Clinical Therapeutics/Volume 27, Number 6, 2005

Newborns and Drug Studies: The NICHD/FDA Newborn Drug Development Initiative
George R Giacoia, MD; and Donald R. Mattison, MD

Obstetric and PediatricPharmacologyBranch, Centerfor Researchfor Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Rod(vii~e, Maryland
ABSTRACT Background: Progress has been made in research on the effects of drug therapy on pediatric patients, but neonates are still an understudied population. Those most fikely to receive drug therapy (eg, preterm infants) are least likely to be studied. Objectives: The purposes of this article are to summarize an initiative developed jointly by the National Institute of Child Health and Human Development (NICHD) and the US Food and Drug Administration (FDA) and to introduce a series of articles developed as a result of this initiative. Methods: Information for this article was gathered from the proceedings of a workshop cosponsored by the NICHD and the FDA that took place March 29 and 30, 2004, in Rockville, Maryland. Results: Dosing based on use in adults and older children has resulted in adverse events among newborn infants, and may have long-term effects. Moreover, formulations appropriate for use in neonates are often unavailable, and compensatory efforts such as mixing crushed tablets into formula may interfere with accurate dose delivery. Under the Best Pharmaceuticals for Children Act of 2002, government agencies work with experts in pediatrics and pediatric research to develop and prioritize a list of off-patent drugs for which pediatric studies are urgently needed. Four such listings were published in the Federal Register from January 2003 through January 2005. The NICHD and FDA have also initiated the Newborn Drug Development Initiative (NDDI), a multiphase program to determine gaps in knowledge concerning neonatal pharmacology and clinical trial design and to explore novel study designs for use in newborns, with the ultimate goal of increasing our knowledge about the safety and efficacy of drugs used to treat newborns. Conclusions: Most drugs used to treat newborns still lack appropriate dosing, efficacy, and safety stud796 ies in this vulnerable population. The NICHD and FDA developed the NDDI as an ongoing process to identify and suggest strategies for addressing obstacles to conducting drug trials in the newborn. (Clin Tber. 2005;27.-796-813) Copyright 2005 Excerpta Medica, Inc. Key words: neonate, National Institute of Child Health and Human Development, US Food and Drug Administration, NDDI.

INTRODUCTION More than 40 years ago, Harry Shirkey coined the term "therapeutic orphans," referring to the plight of children receiving drugs without the benefit of pediatric drug studies to characterize safety and efficacy, t Great strides have been made in drug testing in children since the rnid-1990s, with the estabfishment of the National Institute of Child Health and Human Development (NICHD) Pediatric Pharmacology Research Network, passage of the US Food and Drug Administration (FDA) Modernization Act of 1997 (FDAMA), 2 the Best Pharmaceuticals for Children Act of 2002 (BPCA),3 and the Pediatric Research Equity Act of 2003. 4 FDANIA provided a "carrot" of 6 months of market exclusivity for on-patent drugs in return for studies in children, resulting in a number of studies in older children. The number of drugs studied in newborns, however, has remained very small and, for the most part, those studied were full-term infants. In contrast, the population of infants receiving neonatal intensive
Accepted[or publicati~ March 20, 2005.
doi: 10.1016/j.climhera.200S.06.008 0149-29181051519.00 Primed in the USA. Reproduction in whole or par is not permitted. Copyright 2005 Excerlxa Medica, Inc.

Volume 27, Number 6

G.R G i a ~ a and D.R. Matlison

care is primarily preterm infants, and most of the drugs given in this setting have not been tested; as a consequence, they are not labeled for use in this age group, s This problem is compounded by the frequent off-label use, in neonates, of drugs that have been approved for adult indications. In addition, polypharmacy is common during hospital stays. 6 It is of interest that most of the adverse drug events frequently mentioned to support the need for more drug testing in children occurred in this most vulnerable of the pediatric populations--the term and premature neonate.7,s The purpose of this article is to summarize an initiative developed jointly by the NICHD and the FDA and to introduce a series of articles developed as a result of this initiative.

