Pediatric Pharmacology Research Units Research Articles

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Ontogeny of Pediatric Pharmacogenetics: Celebrating the Past and Vision for the Future.

Ontogeny of Pediatric Pharmacogenetics: Celebrating the Past and Vision for the Future.

50 Years Ago in The Journal of Pediatrics: Editorial Comment: Therapeutic Orphans

Shirkey H. J Pediatr 1968;73:119-20 Both the drug laws of 1938 and 1962 were catalyzed by pediatric tragedies—the deaths from sulfanilamide elixir made with the untested but toxic diethylene glycol and the birth defects, particularly phocomelia, from maternal ingestion of thalidomide, respectively. The result was that drugs introduced after 1962 had to be tested in children or had to carry an “orphaning clause,” stating it was not recommended for children. In 1968, Harry Shirkey, a pediatrician and pediatric pharmacologist, criticized the prevailing climate “created by present regulations of human experimentation [that] makes drug testing difficult” and urged all pediatricians and pediatric subspecialists to take on the “responsibility for developing active programs of clinical pharmacology and drug testing in infants and children” lest children become “therapeutic orphans.” More than 25 years would pass before the National Institutes of Health would create the Pediatric Pharmacology Research Unit Network to support pharmaceutical testing of children (1994). At that time, nearly 80% of drugs lacked a pediatric label.1Christensen M.L. Chesney R.W. Has the ‘therapeutic orphan’ finally been adopted?.J Pediatr Pharmacol Ther. 2003; 8: 175-176PubMed Google Scholar Between 1997 and 2002, new federal laws and regulations “increased both the number of medications in pediatric clinical trials and the number that are labeled for use in children.”2Steinbrook R. Testing medications in children.N Engl J Med. 2002; 347: 1462-1470Crossref PubMed Scopus (193) Google Scholar The new drug testing was encouraged by both a carrot and a stick.2Steinbrook R. Testing medications in children.N Engl J Med. 2002; 347: 1462-1470Crossref PubMed Scopus (193) Google Scholar The carrot was the “pediatric exclusivity provision,” which granted an additional 6 months of patent protection or market exclusivity for new molecular entitles voluntarily tested in children. The stick was the “Pediatric Rule,” a requirement by the Food and Drug Administration that, in some circumstances, pharmaceutical companies would be required to test their molecular entitles to get approval from the Food and Drug Administration. Although this regulation was struck down, Congress passed other legislation. By 2002, new policies from the National Institutes of Health and Congressional regulations promoting pediatric research led Christensen and Chesney to proclaim that the “‘Therapeutic Orphan’ has finally been adopted.”1Christensen M.L. Chesney R.W. Has the ‘therapeutic orphan’ finally been adopted?.J Pediatr Pharmacol Ther. 2003; 8: 175-176PubMed Google Scholar The adoption was further solidified by the enactment of the Food and Drug Administration Safety and Innovation Act in 2012, which made these mandates permanent, although funding comes up for renewal every 5 years.

Ensuring safe and effective medication use in pediatric patients.

This is a tremendous honor to receive peer recognition carrying the name of late Dr Sumner Yaffe. I was fortunate to have worked with him over many years through professional organizations and as a part of the pediatric pharmacology research units (PPRUs). Dr Yaffe established pediatric pharmacology programs in Buffalo and Philadelphia and made important contributions to enhance pediatric care with his research, practice, and teaching. He led the development of PPRUs and the neonatal networks, and was a force behind the framing of what became the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA). He was indeed a visionary leader and mentor in the field of pediatric pharmacology. The objectives of my presentation today are to briefly share my background, reflect on our work, and discuss potential opportunities to advance pediatric pharmacy, pharmacology, and therapeutics.

