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 October 1, 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 October 1, 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. Orphan Indications 3 orphan drug database. We calculated the proportion of The diseases targeted by the 136 pediatric orphan indications that The third category included pediatric orphan indications were were for novel drugs, non-novel indications for drugs that only had most commonly categorized as drugs approved to treat $1 common orphan indications when orphan genetic and/or metabolic (16.9%), disease, and non-novel drugs drug exclusivity began. We used hematologic (16.9%), immunologic approved only to treat rare diseases. FDA approval histories to further and/or rheumatologic (12.5%), and We determined the number of unique classify indications assigned to this cancer (11.8%). In contrast, of the diseases targeted by pediatric orphan category into 2 subgroups: those that 266 non-pediatric orphan indications, indications in each of the 3 categories. targeted a different subset of a rare 164 (61.7%) targeted cancer For pediatric orphan indications for disease for which a drug was already (Supplemental Table 4). non-novel drugs (ie, the second and approved (ie, an expansion of The 136 pediatric orphan indications third categories), we assessed the previous orphan indication) and targeted 87 unique diseases (1 “vintage” of the drug by calculating those that targeted a new disease for disease for every 1.6 indications); 21 the amount of time between the date which the drug was not already of these diseases were targeted by $1 13 on which the drug’s active moiety approved. pediatric orphan indication. Among was first FDA approved and the date the 87 unique diseases, the most on which orphan drug exclusivity 13,15 commonly targeted were cystic Breakthrough Designation began. Finally, we calculated the fibrosis (12 pediatric orphan We used FDA breakthrough proportion of eligible pediatric indications), acute lymphoblastic designation as our measure of orphan indications that were for leukemia (12), and hereditary whether pediatric orphan indications drugs with breakthrough designation. angioedema (6) (Supplemental may have represented major Table 5). therapeutic advances. This RESULTS designation, which allows for Categorization of Pediatric Orphan expedited review, is granted if drugs Number of Pediatric Orphan Indications treat a serious or life-threatening Indications Of the 136 pediatric orphan condition and if preliminary clinical There were 402 FDA-approved indications, 60 (44.1%) were for evidence suggests the drug may orphan indications between 2010 and novel drugs, 45 (33.1%) were for substantially improve existing 2018. The number of approved non-novel drugs approved to treat treatments.11 This designation was orphan indications rose from 15 in common diseases, and 31 (22.8%) first made available on July 9, 2012, 2010 to 89 in 2018. Of the 402 were for non-novel drugs approved but it is not available to products orphan indications, 42 (10.4%) were only to treat rare diseases (Fig 2). that are not reviewed by the FDA approved for children only, 247 Among the 136 pediatric orphan Center for Drug Evaluation and (61.4%) for adults only, and 113 indications, 76 (55.9%) were for non- Research (CDER), such as (28.1%) for both. Furthermore, 122 novel drugs. For these 76 indications, fractionated plasma products. For (30.3%) were classified as targeting the mean and median vintage was eligible pediatric orphan indications pediatric diseases. 17.9 and 11.6 years, respectively. approved by the CDER on or after this date, we used data from the Of the 402 orphan indications, 136 The 60 pediatric orphan indications FDA Web site to determine if the (33.8%) were classified as pediatric for novel drugs are listed in Table 1. drug received breakthrough (approved only for children or These 60 indications targeted 44 designation.11 targeted pediatric diseases). The unique diseases, indicating that some

