An Update on the Therapeutic Orphan

Thirty years ago, Dr Harry Shirkey recognized the serious dilemma of pediatric drug labeling, called therapeutic orphan, to capture its concept, and described remedial measures to minimize the dilemma. This review offers a brief exposition of the therapeutic orphan's arduous journey toward the goal of labeling of all drugs used for children.Aside from legal and US Food and Drug Administration (FDA) policy requirements to secure new drug application approval to market a drug, some may question reasons for a pediatric drug label, especially if a label exists for adult use and pediatric use information is distributed in literature reports. Major pragmatic reasons for a pediatric label are presented in Table 1. A label testifies to carefully reviewed clinical trial data that offer substantial evidence to support pediatric indications for which the drug has approved use. Perhaps of unappreciated importance is availability of information on the label. Time-consuming literature review and analysis often are not necessary when a pediatric label exists. Label information is compiled for the pediatric drug formulation, and it is this formulation that is approved. Literature reports often contain one or more formulations prepared by the investigator, and good manufacturing procedures or bioavailability estimates may be less than desired. A formulation on the label frequently has been evaluated for characteristics acceptable to children and hence compliance is strengthened. The drug, having met pediatric labeling requirements, is available for children and obviates the awkward double standard—one for adults (label necessary for marketing) and one for children (pediatric label not necessary for marketing or use). To the lay public, this pediatric labeling allows third-party reimbursement of drug costs otherwise denied. This relieves young parents of a truly indefensible economic burden, which in some cases has denied drug treatment to children. Add to this the refusal of some malpractice insurance companies to cover legal proceedings involving off-label use of a drug. For these and other reasons, a pediatric label is the essence of rational therapeutics for children.Dr Shirkey noted wide use of the pediatric disclaimer clause in drug labels after the 1962 drug amendments, which many believed would increase pediatric labeling. Four pivotal articles1–4developed the concept and ramifications of the therapeutic orphan. These were preceded by his textbook Pediatric Therapy, the first edition of which was published in 1964.5 Salient features of the concept included:The FDA regulatory position was stated clearly: Drugs for use in children must be tested in children.6 For the next 30 years, a struggle ensued to comply with the FDA position of substantial evidence with data from pediatric clinical trials. But these trials required features considered unavailable. To obtain the necessary resources, validation of the therapeutic orphan dilemma was necessary, as was concurrent attention to real or perceived limitations to research in children.The Physicians' Desk Reference (PDR) remains a frequently consulted text about drug therapy. Accordingly, the first objective evaluation of labeled drugs available for children resulted from a review of 2000 drugs in the 1973 PDR.7 Seventy-eight percent of drugs were found to be without pediatric labeling or sufficient use information for children. Over the next 25 years, a continuum of validations from multiple sources was undertaken (Table 2).8–11Notable was one report9 in which 81% of drugs in the 1991 PDR were without pediatric information, with most having age-restricted labeling. Little change in the frequency of pediatric labeling had occurred in 18 years for the PDR (78% vs 81%; compare references 7 and 9). Recently approved new molecular entities (NME) revealed little change in frequency (Table 3).10–12 A labeling deficit remains for those drugs with potential pediatric use. These data validate undeniably both the dilemma and its longstanding nature.A very practical validation of the dilemma derives from analysis of off-label prescribing of drugs to children. FDA analyses of 11 drugs with pediatric age disclaimers revealed an unexpected frequency of off-label prescribing (Table 4).13 Notable among these are the psychoactive drugs Zoloft and Prozac, and also Alupent, widely used for treatment of asthma. These data validate the therapeutic orphan dilemma as being one for both drug reference sources (PDR and label) and also for actual use of prescription drugs in children.Before and as a consequence of recommendations from the Institute of Medicine Workshop in 1991,14 lists of drugs important for pediatric use have been developed (Table 5).11,13,15,16 Both the number and names of drugs vary according to the perspective and goal of the source. However, two clear statements emerge from review of the lists: first, many drugs require a deorphaning label because of likely pediatric use and, second, a consensus approach to produce a combined list for priority action is greatly