Pediatric News

Pediatric News

Orphans in the world of drugs

Orphans in the world of drugs

The Dawn of Pediatric Personalized Therapeutics

Address.correspondence.to.Stephen.P..Spielberg,.MD,.PhD,. Marion.Merrell.Dow.Chair.in.Pediatric.Pharmacogenomics;. Director,.Center.for.Personalized.Medicine.and.Therapeutic. Innovation,.Children’s.Mercy.Hospital,.2401.Gillham. Road,.Kansas.City,.MO.64108,.email:.sspielberg@cmh.edu © 2010 Pediatric Pharmacy Advocacy Group It is a great honor for me to have been awarded the Sumner Yaffe Lifetime Achievement Award in Pediatric Clinical Pharmacology. Dr. Yaffe has been a lifelong mentor and colleague, a true definer of a discipline, creator of the Pediatric Pharmacology Research Units (PPRU) sponsored by the NICHD, and a dear friend. I am tremendously grateful to the PPAG for honoring me with this award in his name. The last years have been important ones for pediatric therapeutics. The scientific basis has been driven by huge advances in pediatric clinical pharmacology, fundamental understanding of the ontogeny of drug disposition and of drug response. United States legislation including the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act have changed the drug development process, leading to new knowledge about the safe, effective use of medicines in children. Research networks including the Pediatric Pharmacology Research Units (PPRUs), the Children’s Oncology Group, and now the Clinical and Translational Science Award (CTSA) network have increased pediatric investigative activities throughout the country. The National Institutes of Health (NIH) and the Food and Drug Administration (FDA) have ABBREVIATIONS ADRs,.adverse.drug. reactions;.CTSA,. Clinical. and.Translational. Science. Award;. CYP2D6,. Cytochrome.P2D6.System;.CYP2D9,.Cytochrome.P2D9. System;.EMEA,.European.Medicines.Evaluation.Agency;. FDA,.Food.and.Drug.Administration;.GENDEP,.Genome. Based.Therapeutic.Drugs. for.Depression;.GWAS,.whole. genome.association. studies;.MDD,.major. depressive. disorder;.NICHD,.National. Institute.of.Child.Health.and. Human.Development;.NIH,.National.Institutes.of.Health;. PPRU,. Pediatric. Pharmacology.Research.Units;. SSRIs,. selective.serotonin.reuptake.inhibitors. both played critical roles, with the FDA Critical Path initiative in many ways reflecting scientific thinking about translational medicine driving

Drug Therapy for Children in China

The population of China is huge and includes 400 million children. For China, as for other countries in the world, there remain a number of questions from the past about drug therapy for children, such as unlicensed and off-label drug usage. Recently, China has updated Good Clinical Practice (GCP) guidelines, including those for pediatric drug clinical trials. Pediatric pharmacology research units need to be set up throughout the country. To provide better medicines to children in China is an enormous undertaking.

Association of the Histamine N‐Methyltransferase C314T (Thr105Ile) Polymorphism with Atopic Dermatitis in Caucasian Children

To investigate potential associations between the histamine N-methyltransferase (HNMT) gene, HNMT, C314T (Thr105Ile) polymorphism and atopic dermatitis in a cohort of Caucasian children. Prospective, multicenter, genotype-association study. Four academic, tertiary care medical centers within the Pediatric Pharmacology Research Unit network. Two hundred forty-nine Caucasian children aged 6 months-5 years with atopic dermatitis (127 patients) or without (122 control subjects). Buccal swabs (one swab/cheek) were performed to obtain epithelial cells for extraction of genomic DNA. Data were collected on severity of atopic dermatitis, oral antihistamine treatment, and treatment response through parental report. The HNMT genotypes were successfully obtained in 116 control subjects and 122 patients with atopic dermatitis. Frequencies of the T314 variant allele (0.12 vs 0.06, p=0.04) and combined CT/TT genotype (0.24 vs 0.12, p=0.02) were significantly higher in children with atopic dermatitis compared with control subjects. Children with genotypes conferring reduced HNMT activity were 2 times more likely to have atopic dermatitis than those who were homozygous for the C314 reference allele. Increased histamine levels in patients with atopic dermatitis may result, at least in part, from reduced enzymatic inactivation via HNMT. Genetically associated reduction in histamine biotransformation may therefore contribute to the pathogenesis, persistence, and progression of atopic dermatitis. If confirmed, these data indicate that HNMT genotype might represent a common risk factor for development of atopic dermatitis, asthma, and allergic rhinitis and may be useful in identifying individuals who are candidates for early preventive pharmacotherapeutic intervention. Additional longitudinal studies will be required to assess the relationship between genotype, disease severity, and antihistamine response.

