Pediatric Orphan Drug Indications: 2010–2018 Lauren Kimmel, BS,a Rena M. Conti, PhD,b Anna Volerman, MD,c,d Kao-Ping Chua, MD, PhDa BACKGROUND: Orphan drug development is crucial for children, who are disproportionately abstract affected by rare diseases. Data are lacking on the number, nature, and benefit of recently approved pediatric orphan indications. METHODS: We classified the 402 orphan indications the US Food and Drug Administration approved between 2010 and 2018 as “pediatric” if they were approved for children only or targeted pediatric diseases. We determined the number of unique diseases targeted by pediatric orphan indications and calculated the proportion that were for (1) novel drugs, (2) non-novel drugs approved to treat $1 common disease, and (3) non-novel drugs approved only to treat rare diseases. Among pediatric orphan indications eligible for US Food and Drug Administration breakthrough designation (granted to drugs potentially representing major therapeutic advances), we calculated the proportion receiving this designation. RESULTS: Of the 402 orphan indications, 136 (33.8%) were pediatric. These 136 indications targeted 87 unique diseases; 21 diseases were targeted by $1 indication. Of the 136 pediatric orphan indications, 60 (44.1%) were for novel drugs, 45 (33.1%) were for non-novel drugs approved to treat $1 common disease, and 31 (22.8%) were for non-novel drugs approved only to treat rare diseases. Among 97 indications eligible for breakthrough designation, 20 (20.6%) received this designation. CONCLUSIONS: Recent orphan drug development has increased the availability of treatments for pediatric rare diseases. Most pediatric orphan indications expanded use of existing drugs, and many targeted the same disease. Some indications may represent breakthroughs, but substantial unmet need for treatments remains for most pediatric rare diseases. aDepartment of Pediatrics and Susan B. Meister Child Health Evaluation and Research Center, Medical School, WHAT’S KNOWN ON THIS SUBJECT: Orphan drug University of Michigan, Ann Arbor, Michigan; bInstitute for Health System Innovation and Policy and Department of development is crucial to children, who are Markets, Public Policy, and Law, Questrom School of Business, Boston University, Boston, Massachusetts; and disproportionately affected by rare diseases. However, c d Section of General Internal Medicine, Department of Medicine and Section of Academic Pediatrics, Department data are lacking on the number, nature, and benefitof of Pediatrics, University of Chicago, Chicago, Illinois recently approved pediatric orphan indications. Ms Kimmel, Ms Conti, Dr Volerman, and Dr Chua conceptualized and designed the study, analyzed and interpreted the data, and reviewed and revised the manuscript; and all authors approved the WHAT THIS STUDY ADDS: Among 402 orphan final manuscript as submitted and agree to be accountable for all aspects of the work. indications US Food and Drug Administration approved between 2010 and 2018, 136 (33.8%) were pediatric. Of DOI: https://doi.org/10.1542/peds.2019-3128 these, 44.1% were for novel drugs, and 20 received Accepted for publication Jan 13, 2020 breakthrough designation. Orphan drug development Address correspondence to Kao-Ping Chua, MD, PhD, Department of Pediatrics, University of has benefited children with rare diseases, mostly by Michigan Medical School, 300 North Ingalls St, SPC 5456, Room 6E18, Ann Arbor, MI 48109-5456. expanding the use of existing drugs. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Pediatrics To cite: Kimmel L, Conti RM, Volerman A, et al. Pediatric Orphan Drug Indications: 2010–2018. Pediatrics. 2020; fi FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to 145(4):e20193128 this article to disclose. Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 145, number 4, April 2020:e20193128 ARTICLE “Orphan drugs” are drugs with at and 2009.10 In the current study, we We also classified whether the least 1 US Food and Drug assessed the number of pediatric disease targeted by the indication Administration (FDA) approved orphan indications approved between was a “pediatric disease,” defined as orphan indication to treat rare 2010 and 2018, the number and a disease that typically has its onset diseases affecting ,200 000 types of diseases targeted by these in childhood or predominantly affects Americans.1 These drugs are pediatric orphan indications, the children. Classification decisions were increasingly salient to patients, proportion of these indications that made independently by 2 authors innovators, and payers in the United were for novel drugs, and the (A.V., a general internist and States.1,2 During the 10-year period proportion that were for drugs pediatrician; K.C., a general between 2000 and 2009, 148 orphan receiving FDA breakthrough pediatrician). A consensus-based indications were approved.3 In designation, which is an expedited approach was used to resolve comparison, almost the same number review pathway granted when disagreements. The 2 