An Update on the Therapeutic Orphan

Abstract

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, s