Six-month, prospective, longitudinal, open-Label caffeine and dextromethorphan phenotyping study in children with growth hormone deficiency receiving recombinant human growth hormone replacement

Background: Recombinant human growth hormone (r-hGH) is increasingly being used in children. Although growth hormone (GH) may alter the clearance of concomitantly administered medications, its effects on individual drug-metabolizing enzymes in children have not been characterized. Objective: The goal of this study was to assess the activities of cytochrome P450 (CYP) 1A2, N-acetyltransferase 2, xanthine oxidase, and CYP2D6 in children with isolated idiopathic GH deficiency before and 3 and 6 months after initiation of r-hGH treatment. Methods: This 6-month, prospective, longitudinal, open-label phenotyping study was conducted at 4 academic tertiary care centers within the Pediatric Pharmacology Research Unit network. Prepubertal or early pubertal children (4-14 years) with short stature and isolated idiopathic GH deficiency were enrolled. Patients were given 4 ounces of a cola beverage and 0.5 mg/kg of dextromethorphan (DM) before and 3 and 6 months after initiation of r-hGH treatment. Urine was collected for 8 hours after probe substrate administration, and enzyme activity was assessed using validatedcaffeine/metaboliteandDM/metabolitemolar ratios. Patients with a DM/dextrorphan molar ratio ≥0.3 were classified as poor metabolizers, and those with a ratio <0.3 were classified as extensive metabolizers. Anthropometric and biochemical responses were assessed at each visit. Blood was also obtained for determination of serum insulinlike growth factor-1 (IGF-1) levels and CYP2D6 genotype. Results: Fourteen patients (mean [SD] age, 11.5 [2.6] years [age range, 4.5-14.6 years]; 11 males, 3 females; 100% white; median height and weight, 131.8 cm and 29.2 kg, respectively) completed the 3 study visits. However, data from 2 patients were excluded from analysis due to procedural violations. In all patients, growth velocity and serum IGF-1 concentrations were significantly higher ( P < 0.001) after r-hGH treatment (mean doses, 0.32 and 0.33 mg/kg per week at 3 and 6 months, respectively). However, molar ratio values did not significantly change after initiation of r-hGH. Conclusions: In this study population of children with isolated idiopathic GH deficiency, no significant differences in caffeine/metabolite and DM/metabolite molar ratios were observed after initiation of r-hGH treatment.

Still orphans

Approximately 40 years ago, in the wake of thalidomide-induced phocomelia, Dr. Harry Shirkey1 labeled children as therapeutic orphans, raising awareness of the paucity of medication safety and efficacy data in children. In the interim, there have been some gains for children as the result of workshops focusing on pediatric drug development,2,3 programs such as the Pediatric Pharmacology Research Unit Network, and laws such as the Best Pharmaceuticals for Children Act (BPCA) of 2002 that grants an additional 6 months of marketing exclusivity for new medications in which pediatric studies are performed and provides for mechanisms that fund the study of off-patent medications used in children. Since the legislation’s implementation, >100 products have been granted exclusivity, including gabapentin, lamotrigine (LTG), oxcarbazepine, and levetiracetam. Of note, approximately a third of the products studied required relabeling because of important differences in dosage, safety, or efficacy in children.4,5 Despite advances, the picture has only minimally improved for children <2 years of age. Although they represent a significant proportion of patients with new onset epilepsy, none of the antiepileptic medications approved since 1993, including those granted …