METHODS Information for this article was gathered from the proceedings of a workshop cosponsored by the NICHD and the FDA that took place March 29 and 30, 2004, in Rockville, Maryland.
UNIQUENESS O F N E W B O R N POPULATION Maturational heterogeneity, distinctive physiologic and metabolic characteristics, and conditions or dis. eases that are unique to this period of life characterize the neonate as a special population. Conditions affecting preterm infants are different from those typically affecting full-term infants. However, there is an overlap in certain conditions (eg, necrotizing enterocolitis); therefore, therapies may need to be evaluated in neonates at a range of gestational ages. Not infrequently, different conditions coexist in the sick neonate, making it difficult to evaluate the efficacy of using outcome measures such as mortality. The physiologic and metabolic characteristics of low-birth-weight infants, as well as the pathophysiologic abnormalities associated with the various conditions they experience, can influence the biodisposition and effects of drugs typically seen in the newborn population. Although not sufficiently studied, the rapid and variable maturation of physiologic and pharmacologic processes during the first month of life requires modifying treatment regimens for some drugs. Immaturity of physiologic processes and organ function ~-16 may lead to marked differences in absorption, ~7-~9 distribution,Z0, z~ metabolism, zz-~ and/or excretionZT,zs between preterm and term infants and older infants and children, z~-31 June 2005

Use of Drugs in Newborns Traditionally, drugs have been introduced to the neonatal intensive care setting on the basis of efficacy in adults, single cases, or small case series. As a consequence, pediatric doses are empirically derived, safety is unknown, and efficacy is presumed but not demonstrated. The introduction of tolazoline for the treatment of pulmonary hypertension of the newborns illustrates the problem of drugs becoming widely used without appropriate efficacy and safety studies. The fLrSt report of the use of tolazoline in newborns was published as a letter to the editor. 3z The drug was used in 5 preterm newborns with pulmonary hypoperfnsion complicating hyaline membrane disease. The dose was empirically derived (2 mg/kg). The author stated, "no severe gastrointestinal difficulties as those reported in adults were found," and "considerable normalization of various abnormalities" occurred. 32 In the ensuing years, tolazoline became widely used for hypoxemia refractory to mechanical ventilation.3~, ~4 Patients in a number of studies were full-term infants affected by pulmonary hypertension.3s Efficacy was based mostly in improvements in arterial oxygenation and not on outcome. ~ No randomized, placebo-controlled studies were carried out. It took more than 15 years of use before dosing recommendations became available. 37 A study published in 1986 demonstrated a prolonged half-life in patients with decreased renal function and suggested that the infusion rates be substantially reduced.3s.39 Adverse events, including gastrointestinal hemorrhage and duodenal perforation, were reported.4.41 The drug was labeled for use in newborns with pulmonary hypertension despite the absence of controlled clinical trials. The high incidence of bleeding, lack of efficacy, and development of extracorporeal membrane oxygenation and the use of nitrous oxide42 resulted in the abandonment of this therapy. This example illustrates a major problem in neonatology: it is standard practice for a drug to be incorporated into the therapeutic armamentarium before efficacy has been demonstrated. When a drug therapy becomes the standard of care, ethical considerations prevent the use of placebo-controlled trials. Few drugs labeled for adult indications--and subsequently used off-label in the intensive care nurse_n/have proved efficacious. The notable exceptions have been drugs specifically designed for use in the newborn population (eg, surfactant for respiratory dis797

Clinical "Owrapma~ tress syndrome, nitrous oxide for persistence of pulmonary fetal circulation). The scarcity of adequate clinical trials in newborns can be attributed to several factors: (1) ethical concerns, (2) lack of incentives for pharmaceutical sponsors, (3) limited numbers of patients available for study, and (4) lack of appropriate study designs, particularly for drug studies in premature and low-birth-weight infants. The uniqueness of neonatal conditions and diseases is such that extrapolation of efficacy studies for adult indications is rarely possible.43 be the difficulty of distinguishing between drug effects on growth/development and abnormalities related to prematurity and conditions associated with preterm delivery. 47
Formulations In most instances, formulations appropriate for treatment of neonates are not available. Tablets and capsules are unsuitable, and the lack of liquid oral formulations has led to the practice of crushing or pulverizing tablets or opening capsules and mixing with formula or a solid food. There are no data documenting that the desired dose is absorbed.48 Tablet splitting is associated with substantial variability between doses. The oral administration of injectable formulations can also be problematic. Some drugs are chemically degraded by gastric acid. In other cases, the concentration of the formulation may be too diluted, requiring prohibitively large fluid volumes for small infants. Injections may also contain potentially toxic excipients and the taste may be unacceptable to newborns.4 Taste perception and preferences develop early in fetal development. Studies in preterm infants have documented their preference for sweets and aversion to bitter taste, s Although a methodology is available for testing the taste preferences of newborns and infants, st palatability studies of commercial oral drug formulations are not available. Excipients present in the commercially available parenteral and topical formulations may lead to serious adverse events. Propylene glycol, benzyl alcohol, and polyethylene glycol have been implicated in neonatal toxicity, and diminished renal function in preterm infants may increase the risk of toxicity, s2-s9 Hyperosmolality has reportedly resulted from IV administration of multivitamin preparations containing propylene glycol,s2 The increased permeability of the skin in preterm infants facilitates the transdermal absorption of propylene glycol; toxicity in preterm infants hasincluded coma and increase in osmolal gap.S2,s5 A gasping syndrome has been described in premature infants receiving benzyl alcohol as a preservative in parenteral preparations, s*.s7 Metabolic acidosis (presumably from the benzoic acid metabolite) has increased intraventricular hemorrhage,Ss,s9 and mortality has led to the recommendation that benzyl alcohol not be used as a preservative in the formulation of drugs to be used in newborns, s4-s7 Volume 27, Number 6

