drug was found efficacious in any of these subpopulations, then it was considered a positive trial.
Drugs were organized into therapeutic groups based on the FDA division that reviewed the drug for the indication in question. The designation “small disease population” was assigned by using publicly available data from the FDA Office of Orphan Products,9 the National Organization for Rare Disorders,10 and various disease prevalence statistics from the Centers for Disease Control and Prevention and peer-reviewed articles. FDA Orphan Products and National Organization for Rare Disorders define an orphan or rare disease, respectively, as one that affects <200 000 patients in the United States.
We obtained aggregated annual US domestic sales data for moieties in the year PE was granted. Sales data from 1999 to 2012 come from IMS Health IMS National Sales Perspective, which measures the volume of drug products sold from manufacturers into retail and non-retail pharmacy settings. Sales data for the 2 moieties granted PE in 1998 were not available from IMS Health and were excluded from regression analysis but were retained in the rest of the study. Drugs were designated as “blockbusters” when the combined annual sales of products containing the PE-awarded moiety were ≥$1 billion in the year PE was granted. There is no adjustment for inflation. For example, GlaxoSmithKline studied Epivir in children who had hepatitis B and was granted PE for the lamivudine moiety in 2000. Sales for lamivudine are thus aggregated year 2000 sales for all GlaxoSmithKline products containing lamivudine: Combivir, Epivir, Epivir HBV, and Trizivir. For any drug granted PE in December of a study year, sales data are for the following year. If a drug was granted PE before it was marketed to the public, then sales data are for the first year marketed.
Stata 12 statistical software was used for discrete probit regressions and Wilcoxon rank-sum tests (Stata Corp, College Station, TX). Probit regressions use a Boolean dependent variable for whether a drug was found efficacious in PE trials. Independent variables include therapeutic group, year PE was granted, blockbuster sales status, small disease population, and whether the FDA or the sponsoring company initiated the request for pediatric studies. Average marginal effects and marginal effects at the mean are reported. Therapeutic group effects in the regression are relative to the 2 therapeutic groups most likely to demonstrate efficacy: gastrointestinal and pain/anesthesia. P values <.05 are reported for statistical significance. No correction was made for multiple comparisons.
From 1998 through 2012, the FDA issued 401 WRs under the PE program (Fig 1). Occasionally, a product received >1 WR involving different indications (n = 17). Fifty-seven WRs (14%) were declined by the sponsoring company or later rescinded by the FDA. The lowest declined/rescinded rate was in oncology (4%; 2 of 49), whereas the highest rate was 23% in pulmonary/allergy (7 of 30).
During the same period, studies were completed for 189 drugs that were subsequently granted PE. Of these, 173 (92%) had new pediatric labeling resulting from the PE program. Labeling changes include a new or expanded pediatric indication (n = 108), new dosing information (n = 26), and safety concerns (n = 48) (Table 1). Products can have >1 type of change in the labeling. Seven drugs were found efficacious in some of the pediatric subpopulations requested, but not in others. For example, a drug could be successful in adolescents but not in younger children. WRs seldom included studies in the neonatal population.11
Thirty-five drugs were studied in indications that did not match the original approved indication in adults. Of these, 15 were then approved for the new pediatric indication.
Three drugs granted PE, desflurane, mometasone, and anagrelide, were not asked to demonstrate efficacy in pediatrics. Desflurane and mometasone provided safety data, whereas anagrelide provided pharmacokinetic data as requested. These drugs were omitted from the regression analysis, which measured the probability of obtaining a new or expanded pediatric indication, but were retained in the rest of the study.
Of the 186 products in which studies were designed to determine efficacy, 78 (42%) were found to be ineffective in the pediatric population for the indications requested by the FDA. All but 16 of these had the negative information added to their product labeling. Of the 16 products not labeled, all failed to demonstrate pediatric efficacy. Fourteen of these were studied or submitted before 2007 when negative pediatric trial data were not required by law to be included in the labeling. The remaining 2 were found to have ongoing technical issues. The summary or medical review of these trials are posted online under the respective drug names.7,8
Although 42% of drugs granted PE and asked to demonstrate efficacy in children failed to do so, the negative study rate was not constant across therapeutic groups ranging from 81% in oncology to 0% in gastrointestinal (Fig 2). Regression analysis found a significantly lower likelihood of demonstrating efficacy in children for 5 therapeutic groups (oncology, cardiovascular, endocrine, P < .01; urology, neurology, P < .05) after controlling for other explanatory variables (Table 2). Psychiatry drugs were less likely to demonstrate efficacy, but the significance level (P = .055) was above our threshold. Oncology drugs were the least likely to demonstrate efficacy (19% positive) with a 60% to 70% reduction in the likelihood of a successful trial compared with gastrointestinal (100% positive) and pain/anesthesia (80% positive).