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 4, April 2020 3 Examples of these indications are listed in Table 2. Among the 31 indications, 25 (80.6%) targeted a different age- or biomarker-based subset of a rare disease that the drug had already been approved to treat. For example, lumacaftor–ivacaftor (Orkambi) was initially approved in 2015 as an orphan drug for patients with cystic fibrosis who were aged $12 years with the F508del CFTR gene mutation and subsequently gained 2 additional orphan indications for patients with cystic fibrosis with this mutation who were aged 6 to 11 years and aged 2 to 5 years. In contrast, of the 31 pediatric orphan indications for orphan-only drugs, 6 (16.1%) targeted a rare disease for which the drug had not previously been approved. One example is FIGURE 1 canakinumab (Ilaris), which received Number of pediatric orphan indications and percentage of orphan indications classified as pediatric fi – an orphan indication for tumor orphan indications between 2010 and 2018. A, Number of orphan indications classi ed (2010 2018) – as pediatric or non-pediatric and the total number of orphan indications. B, Percentage of all orphan necrosis factor receptor associated indications classified as pediatric orphan indications per year. periodic syndrome in 2016 after previously receiving orphan indications for rare diseases such as targeted the same disease. For approved for several common cryopyrin-associated periodic example, 4 targeted hereditary autoimmune conditions in adults, syndrome. angioedema (Supplemental Table 6). such as rheumatoid arthritis, at the time it received a pediatric orphan Breakthrough Designation The 45 pediatric orphan indications indication for juvenile idiopathic Of the 136 pediatric orphan for non-novel drugs approved to treat arthritis in children ages 2 to 3 years indications, 97 were approved by $1 common disease targeted 34 in 2014, which is 6 years after it CDER after July 9, 2012, and therefore unique diseases (Supplemental received an orphan indication for this were eligible for breakthrough Table 7). Examples of these disease in children 4 years and older. designation. Of these, 20 (20.6%) indications are listed in Table 2. For Propranolol was initially approved in were for drugs that received example, adalimumab (Humira) was 1967 for common diseases such as breakthrough designation (Table 3). hypertension before receiving Among these 20 indications, 12 were a pediatric orphan indication in 2014 for novel drugs and 8 for non-novel for proliferating infantile drugs; all of the latter drugs were hemangioma (Hemangeol). approved only to treat rare diseases Hydroxyurea was also initially when orphan drug exclusivity began approved in 1967 for multiple types (Fig 2). of cancer and adults with sickle cell anemia before receiving a pediatric DISCUSSION orphan indication in 2017 for children with sickle cell anemia In this analysis of 402 orphan (Siklos). indications approved between 2010 and 2018, one-third were approved The 31 pediatric orphan indications for children only or targeted pediatric for non-novel drugs approved only to diseases. The 136 pediatric orphan FIGURE 2 treat rare diseases targeted 21 indications targeted 87 unique Categorization of pediatric orphan indications. diseases (Supplemental Table 8). diseases, and 21 of these diseases

Downloaded from www.aappublications.org/news by guest on October 1, 2021 4 KIMMEL et al TABLE 1 Pediatric Orphan Indications for Novel Drugs, 2010–2018 (N = 60) Generic Name Disease Population(s) Generic Name Disease Population(s) Antihemophilic factor Hemophilia A Factor XIII concentrate (human) Congenital factor XII deficiency (recombinant), Fc fusion protein Anti–inhibitor coagulant complex Hemophilia A; B Fish oil triglycerides Parenteral nutrition–associated cholestasis Asfotase alfa Hypophosphatasia Icatibant Hereditary angioedema Benznidazole Chagas disease Inotuzumab ozogamicin Acute lymphoblastic leukemia Blinatumomab Acute lymphoblastic leukemia Ivacaftor Cystic fibrosis Botulism antitoxin heptavalent (A, Botulism Lanadelumab-flyo Hereditary angioedema B, C, D, E, F, G) (equine) Burosumab-twza X-linked hypophosphatemia Lomitapide Familial hypercholesterolemia C1-esterase inhibitor Hereditary angioedema Lumacaftor–ivacaftor Cystic fibrosis (recombinant) C1-esterase-inhibitor (human, Hereditary angioedema Macimorelin acetate Growth hormone deficiency pasteurized) Cannabidiol Lennox-Gastaut syndrome Metreleptin Lipodystrophy Carglumic acid N-acetylglutamate synthase deficiency Migalastat hydrochloride Fabry disease Cerliponase alfa Tripeptidyl peptidase 1 deficiency Miltefosine Leishmania donovani/braziliensis/ guyanensis/panamensis Cholic acid Bile acid synthesis disorders Mipomersen Familial hypercholesterolemia Clobazam Lennox-Gastaut syndrome Moxidectin Onchocerca volvulus Coagulation factor IX Hemophilia B Nusinersen Spinal muscular atrophy (recombinant) Coagulation factor IX Hemophilia B Pegvaliase-pqpz Phenylketonuria (recombinant), Fc fusion protein Coagulation factor X (human) Factor X deficiency Ponatinib Acute lymphoblastic leukemia Coagulation factor XIII A-subunit Hemophilia A Recombinant fusion protein; coagulation Hemophilia B (recombinant) factor IX with albumin Deferasirox Non–transfusion-dependent Recombinant human acid Pompe disease thalassemia syndromes a-glucosidase; alglucosidase alfa Deferiprone Thalassemia syndromes Recombinant von Willebrand factor von Willebrand disease Deflazacort Duchenne muscular dystrophy Sebelipase alfa Lysosomal acid lipase Dinutuximab Neuroblastoma Stiripentol Dravet syndrome Elapegademase-lvlr Adenosine deaminase; severe Taliglucerase alfa Type 1 Gaucher disease combined immunodeficiency Eliglustat Gaucher disease Tezacaftor and ivacaftor combination Cystic fibrosis therapy Elosulfase alfa Mucopolysaccharidosis type IVA Tisagenlecleucel Acute lymphoblastic leukemia Emapalumab-lzsg Hemophagocytic lymphohistiocytosis Uridine triacetate Orotic aciduria Emicizumab-kxwh Hemophilia A Varicella zoster immune globulin Varicella (human) Erwinia L-asparaginase Acute lymphoblastic leukemia Velaglucerase alfa Gaucher disease Eteplirsen Duchenne muscular dystrophy Vestronidase alfa-vjbk Mucopolysaccharidosis type VII Evolocumab Familial hypercholesterolemia Voretigene neparvovec-rzyl Retinal dystrophy were targeted by .1 indication. The orphan indications between 2000 and life-altering or life-saving benefits to majority of pediatric orphan 2009 were pediatric.10 Although this many children with rare diseases. indications were not for novel drugs proportion was similar to that found Although the success of recent but rather represented expanded in our study, the absolute number of pediatric orphan drug development is uses of existing drugs, some of which pediatric orphan indications has risen cause for optimism, the fact that are decades old and some of which dramatically over the past decade, many pediatric orphan indications are approved to treat common coinciding with the rise in the targeted the same disease suggests diseases. Twenty pediatric orphan number of orphan indications more that innovators are not solely focused indications were for drugs granted generally. The rising number of on developing treatments for the FDA breakthrough designation, pediatric orphan indications, coupled 95% of rare diseases with no suggesting that the drugs potentially with the fact that many were for therapeutic options.9 For example, 4 could substantially improve existing drugs that may have represented pediatric orphan indications for novel treatments for serious conditions. therapeutic breakthroughs, suggest drugs targeted hereditary In a previous analysis, the authors that recent pediatric orphan drug angioedema. As another example, found that one-third of FDA-approved development may have provided among the 31 pediatric orphan

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 4, April 2020 5 TABLE 2 Examples of Pediatric Orphan Indications for Non-Novel Drugs Generic Name (Trade Pediatric Orphan Indication Date of Initial Orphan Drug Years Between Approved Only Examples of Previous FDA- Name) FDA Approval Exclusivity Initial FDA To Treat Rare Approved Indications When for Drug’s Start Date Approval and Diseases When Orphan Drug Exclusivity Began Active Moiety Orphan Drug Orphan Drug Exclusivity Exclusivity (Vintage) Began Lumacaftor–ivacaftor Cystic fibrosis in children July 2, 2015 September 28, 1.2 Yes Cystic fibrosis in adults and (Orkambi) aged 