needed. Of note is such a list mandated by pending legislation (vide infra). Given validations of the dilemma and its scope, multiple organizations have labored to resolve impediments to pediatric clinical trials, to change guidelines for the substantial evidence rule, and to encourage industry participation. Some of these labors and their results are discussed below.The AAP Committee on Drugs (COD) was formed in 1968 to replace the Committee on Dosage, formed in 1950.17 The COD was established to monitor, review, and resolve issues resulting from the therapeutic orphan dilemma. The COD has had seven chairpersons, the first of whom was Dr Shirkey and the second, Dr Sumner Yaffe. It has issued 91 policy statements on use of drugs in children, and five new statements are being developed. The COD and Committee on Bioethics statements are highly pertinent to clinical trials10,18and off-label prescribing,19 and they offer assistance to both investigators and physicians caring for children. Clear and ethical means exist for participation of children in clinical trials, and off-label prescribing, although legal, is not acceptable in lieu of pediatric labeling.11Concurrent with AAP actions, the FDA promulgated policies and guidelines on behalf of children. The sequence of major actions is summarized in Table 6.20–23These actions stipulated procedures for clinical trials acceptable to collect data for pediatric labeling submissions. Of special note is the 1994 revision, which allowed existing data extrapolations and clinical trials focused on dose and safety.23 In many circumstances, this applies to drugs currently available and hence should promote labeling at a greatly decreased cost to industry. As an additional measure of demonstrated significance to drugs for children, the Orphan Products Development (OPD) program of the FDA was authorized in 1983. Approximately one third of orphan product designations have a pediatric indication, and approximately half of those with marketing approval via OPD Program grant support have a pediatric indication (Table 7).24,25 Although targeted for rare diseases and limited market potential, the OPD program is an important avenue for pediatric labeling.In 1975 the USP established its Pediatric Advisory panel, with Dr Shirkey as its first chairperson. Those with expertise and interest in pediatric therapeutics review the pediatric sections of monographs of individual drugs. Monographs are compiled with both label and literature information. Although the label and PDR are restricted to FDA-approved information, monographs are not and, hence, offer a resource of collated data on pediatric drug use. A compendium of these monographs is published annually as the USP–Drug Information (USP-DI).26 Many refer to the USP–DI as an authoritative resource that includes pediatric drug information frequently. Additionally, a lack of pediatric drug information monograph gives an index of need, because neither label nor literature review by the USP and the Pediatric Advisory Panel disclosed reliable data for inclusion in the USP–DI.PhRMA provides an overview of industry efforts to address the dilemma of the therapeutic orphan. The scope of the 1990 and 1997 PhRMA surveys is presented in Table 8, and results collated by disease category are shown in Table 9.27 Drugs for a disparate number of diseases are under study for use in children. Yet to be determined is the proportion that achieve pediatric labeling. From data in Tables 2 and 3 for NMEs approved each year, the proportion that achieve labeling is likely to be small. However, the monitoring effort by PhRMA is to be applauded for its industry perspective and effort in recognition of the dilemma.Manpower in pediatric clinical pharmacology remains of great concern since its limitations on clinical trials were emphasized in 1972.28 Both design and implementation of pediatric clinical trials require professionals with special training and experience. As one index of manpower, results of American Board of Clinical Pharmacology certification of candidates for the period 1991–1996 were reviewed. Compared with respective categoric totals, 6% certified in clinical pharmacology and 16% certified in applied pharmacology were listed as pediatric.29 This represents 19 (8%) persons with pediatric interest of the 231 certified. This low number is a consequence of the lack of pediatric clinical pharmacology training programs. Solutions to this this problem should be sought now, if we are to respond to the emerging federal and industry mandate for clinical trials leading to increased pediatric labeling.Currently of note is the pending Better Pharmaceuticals for Children Act.30 Two important components include 1) that the Secretary of the US Department of Health and Human Services, with the counsel of pediatric pharmacology professionals, identify drugs most in need of pediatric studies; and 2) that incentives of a 6-month exclusivity are offered to companies that sponsor pediatric studies, in an effort to offset the economic imbalance of a limited market versus development.The