Whether the FDA or the sponsoring company initiated the request for pediatric studies was not a significant predictor of demonstrating efficacy. Twenty-eight (15%) products granted PE were from FDA-initiated requests. Dermatology/ophthalmology products were negatively correlated with a sponsor-initiated request (r = −0.21), implying that this FDA division was most likely to initiate dialogue for products that were later granted PE.
There is a trend of more negative trials over our time period, which was associated with a 2% reduction in positive trial outcomes for each successive year of the PE program’s existence (P < .05). Concurrently, the FDA sent significantly fewer WRs over time, with an average of 58 WRs per year from 1998 to 2001 compared with 16 per year from 2002 to 2012, a 72% decline.
Fifty-two (28%) products were studied for an indication with a small disease population. All 16 oncology drugs fell into this group as well as 61% of endocrine and 44% of pain/anesthesia products. Pulmonary/allergy, psychiatry, and urology had no studied indications designated as affecting a small disease population. Small disease population was not a significant predictor of trial outcome in the regression analysis.
Fifty (27%) of the 187 drugs for which sales data were available were designated as blockbusters. Blockbuster designation was not a significant predictor of trial outcome in our regression analysis. However, a rank-sum test found a significantly higher percentage of blockbusters participating in the latter portion of the PE program, 2006 to 2012: 37% vs 20% (P = .01).
Of the 189 products studied under the PE program from 1998 through 2012, 173 (92%) received new pediatric labeling information, with 108 (57%) given a new or expanded pediatric indication. This information better informs caretakers on the safety and efficacy of the product and, in many cases, provides additional dosing and safety information. Seventy-eight drugs were unable to demonstrate efficacy in children, with 62 receiving new labeling. However, many of these products were already used therapeutically in children at similar dosing levels found in the PE trials. In addition, a new pediatric safety signal was identified in a quarter of the drugs granted PE (n = 48). These results demonstrate why we cannot assume that a product with proven safety and efficacy in adults will perform similarly in children. The information needed to make this determination can usually only be obtained by directly studying the product in the pediatric population. An exception to this approach is use of adult and other data to extrapolate efficacy in the pediatric population, which is only acceptable under specific circumstances.12,13
This study’s findings of more negative trials with each successive PE program year (P < .05) may reflect increasing complexity in the PE trials requested by the FDA. Similarly, these results may be attributable to less complicated development programs initiated early in the PE program’s existence in which diseases were selected that had fewer unknowns about their pediatric manifestation and the required clinical endpoints for testing. Earlier studies would also be less likely to enroll patients in the youngest, more difficult to study pediatric age groups until data were generated from the older pediatric population.
In the beginning of the PE program (1998–2001), the FDA issued on average 59 WRs per year in an attempt to reduce the backlog of unmet pediatric drug safety and efficacy needs. Ninety-five studies were requested in 1999 alone. After completing this backlog, the number of WRs fell by 72% to an average of 16 per year from 2002 to 2012. The early backlog of studies may be seen as “low hanging fruit” in which simpler pediatric studies with greater a priori clinical knowledge could be completed more easily. Information from these studies informed more recent trials in younger age groups and in more difficult to study pediatric populations/indications. Learning from earlier requested trials, FDA requests have become more precise in requiring extensive proof of concept in trial design via dose ranging studies and validation of endpoints.