6–11 y homozygous 2016 children aged $12 y for the F508del CFTR homozygous for the F508del mutation CFTR mutation Lumacaftor–ivacaftor Cystic fibrosis in children July 2, 2015 August 7, 2018 3.1 Yes Cystic fibrosis in adults and (Orkambi) aged 2–5 y homozygous for children aged $6y the F508del CFTR mutation homozygous for the F508del CFTR mutation Ivacaftor (Kalydeco) Cystic fibrosis in children January 31, July 31, 2017 5.5 Yes Cystic fibrosis in children aged aged $2 y with specific 2012 $2 y with other CFTR CFTR mutations (eg, mutations (eg, E56K, P67L, 71113A G, E831X) R74W) Canakinumab (Ilaris) Tumor necrosis factor June 17, 2009 September 23, 7.3 Yes Cryopyrin-associated periodic receptor–associated 2016 syndromes in adults and periodic syndrome in children aged $4y; pediatric and adult systemic juvenile idiopathic patients arthritis in adults and children aged $2y Ledipasvir–sofosbuvir Chronic hepatitis C in children October 10, April 7, 2017 2.5 No Chronic hepatitis C in adults (Harvoni) aged 12 and older or who 2014 weigh $35 kg Adalimumab (Humira) Juvenile idiopathic arthritis in December 31, September 30, 11.8 No Adults with autoimmune children aged 2–3y 2002 2014 diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn disease; children aged $4 y with juvenile idiopathic arthritis; children $6 y with Crohn disease AbobotulinumtoxinA Lower limb spasticity in December 9, July 29, 2016 24.7 No Adults with cervical dystonia; (Dysport)a children aged $2 y with 1991 cosmesis in non-elderly cerebral palsy adults with glabellar lines Propranolol Proliferating infantile November 13, March 14, 46.4 No Hypertension, arrhythmias hydrochloride hemangioma 1967 2014 migraine, myocardial (Hemangeol) infarctionb Hydroxyurea (Siklos) Children $2 y with sickle cell December 7, December 21, 50.1 No Adults with certain types of anemia 1967 2017 head and neck cancer; adults with sickle cell anemiab a AboboulinumtoxinA is a specific formulation of botulinum toxin type A, which was first FDA approved in 1991. b Siklos and Hemangeol have no other indications other than the pediatric orphan indication listed but are not new molecular entities because their active moieties had previously been approved by the FDA for other indications (examples of which are listed in the last column).

indications for drugs approved only who could benefit. However, it is children. Every indication also entails to treat rare diseases, 25 targeted important to ensure that this societal costs. Although a formal cost- additional age- or biomarker-based investment does not divert limited effectiveness analysis was beyond the subsets of a rare disease that the drug resources from efforts to discover scope of this analysis, in this study we was already approved to treat. It is treatments for rare diseases that identified a few examples of pediatric desirable to invest in the discovery of have none. orphan indications for which benefits multiple treatment options for may have been modest compared to a single disease, such as hereditary Every pediatric orphan indication these costs. Consider hydroxyurea: in angioedema, and to invest in the provides a degree of benefitto 2017, 50 years after initial approval expansion of previous indications to patients, as approval requires formal in 1967, an orphan version of this the maximum number of patients testing of safety and efficacy in drug (Siklos) was approved to

Downloaded from www.aappublications.org/news by guest on October 1, 2021 6 KIMMEL et al TABLE 3 Pediatric Orphan Indications for Drugs Receiving FDA Breakthrough Designation Generic Name Trade Marketing Approval Category Disease Population(s) Targeted by Indication Name Date Canakinumab Ilaris September 23, 2016 Non-novel, rare Tumor necrosis factor receptor–associated periodic syndrome disease only Canakinumab Ilaris September 23, 2016 Non-novel, rare Hyperimmunoglobulin D syndrome; mevalonate kinase deficiency disease only Canakinumab Ilaris September 23, 2016 Non-novel, rare Familial Mediterranean fever disease only Ivacaftor Kalydeco February 21, 2014 Non-novel, rare Patients with cystic fibrosis aged $6 y with certain CFTR mutations (eg, disease