Untying the Gordian Knot

In Response: We appreciate the thoughtful comments by Drs. Su, Zuppa, and Adamson (1) in response to our editorial, “Pediatric Research and Scholarship : Another Gordian Knot?” (2). We discussed the difficulties in pediatric pharmaceutical research and in developing data to support pediatric drug labels. We do not suggest that investigator-initiated studies cannot meet the Food and Drug Administration's (FDA) definition for adequate and well-controlled studies. However, most pediatric studies involve small numbers of patients in investigator-initiated trials that do not meet the FDA's definition for adequate and well controlled studies. Adequately trained investigators can and do perform these studies, but usually under the sponsorship of a pharmaceutical company. The Pediatric Pharmacology Research Unit is a very valuable resource allowing implementation of pediatric research trials. The accompanying letter highlights this valuable resource. As the correspondents state, they were unable to engage the previous pharmaceutical sponsor to initiate pediatric studies of dexmedetomidine. As related to one of the authors (JRT, personal communication), the sponsor claimed that they were unable to initiate pediatric trials until the FDA was satisfied with an adult trial with more than 24 h infusion of dexmedetomidine. That study is underway and was not required for the initial approval of the drug. Regardless of the etiology, progress with pediatric studies and labeling has been delayed. Following publication of data which might support a labeling change, it should be acknowledged that only the sponsor can request labeling changes, or special consideration for labeling changes can be considered at the initiative of the FDA. We are delighted to hear of the success of the correspondents in their preparation of the current trials by having contacted the FDA and used an Investigational New Drug application to support the current studies. This route should be considered for any new pharmaceutical that investigators believe will have significant impact in pediatric care but does not have the support of the sponsor. We are pleased to have had initial communications with the manufacturer of dexmedetomidine, Hospira, Inc., in initiating sponsor-funded pediatric trials. A Gordian Knot may not easily be untied, but one historical anecdote states that Alexander the Great “cut through it with a sword.” As Dr. Su and colleagues suggest, maybe the solution is not so complex if interested parties decide it is a priority. We appreciate the opportunity to focus attention on the easily disregarded needs of children's health in anesthesia and other fields of medicine. Joseph R. Tobin, MD Wake Forest University School of Medicine Winston Salem, NC Steven L. Shafer, MD Stanford University Stanford, CA Peter J. Davis, MD University of Pittsburgh School of Medicine Pittsburgh, PA [email protected]

Untying the Gordian Knot

To the Editor: In their editorial that accompanied four articles on dexmedetomidine use in children, Drs. Tobin, Shafer, and Davis (1) assessed the broad impact of the pharmaceutical industry's lack of interest in conducting appropriate drug development studies for children. Yet the solution to “untying the Gordian knot” extends beyond the Food and Drug Administration (FDA) and industry. A critical factor largely absent from the discussion is training clinical investigators to meet the needs of pediatric drug development. We take issue with the contention that investigator-initiated studies cannot meet “… the FDA's definition for adequate and well controlled studies, …” because adequately trained investigators can certainly undertake such studies when given adequate support. Our recent experience with dexmedetomidine shows how this can be done. From October 2003 to December 2005, we repeatedly attempted to engage various members of Abbott Pharmaceuticals to initiate appropriate pediatric studies. These efforts failed. However, we garnered limited support from the National Institute of Child Health and Human Development's Pediatric Pharmacology Research Unit (PPRU), allowing us to implement a pediatric, drug development plan for dexmedetomidine. The PPRU comprises 13 academic sites that develop and perform clinical pharmacologic research in the pediatric population, often in collaboration with industry partners. The network includes experts in quantitative drug analysis, pharmacokinetic/pharmacodynamic (PK/PD) modeling, pediatric clinical trial design, and a wide range of pediatric subspecialties. Our initial trial is a PK/PD study of dexmedetomidine administered as a continuous infusion in infants after open-heart surgery. This dose-escalation study evaluates both the PK profile in this population and concentration-response relationships with respect to hemodynamic variables, tracheal extubation readiness, quality of sedation, and overall safety. The trial is nearly complete, and has produced a preliminary model of dexmedetomidine PK in infants. This model will enable us to design the next stage of investigations. As described in the accompanying editorial (2), our investigator-initiated study is being performed under an Investigational New Drug application, and our interaction with the FDA has been productive. There is a paucity of funding and an insufficient number of programs available to train experts in pediatric drug development. Although there are more than 250 children's hospitals in the United States, only a few train pediatric subspecialists in clinical pharmacology. Future efforts to assure appropriate design of clinical pharmacologic studies in children must include a comprehensive effort to train young investigators. These investigators are desperately needed in academia, industry, and the FDA. The solution to this Gordian knot is perhaps not that complex. Society, academia, government, and industry must simply decide that it is important enough to untie. Felice Su, MD Athena F. Zuppa, MD, MSCE Department of Pediatrics Division of Clinical Pharmacology and Therapeutics Department of Anesthesia and Critical Care Medicine Division of Critical Care Medicine The Children's Hospital of Philadelphia Peter C. Adamson, MD Department of Pediatrics Division of Clinical Pharmacology and Therapeutics Philadelphia, PA [email protected]

A Historical Perspective on Pharmacological Studies of Gentamicin for Therapy of Neonatal Meningitis