Drugs in 5 therapeutic groups had a significantly lower likelihood of demonstrating efficacy in PE trials compared with drugs in 2 more successful groups. Oncology drugs had the lowest likelihood with a 60% to 70% reduction (P < .01) when compared with gastrointestinal and pain/anesthesia drugs. To put this in perspective, from 1998 to 2012, the FDA issued 49 WRs for pediatric oncology studies under the PE provision. Studies were completed for 16 oncology drugs and only 3 were subsequently approved for pediatric use (Fig 1, Table 1). There are a number of explanations for the apparent lack of efficacy in pediatric oncology drugs. First, pediatric cancers are rare, but more importantly are usually biologically distinct from adult cancers.14–16 Thus, the existing clinical knowledge on adult cancers is not always applicable to pediatric trials. In such situations, there is no opportunity to extrapolate pediatric therapeutic efficacy from adult oncology study results.15 Moreover, these products are studied in heavily pre-treated, relapsed, and refractory patients who may have likely developed resistance to the same class of products.17
Cardiovascular drugs had a 40% to 47% lower likelihood (P < .01) of demonstrating efficacy when compared with gastrointestinal and pain/anesthesia drugs. Benjamin et al analyzed the patient level data in 6 antihypertensive drugs studied under PE.18 Their analysis found that differences in dose ranging, weight-based dosing, development of a pediatric formulation, and choice of clinical endpoint all affected trial outcome, whereas sample size did not. Unsuccessful trials did not use weight-based dosing and used the same primary endpoint as adult trials (systolic blood pressure). It is possible that these factors, which we did not review, similarly affected the outcomes of pediatric oncology and other trials.
The highly variable efficacy rates by therapeutic group highlight the difficulties encountered in extrapolating efficacy from adults or older pediatric populations to younger pediatric populations. If one can extrapolate efficacy, then the only studies required are those that evaluate pharmacokinetics/pharmacodynamics and safety. Sometimes proof of concept studies may be required to support extrapolation, but these are not large, randomized control trials and thus more likely to succeed in accomplishing their goals. For a number of gastrointestinal, pain, and infectious disease indications, the course of the disease and the expected response are sufficiently similar in adults or older pediatric populations to permit the extrapolation of efficacy. In cancer, the disease typically is not the same in adult and pediatric populations and extrapolation is not possible. It is therefore reasonable to assume that the fewer the similarities between pediatric and adult diseases, the more unknowns there will be during research, including endpoints, course of disease, and expected response to therapy. As we build our knowledge by establishing and validating pediatric endpoints, identifying consistent relationships between adult and pediatric pharmacological responses, and continuing to explore failures of trial design, we should be able to design more successful pediatric trials. One example is the lesson learned from pediatric migraine trials in which Sun et al suggest that to mitigate high placebo response rates, study designs need to exclude early placebo responding patients.19
We omitted different sponsoring companies from this study’s regression analysis, as there was insufficient variability of therapeutic group and trial success within individual sponsoring company groups. We also omitted “difficulty of trial completion,” as there is no formal metric for this. However, we do know that companies sometimes have trouble with patient recruitment, especially in diseases that affect very few patients. We included small patient population as a surrogate for difficulty. Other omitted explanatory variables include neonatal or infant populations in the trial, trial design, use of unvalidated endpoints or unvalidated biomarkers, geographical location of the trial centers, and any ethical issues arising during the trial.
Over a 15-year period, PE has resulted in pediatric safety and efficacy studies for 189 products, many of which could not be required under other mechanisms. Over half of the pediatric studies provided data that resulted in a new pediatric indication or pediatric population being approved for use. However, efficacy was not demonstrated for 78 (42%) drugs in the pediatric population. Therapeutic group and year of exclusivity were significantly related to the probability of proving efficacy, whereas drug sales, small disease population, and initiation process were not significantly related.
Both positive and negative studies resulting from PE generate clinical knowledge that improves the construct of subsequent trials. Pediatric migraine and hypertension trials are 2 examples in which assessments of failures resulted in better subsequent trial design. Knowing that a product could not be proven effective or is toxic at a certain dose is clinically useful. Leflunomide, for example, was studied in a superiority trial comparing it to the standard treatment of juvenile idiopathic arthritis. It was found effective 68% of the time but failed to meet the predetermined efficacy endpoints in the WR. Extensive information on the trial was provided in the labeling but the drug was not granted a new pediatric indication.