only G1224E, G1349D) Ivacaftor Kalydeco December 29, 2014 Non-novel, rare Patients with cystic fibrosis aged $6 y with certain R117H CFTR mutation disease only Ivacaftor Kalydeco March 17, 2015 Non-novel, rare Patients with cystic fibrosis aged 2–5 y with certain CFTR mutations (eg, disease only G1224E, G1349D) Lumacaftor–ivacaftor Orkambi September 28, 2016 Non-novel, rare Patients with cystic fibrosis aged 6–11 y homozygous for the F508del CFTR disease only mutation Lumacaftor–ivacaftor Orkambi August 7, 2018 Non-novel, rare Patients with cystic fibrosis aged 2–5 y homozygous for the F508del CFTR disease only mutation Blinatumomab Blincyto December 3, 2014 Novel drug Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia Cerliponase alfa Brineura April 27, 2017 Novel drug Patients aged $3 y with tripeptidyl peptidase 1 deficiency Burosumab-twza Crysvita April 17, 2018 Novel drug X-linked hypophosphatemia in patients aged $1y Emapalumab-lzsg Gamifant November 20, 2018 Novel drug Hemophagocytic lymphohistiocytosis Emicizumab-kxwh Hemlibra November 16, 2017 Novel drug Hemophilia A Sebelipase alfa Kanuma December 8, 2015 Novel drug Lysosomal acid lipase Uridine triacetate n/a September 4, 2015 Novel drug Hereditary orotic aciduria Inotuzumab n/a August 17, 2017 Novel drug Relapsed or refractory B-cell precursor acute lymphoblastic leukemia ozogamicin Tezacaftor and n/a February 12, 2018 Novel drug Patients with cystic fibrosis aged $12 y homozygous for the F508del CFTR ivacaftor mutation Lumacaftor–ivacaftor Orkambi July 2, 2015 Novel drug Patients with cystic fibrosis aged $12 y homozygous for the F508del CFTR mutation Asfotase alfa Strensiq October 23, 2015 Novel drug Perinatal-, infantile-, and juvenile-onset hypophosphatasia Lanadelumab-flyo Takhzyro August 23, 2018 Novel drug Patients with hereditary angioedema aged $12 y n/a, not applicable. prevent acute pain crises and reduce to charge high prices. Indeed, the drug development and also suggest the need for transfusion in children average wholesale price for Siklos is that additional reforms may be needed with sickle cell anemia, although $6.00 per 100 mg tablet, compared to to address the remaining unmet need hydroxyurea has been used off-label $0.95 per 200 mg capsule for Droxia, for treatment among children with for this purpose for years.16 FDA a hydroxyurea formulation also used rare diseases. To achieve this goal, the approval of previously off-label uses for children with sickle cell anemia.17 US Congress recently passed the of prescription drugs may be Because it is increasingly common for Research to Accelerate Cures and clinically valuable, as approval patients and their families to pay Equity Act of 2017.22 Before 2017, the requires the sponsor to demonstrate a fraction of the costs of drug therapy Pediatric Research Equity Act did not the drug’sefficacy, identify out of pocket, high prices for orphan require drug manufacturers seeking appropriate dosing, and determine drugs may create financial burden approval for an adult indication to clinical risks. However, because of and barriers to adherence for patients include children in clinical testing if the orphan approval, no new and families.18–21 High prices may the disease did not affect children or if hydroxyurea-containing medications also strain the budgets of private the drug had orphan designation. The can be marketed to prevent pain insurers and state Medicaid Research to Accelerate Cures and crises and reduce the need for programs, the latter of which compete Equity Act of 2017 amended the transfusion in children with sickle for scarce annual resources with Pediatric Research Equity Act to cell anemia until 2024, the end of other potentially beneficial programs require pediatric testing when a drug the 7-year period of orphan drug for children, such as public education. intended to treat an adult cancer has exclusivity. The lack of competition a common molecular target in during this period means that the Overall, our results illustrate many pediatric cancer and additionally manufacturer has considerable ability successes of recent pediatric orphan eliminated the orphan exemption for