Address correspondence to: George H. McCracken, Jr., MD, UT Southwestern Medical Center, Dallas, Department of Pediatrics, Division of Infectious Diseases, 5323 Harry Hines Blvd., F3-202, Dallas, TX 75390-9063, email: george.mccracken@utsouthwestern.edu © 2006 Pediatric Pharmacy Advocacy Group ABBREVIATIONS CSF, cerebral spinal fluid; IL-1β, interleukin-1 beta; LPS, lipopolysaccharide; MIC, minimal inhibitory concentration; PPRU, Pediatric Pharmacology Research Unit Much of my early career in Pediatric Infectious Disease was devoted to defining the optimal management of neonatal meningitis caused by Gram negative enteric bacteria. To accomplish this required an understanding of clinical pharmacology of antibiotics in newborn infants, an area rarely explored in the period before the late 1960s when I started my investigative career. Indeed, in 1968 Dr. Harry Shirkey, a pharmacist-turned-pediatrician, lamented the fact that infants and children were often denied use of many drugs because of the lack of data on their pharmacokinetics, safety and efficacy.1 He termed these patients “therapeutic orphans” and encouraged the development of active programs of clinical pharmacology and drug testing in pediatric patients, especially in infants and young children. It was in this setting that I launched my investigations of the clinical pharmacology of antibiotics in newborn and young infants, particularly as they pertained to treatment of bacterial meningitis. Now, 38 years later, I am thrilled to receive the Sumner J. Yaffe Lifetime Achievement Award in Pediatric Pharmacology and Therapeutics from the Pediatric Pharmacy Advocacy Group in recognition of these and other studies that helped to clarify the safe and effective use of antibiotics in infants and children. I am honored to receive this award named for Dr. Yaffe, who was as instrumental as anyone in promoting the critical impor-

Tetracycline: Studies on absorption, distribution, excretion and clinical trial in children

Chlortetracycline was isolated from Streptomyces aureofaciens in 1944, and in 1953 tetracycline was derived from chlortetracycline by chemists at Pfizer and Lederle pharmaceuticals. Chlortetracycline, which was not developed for humans because of toxicity concerns, is still an additive to animal feed. Schwarzer and colleagues performed a pharmacokinetic study of tetracycline in infants and children seeking to derive dosage guidelines. Recognizing that children are not “miniature adults,” studies of this type were and are needed. In 1994 only five of the 80 drugs most commonly administered to infants and children were labeled for pediatric use. In response to this need, the National Institute of Child Health and Human Development, under the leadership of Dr Duane Alexander, the vision of Dr Sumner Yaffe, and the hard work of Drs George Giacoia and Gilman Grave, established a Network of Pediatric Pharmacology Research Units. These units obtain data that place drug administration to children on a scientific basis. Recently the Food and Drug Administration added funds to the program recognizing the importance of performing such studies with child-friendly protocols with minimal risk to children.

The testing of antihypertensive medications in children: report of the Antihypertensive Agent Guidelines Subcommittee of the Pediatric Pharmacology Research Units.

The testing of antihypertensive medications in children is timely because physicians caring for hypertensive children—especially pediatric nephrologists, cardiologists, endocrinologists, and adolescent medicine physicians, as well as clinical pharmacologists—have as therapeutic options almost no approved drugs for children, and somewhat outdated official recommendations.1,2 In the balance of this need lie the problems inherent in using pediatric populations for clinical trials—a problem that has been recognized by leaders in the pharmaceutical industry. A representative of the pharmaceutical industry concurred that a particularly difficult pediatric population are hypertensives. The incidence (and prevalence) of hypertension in childhood is low, between 2% and 5% in some series.1 Even in many of the population groups in which numerous epidemiologic studies have shown that adult hypertension is frequent—participants with diabetes mellitus, obesity, certain racial groups (black, Native American, Latino), and in families with essential hypertension—the prevalence of hypertension during childhood is low, but blood pressure values may progress over time to be hypertensive.2,3 Placebo control and placebo arm of treatment trials are problematic because the only children in whom recommendations for therapy exist are those whose blood pressures are above the 95th percentile.2,3 The identification of hypertension is further beset by a considerable number of technical issues, including white coat hypertension, appropriate cuff size for arm length or weight, height related norms, current paucity of validation of ambulatory blood pressure measurements, and measurement devices in North American children, which Korotkoff sounds to evaluate (4th or 5th) and at which ages, and whether the 4th or 5th sound is more relevant in children under 13-years of age.4 Studies in children who are the offspring of adult hypertensive participants have shown that reproducible stress testing (eg, playing a video game at an accelerating speed) may unmask a tendency for blood pressure elevation for chronological …