Moreover, the PE program asks for studies in conditions for which there may be little existing knowledge from adults, including pediatric-only and rare pediatric diseases in which there are unknowns regarding disease physiology, endpoint validation, and pharmacologic response. Thus, a failure to show efficacy does not imply a failure to provide critical information. The importance of providing negative pediatric trial information is reflected in legislation.4 Because of the paucity of pediatric product development trials, the data from these trials becomes critical for further advancement in the field. The challenge is to properly use this new information, both positive and negative, to better design the next era of pediatric clinical trials.
- Accepted May 15, 2014.
- Address correspondence to Gerold T. Wharton, MS, 10903 New Hampshire Ave, Building 32, Room 5159, Silver Spring, MD 20993-0002. E-mail:
↵Mr Wharton created and analyzed the datasets used for this study, drafted the manuscript, and approved the final manuscript as submitted; Dr Murphy conceptualized and designed the study framework, supervised the project, analyzed subsets of the data, reviewed and revised the manuscript, and approved the final manuscript as submitted; Ms Avant designed the study framework, collected and analyzed the labeling change data in this project, audited the manuscript data, reviewed and revised the manuscript, and approved the final manuscript as submitted; Dr Goldsmith designed the study framework and collected and analyzed IMS Health sales data; Dr Chai obtained IMS Health sales data used in this project, reviewed and revised the manuscript, and approved the final manuscript as submitted; Dr Rodriguez (retired) conceptualized the study framework, supervised the project, reviewed and revised the manuscript, and approved the final manuscript as submitted; and Dr Eisenstein conceptualized and designed the study framework, reviewed and revised the manuscript, and approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: Dr Eisenstein reported receiving research funding from Medtronic Endovascular; the other authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found on page e562, online at www.pediatrics.org/cgi/doi/10.1542/peds.2014-1585.
- American Academy of Pediatrics
- ↵US Food and Drug Administration Modernization Act of 1997, Pub L No. 105–115, 111 Stat 2296
- ↵US Food and Drug Administration. Food and Drug Administration Amendments Act (FDAAA) of 2007. Updated December 2, 2011. Available at: www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm. Accessed December 6, 2013
- ↵US Food and Drug Administration. FDA Pediatric Exclusivities Granted Table. Updated December 2013. Available at: www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM223058.pdf. Accessed December 6, 2013
- ↵US Food and Drug Administration. New Pediatric Labeling Information Database. Updated September 30, 2013. Available at: www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase. Accessed December 6, 2013
- ↵US Food and Drug Administration. Summaries of Medical and Clinical Pharmacology Reviews. Updated November 8, 2012. Available at: www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm161894.htm. Accessed January 12, 2014
- ↵US Food and Drug Administration. Medical, Statistical, and Clinical Pharmacology Reviews of Pediatric Studies Conducted under Section 505A and 505B of the Federal Food, Drug, and Cosmetic Act (the Act), as amended by the FDA Amendments Act of 2007 (FDAAA). Updated July 26, 2013. Available at: www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049872.htm. Accessed January 12, 2014
- ↵US Food and Drug Administration. Search Orphan Drug Designations and Approvals. Available at: www.accessdata.fda.gov/scripts/opdlisting/oopd. Accessed January 12, 2014
- ↵National Organization for Rare Disorders. Rare Disease Database. Available at: www.rarediseases.org/rare-disease-information/rare-diseases. Accessed January 12, 2014
- Laughon MM,
- Avant D,
- Tripathi N,
- et al
- ↵US Food and Drug Administration. Specific requirements on Content and Format of Labeling for Human Prescription Drugs: Revision of “Pediatric Use” Subsection in the Labeling; Final Rule. 21 CFR, pt.201 (1994). Print. Available at: www.fda.gov/ohrms/dockets/ac/01/briefing/3778b1_Tab6_7-21CFR%20Part%20201.pdf. Accessed January 20, 2014
- Hirschfeld S,
- Ho PTC,
- Smith M,
- Pazdur R
- ↵Food and Drug Administration Office of Pediatric Therapeutics and Pediatric and Maternal Health Staff. FDA update: new pediatric information available for 19 oncology products. AAP News. 2013;34(10):21–22. Available at: http://aapnews.aappublications.org/content/34/10/21.full.pdf+html. Accessed January 6, 2014
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