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 4, April 2020 7 cancer drugs.22 This act could increase Our study has several limitations. indications on families and payers. the number of children included in First, we used FDA breakthrough These topics have been examined to cancer drug trials and therefore the designation to measure whether drugs some degree in previous analyses but number of pediatric orphan may have represented substantial are worthy of further study.19,24 indications. improvements over existing treatments. However, other drugs that Another reform that may help were substantial improvements may CONCLUSIONS address unmet need is to allow drug have lacked this designation and/or The number of treatments for rare prices to vary by indication on the may have received other FDA pediatric diseases has increased over fi basis of factors such as bene tto designations for promising drugs (eg, the past decade, and many of these patients and availability of priority, fast-track, and accelerated potentially represented therapeutic 23 therapeutic alternatives. Such approval). Research examining the breakthroughs. However, substantial pricing may incentivize investment in benefit of individual pediatric orphan unmet need for treatment options the discovery of treatments for indications is needed to quantify the remains for most children with rare pediatric rare diseases that have number representing major advances. diseases. Policy makers should none. However, this policy is not Second, we used a consensus-based consider changes to drug without trade-offs. For example, when approach to classify whether diseases development incentives to ensure the benefit of a drug cannot be targeted by orphan indications were that these needs are met. predicted with certainty, innovators pediatric. However, the 2 raters agreed may choose not to invest in on 95% of initial classification development rather than face the decisions and had expertise in both prospect of lower prices if the drug is general pediatrics and general internal ABBREVIATIONS ultimately not as efficacious as hoped. medicine. Third, examining the cost- CDER: Center for Drug Evaluation Future work is needed to evaluate the effectiveness of pediatric orphan and Research effects of this and other potential indications was beyond the scope of FDA: US Food and Drug reforms on pediatric orphan drug this analysis, as was examining the Administration development. budgetary impact of pediatric orphan

FUNDING: Dr Chua is supported by a career development award from the National Institute on Drug Abuse (grant 1K08DA048110-01). The other authors have not received any funding. Funded by the National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

REFERENCES 1. The IQVIA Institute. Orphan Drugs in the Research Innovation Policy and the approval: trends and recent United States: Growth Trends in Rare Economy), vol. Vol 2. Chicago, IL: developments. 2017. Available at: Disease Treatments. Parsippany, NJ: University of Chicago Press; 2019 https://www.fda.gov/files/about%20fda/ The IQVIA Institute; 2018 published/Insights-into-Rare-Disease- 5. Mikami K. Orphans in the market: the Drug-Approval–Trends-and-Recent- 2. America’s Health Insurance Plans. The history of orphan drug policy. Soc Hist Developments-%28October-17–2017% rise of orphan drugs. 2019. Available at: – Med. 2019;32(3):609 630 29.pdf. Accessed September 28, 2019 https://www.ahip.org/wp-content/ uploads/IB_OrphanDrugs-1004.pdf. 6. Srivastava G, Ashley W. Orphan Drugs: 9. The Lancet Diabetes Endocrinology. Accessed November 21, 2019 Understanding the FDA Approval Spotlight on rare diseases. Lancet Process, vol. Vol. 1. Philadelphia, PA: Diabetes Endocrinol. 2019;7(2):75 3. US Food and Drug Administration. Orphan University of Pennsylvania Academic drug designations and approvals. 2017. Entrepreneurship for Medical and 10. Thorat C, Xu K, Freeman SN, et al. What Available at: https://www.accessdata.fda. Health Scientists; 2019 the Orphan Drug Act has done lately for gov/scripts/opdlisting/oopd/index.cfm. children with rare diseases: a 10-year Accessed August 15, 2019 7. Tribble SJ, Lupkin S. Drugmakers analysis. Pediatrics. 2012;129(3): Manipulate Orphan Drug Rules to 516–521 4. Bagley N, Berger M, Chandra A, Create Prized Monopolies. San Garthwaite C, Stern A. The Orphan Drug 11. US Food and Drug Administration. Francisco, CA: Kaiser Health News; 2017 Act at 30. In: Lerner J, Stern S, eds. Breakthrough therapy approvals. 2019. Innovation Policy and the Economy, 8. US Food and Drug Administration. Available at: https://www.fda.gov/drugs/ 2018 (National Bureau of Economic Insights into rare disease drug nda-and-bla-approvals/breakthrough-