Clinical pharmacology research in the pediatric patient: the challenge continues

For most of the 20th century, most drugs labeled by the United States Food and Drug Administration (USFDA) have not been adequately studied in the pediatric population. This lack of data has necessitated the continued dependence of practitioners on sub-optimal prescribing data placing pediatric patients at great risk of serious therapeutic misadventures. Recently, the USFDA has enacted and begun to enforce the Final Rule of 1997 which became effective on 1 April 1999. This rule is the culmination of the persistent efforts of numerous professional organizations, clinicians, academicians, the USFDA and others, to ensure the ready availability of appropriate data for medications intended for or that will be used in children. Unlike the 1994 Rule which voluntarily required pharmaceutical manufacturers to submit pediatric data, the Final Rule mandates submission of such data and, most importantly, empowers the USFDA to afford incentives and penalties for non-compliance including possible removal of already marketed products. This overview addresses many of the important components which must be included in the performance of a comprehensive clinical pharmacologic evaluation serving as the foundation for optimal dosing across the broad age range encompassing pediatric practice. Furthermore, the possible risk and/or benefits of the study must be reasonably defined prior to undertaking the study and clearly shared with the patient's caregivers. Consent should always be obtained from the caregiver and, when appropriate, assent obtained from the underage child. To facilitate such clinical investigations and to foster collaborative efforts with innovators and clinical research programs, the National Institutes of Health through the National Institute of Child Health and Human Development of the NIH established a network of Pediatric Pharmacology Research Units. These units have worked closely together and with other pediatric research centers to facilitate USFDA labeling of a number of commonly used medications. All of these very positive efforts highlight the many challenges that remain for the pediatric investigator and practitioner while underscoring the very positive environment in support of these efforts.

Clinical trials with antipyretic drugs in febrile children: A position statement on exclusion criteria

Clinical trials of antipyret.ic drugs in febrile children are difficult to conduct when exclusion criteria are so restrictive that a sufficient number of patients cannot be recruited to define efficacy for labeled use in the population. Recent use of an antipyretic drug is one such exclusion criterion that limits enrollment and consumes a great amount of triage time and effort. This paper examines the basis for this exclusion criterion, its impact on clinical trials undlerway in the Pediatric Pharmacology Research Unit (PPRU) Network, and alternatives that permit the exclusion of this criterion without compromising the study design or the outcome of data analysis.

The Pediatric Pharmacology Research Unit (PPRU) Network and Its Role in Meeting Pediatric Labeling Needs

This meeting marks a milestone in the quest for solutions to the phenomenon referred to by Harry Shirkey in this country 3 decades ago as the problem of the therapeutic orphan.1 I know that the European colleagues who have come to share their knowledge and experience have long concerned themselves with ways of overcoming this same phenomenon in their respective countries. The person who has been attacking this issue for the longest time in the United States is Sumner Yaffe, the progenitor of this meeting and the man responsible for the development of the Network of Pediatric Pharmacology Research Units (PPRU) from his position as director of the Center for Research on Mothers and Children of the National Institute of Child Health and Human Development (NICHD). Iam indebted to Sumner for the opportunity to chair the PPRU Network Steering Committee and to Jeffrey L. Blumer, the principal investigator (PI) at the Cleveland PPRU site for planning today's watershed event. There have been numerous reasons given by pharmaceutics manufacturers over the years for their failure to sponsor tests that would provide data sufficient to result in approved labeling for pediatric use when new drugs were introduced (for the purposes of this talk, I'll speak to the issues that we face in the United States only, but I recognize that similar issues exist in virtually every country represented at this conference). The advances made in several spheres of endeavor and the creation of the PPRU Network have primarily eliminated virtually all the arguments that have been used over the years to avoid the development of labeling for the use of most drugs for pediatric indications. The most commonly used excuses for failure to provide the results of pediatric studies for labeling of new drugs, or for new pediatric indications for …

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 … Address correspondence to John T. Wilson, MD, Section on Clinical Pharmacology, Department of Pediatrics, Louisiana State University Medical Center, Shreveport, LA 71130.