raters agreed (150) were approved between 2010 preliminary data suggest that a drug on 95% of initial classification and 2014, and 170% more (252) could substantially improve existing decisions. were approved between 2015 and treatments for serious conditions.11 We classified an orphan indication as 2018.3 In 2017, orphan drug a “pediatric orphan indication” if the spending totaled $112 billion, or 25% drug was approved for children only of US prescription drug spending that METHODS or targeted a pediatric disease. year.1 Data Source and Sample Following a previous analysis, The surge in orphan drug We analyzed the FDA orphan drug indications that were approved for development has been driven by the database, which lists all orphan adults only and that targeted 4,5 fi Orphan Drug Act of 1983. The act indications approved since 1983 pediatric diseases were classi ed as 10 incentivizes the development of (Supplemental Fig 3 describes the pediatric. orphan drugs by providing benefits orphan drug approval process).3 The Diseases Targeted by Pediatric such as tax credits and grants for sample included all orphan 6 Orphan Indications clinical testing. Furthermore, the act indications for which the 7-year allows a 7-year period of “orphan period of orphan drug exclusivity Using a similar consensus-based drug exclusivity” during which began between January 1, 2010, and approach, we assigned the diseases a manufacturer’s competitors can December 31, 2018. The Institutional targeted by pediatric orphan market a different drug for the same Review Board of the University of indications into 1 of 19 disease indication but not an alternative Michigan Medical School did not categories (eg, cancer or version of the same drug for the same regulate this study as human subjects cardiovascular). indication, thus allowing the research because data were publicly Categorization of Pediatric Orphan manufacturer wide latitude on available. pricing.6 A single drug can receive Indications multiple orphan indications, each of Identification of Pediatric Orphan To characterize the nature of which grants a new round of Indications pediatric orphan indications, we incentives.7 Any drug can receive an assigned them to 1 of 3 categories: For each orphan indication, we orphan indication, regardless of (1) indications for novel drugs, (2) determined if the drug was approved whether it is novel or has previous indications for non-novel drugs for children only (limited to children FDA-approved orphan or non-orphan approved to treat $1 common aged ,17 years [FDA’sdefinition of indications.7,8 disease, and (3) indications for non- children]), adults only (limited to novel drugs approved only to treat Understanding the number, nature, adults aged $17 years), or both. We rare diseases. and benefit of recently approved considered a drug to be approved for orphan indications is particularly both adults and children if both age The first category included important for children. Half of rare groups were listed explicitly (eg, indications for drugs without diseases affect children, and it is “adults and children with disease X”). a previously approved active moiety estimated that 95% of the ∼7000 rare If no age group was listed in the when orphan drug exclusivity began diseases have no treatment options.9 indication (eg, “patients with disease (ie, on the date of marketing Despite the importance of orphan X”), we classified on the basis of approval). These included orphan drug development to children, the whether the drug’s label stated that indications approved under new drug only previous comprehensive analysis safety and efficacy had been applications listed as “new molecular of pediatric orphan indications was established in adults only, children entities,” orphan indications on the focused on approvals between 2000 only, or both. FDA’s list of new biological license Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 KIMMEL et al application approvals, and orphan Statistical Analysis number of pediatric orphan indications for fractionated plasma We used descriptive statistics to indications ranged from 8 to 18 products or cellular and/or gene calculate the number of FDA- between 2010 and 2016, then therapy products that represented approved orphan indications and the increased to 27 in 2017 and 29 in ’ 12–14 the drug s initial approval. number of pediatric orphan 2018 (Fig 1A). The proportion of all fi indications, both overall and by year. orphan indications classi ed as The second category included pediatric was 53.3% in 2010 and indications for drugs with $1 FDA- We determined which of the 19 disease categories were most subsequently ranged from 25.0% to approved non-orphan indication to 39.4% between 2011 and 2018 $ frequently targeted by pediatric treat 1 common disease when (Fig 1B). orphan drug exclusivity began. We orphan indications, as well as the defined non-orphan indications as number of unique diseases targeted Diseases Targeted by Pediatric indications not included in the FDA by these indications.