Downloaded from www.aappublications.org/news by guest on October 1, 2021 8 KIMMEL et al therapy-approvals. Accessed Forum Health Econ Policy. 2013;16(1): prices-rare-diseases.html. Accessed September 17, 2019 1–33 September 17, 2019 12. US Food and Drug Administration. New 16. Reeves SL, Jary HK, Gondhi JP, Raphael 21. Kaiser Family Foundation; Peterson molecular entity (NME) drug and new JL, Lisabeth LD, Dombkowski KJ. Center on Healthcare. What are recent biologic approvals. 2018. Available at: Hydroxyurea use among children with trends and characteristics of workers https://www.fda.gov/drugs/nda-and-bla- sickle cell anemia. Pediatr Blood with high drug spending? Available at approvals/new-molecular-entity-nme- Cancer. 2019;66(6):e27721 https://www.healthsystemtracker.org/ drug-and-new-biologic-approvals. 17. IBM Watson Health. IBM Micromedex chart-collection/recent-trends- Accessed September 17, 2019 Web applications access. Available at: characteristics-workers-high-drug- spending/#item-start. Accessed 13. US Food and Drug Administration. https://www.micromedexsolutions.com. January 27, 2020 Drugs@FDA: FDA-approved drug Accessed December 6, 2019 products. 2019. Available at: https:// 18. Thomas K. This new treatment could 22. Fink JL. Will the RACE for Children Act www.accessdata.fda.gov/scripts/cder/ save the lives of babies. But it costs lead to new treatments for pediatric daf/index.cfm. Accessed September 17, $2.1 million. The New York Times. May cancer? Cancer. 2017;123(2):189 2019 24, 2019. Available at: https://www. 23. Bach PB. Indication-specific pricing for 14. US Food and Drug Administration. nytimes.com/2019/05/24/health/ cancer drugs. JAMA. 2014;312(16): Licensed biological products with zolgensma-gene-therapy-drug.html. 1629–1630 supporting documents. 2019. Available Accessed August 15, 2019 24. Institute for Clinical and Economic at: https://www.fda.gov/vaccines-blood- 19. Chua KP, Conti RM. Out-of-pocket Review. Assessing the effectiveness and biologics/licensed-biological-products- spending on orphan drug prescriptions value of drugs for rare conditions: supporting-documents. Accessed among commercially insured adults in a technical brief for the ICER Orphan September 17, 2019 2014. J Gen Intern Med. 2019;34(3): Drug Assessment & Pricing Summit. 338–340 15. Lichtenberg FR. The effect of 2017. Available at: https://icer-review. pharmaceutical innovation on longevity: 20. Thomas K, Abelson R. The $6 million org/wp-content/uploads/2017/02/ICER_ patient level evidence from the 1996- drug claim. The New York Times. August Assessing-the-Value-of-Drugs-for-Rare- 2002 Medical Expenditure Panel Survey 25, 2019. Available at: https://www. Conditions_051017.pdf. Accessed and Linked Mortality Public-use Files. nytimes.com/2019/08/25/health/drug- September 23, 2019

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 145, number 4, April 2020 9 Pediatric Orphan Drug Indications: 2010−2018 Lauren Kimmel, Rena M. Conti, Anna Volerman and Kao-Ping Chua Pediatrics originally published online March 3, 2020;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2020/02/28/peds.2 019-3128 References This article cites 8 articles, 1 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2020/02/28/peds.2 019-3128#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Advocacy http://www.aappublications.org/cgi/collection/advocacy_sub Child Health Financing http://www.aappublications.org/cgi/collection/child_health_financin g_sub Federal Policy http://www.aappublications.org/cgi/collection/federal_policy_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

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