NIH recognized a need to provide and sustain sites for pediatric pharmacology research if industry were to undertake clinical trials without delay and to apply enablements developed in the 30 years since recognition of the therapeutic orphan. Formation of the Pediatric Pharmacology Research Unit (PPRU) Network31 was timely in view of converging events23 summarized in several studies.1132–37 A description and status of the Network are presented in Table 10. The number of protocols and recent completion of a Network study for pediatric labeling of a new drug attest to both the need and the success of this endeavor, fostered with support and guidance from the National Institute of Child Health and Human Development (NICHD).Patent expirations and economic forces of the marketplace are leading to an increase in OTC switch of prescription drugs. This presents a new phase in the therapeutic orphan concept if pediatric labeling is not available for these drugs. Concerns include use in children without advice of an intermediary prescriber, increase in drug interactions and toxicity, and even wider off-label use for young age groups. Revised OTC drug labeling proposed recently will not ease these concerns.38 These concerns are deepened if OTC switch drugs do not have pediatric labeling as a prescription product. This and the extent of pediatric labeling for OTC switch drugs were examined for drugs switched from 1976 to 1991, according to a list of generic drugs and trade name OTC drugs.39 Comparisons of pediatric drug labeling were made before and after an OTC switch by using the PDR for the OTC switch year (or the previous year) and the 1997 Non-Prescription-Physicians Desk Reference (NP–PDR).40,41 During this period, 68 generic drugs and 74 corresponding trade name drugs were switched. From the analysis summarized in Table 11, it is apparent that more prescription drugs had pediatric labeling (albeit often age-restricted) before the switch than did OTC drugs. Only three drugs addressed this dilemma by offering pediatric OTC preparations of corresponding trade names.Although analysis of the OTC database is difficult in view of changes in drug name, ingredients, manufacturer, dose strength, age restriction category, and so forth on a trade name basis, the pediatric labeling dilemma appears worse for OTC drugs. Additional examination reveals that the disclaimer age was higher for more OTC drugs, and that more OTC drugs were labeled with the exclusion of children age 12 years and younger (Table 12). These data suggest an attempt to increase safety of the OTC drug by raising the age disclaimer, or that additional information may have been collected after the switch, thereby raising the disclaimer age. Compared with prescription drug age exclusions, the OTC drug age disclaimer was the same for 11 drugs, higher for 9, and lower for 1 drug, and 4 drugs showed OTC pediatric labeling without previous such labeling for prescription drugs. (Note that all OTC drugs were assessed in the 1997 NP–PDR.) A lower age disclaimer may be supported by data available after an OTC switch. However, whether disclaimers for any age group on an OTC label are effective in use restriction remains to be evaluated. Both adults and children have unfettered access to OTC drugs, and the label may not communicate pediatric use limitations appropriately.38 What extent of pediatric labeling should permit an OTC switch? Should a switch not be permitted until the prescription drug has a pediatric label? This is a new dimension of the therapeutic orphan concept, validated apparently for the first time with data for a 20-year period.As the 21st century approaches, child care providers, investigators, regulatory agencies, funding sources, and industry are confronted with a decision: Will the therapeutic orphan remain a fixture in our therapeutic paradigm or will we have the courage to perform those studies necessary to support safe and effective drug therapy for infants and children. The conclusions offered in this work (Table 14) and at the combined meetings of the Pediatric Pharmacology Research Unit Network and the European Society for Developmental Pharmacology (May 2, 1997; Washington, DC) give cause for optimism that the therapeutic orphan will disappear into an awkward moment of medical history.This work was supported by NIH grant #U01-HD31315-04.I appreciate receiving an advance copy of the 1997 NP–PDR from Medical Economics. Data compilation by John Rowell, RN; Angelo Poole, RN; Julie LaPrease, RN; Lori Johnson, MD; Lisa Miller, RN; and Lisa Wurtele, and the typing assistance of Carole Webb, Sherrie Stepp, Rebecca Hudson, and Lisa Winfield are appreciated. Special acknowledgment is given to those who assisted sources of information from the multiple databases: Elaine Holland, Ray Koteras, Charles Coté, and Cheston Berlin (AAP/COD); Alexander Shepherd (ABCP); George Bennett (AMA); Gloria Troendle and Victor Raczkowdki (FDA); Peter Vaccari (FDA OPD); Michael Weintraub (FDA OTC); George Giacoia (NIH); Mark Friedman (PDR); Paul Kaufman (PhRMA); and Keith Johnson (USP).