Toxicky
Both short- and long-term toxicity (especially functional alterations, which may not be evident until later in life) are major concerns in newborns, particularly in those delivered before term. Recognition of adverse drug reactions is hampered by the limited repertoire of signs and symptoms exhibited by immature infants. For example, neonatal toxicity produced by chloramphenicol or benzoic acid may masquerade a s sepsis. 44 Intoxication may occur as the result of many different factors, including limited activity of drugmetabolizing enzymes (DMEs) (eg, limited glucuronidation of chloramphenicol)4s or drug inhibition of a specific DME activity superimposed on an already developmentally decreased enzyme activity. For exampie, coadministration of erythromycin, an inhibitor of cytochrome P450 (CYP) 3A4 with midazolam, a CYP 3A4 substrate, has produced deeper and prolonged sedation in neonates compared with older infants and children.4~ Factors that influence the long-term effects of drug treatment on the development and function of different organ systems include (in addition to the specific action of a drug): duration of exposure, degree of immaturity, specific interactions between drugs and organ development, and effects on growth and development. Unraveling possible long-term effects on skeletal, behavioral, cognitive, immune, and pulmonary development and function would require epidemiologic study of a large number of newborns coupled with mechanistic experimental and clinical studies to demonstrate a canse-effect relationship. However, validation of biomarkers of development and function, as well as drug effect, will improve trial design, long-term safety evaluation, and interpretation. A major challenge that is likely to persist, given the increasing frequency of premature deliveries, will
798

G.P. Giaceia and D.R. Matlisen

BPCA AND THE NEWBORN DRUG DEVELOPMENT INiTiATiVE Among the provisions enacted by BPCA in 2002 was the establishment of a process to study off-patent use of drugs in children. Notably, there was also a recommendation to include newborns in these clinical studies, whenever relevant. The BPCA directs the secretary of the Department of Health and Human Services, acting through the director of the National Institutes of Health (NIH) and in consultation with the commissioner of the FDA (and experts in pediatrics and pediatric research), to develop and prioritize a list of offpatent drugs for which pediatric studies are urgently needed. Four such listings have been published in the Federal Register. The initial list was published in January 2003, and others have been published in August 2003, January 2004, and January 2005 (see the table for a summary of the drugs listed in the Federal Register as of April 2005). ~6s Under BPCA, the design of clinical trials for pediatric populations is based on iterative collaborative activities between the FDA and the NIH to develop written requests (WRs), by which the FDA notifies manufacturers of the need to obtain additional clinical information about drugs for selected indications in specific populations.3 Several drugs on the published lists are for neonatal indications (Table). They include dopamine and dobutamine for cardiovascular interventions in preterm infants; lorazepam for sedation; metoclopramide for gastroesophageal reflux; diuretics (furosemide) for bronchopulmonary dysplasia (BPD); and azithromycin for Cblamydia infections. Efforts to develop WRs for these drugs and indications have been frustrated by a number of scientific issues summarized in the previous section. Additional concerns about the design of these trials were related to the condition or disease, the indication, the off-label use of the drug, or the complexities involved in designing appropriate clinical trials in the newborn population.43 A number of issues further complicate the design of clinical trials of inotropic agents in preterm infants: (1) the lack of a widely accepted neonatal blood pressure standard, (2) the current practice of treating hypotension in low-birth-weight infants with or without evidence of poor tissue perfusion, (3) profound hemodynamic alterations due to patent ductus arteriosus and decreased left ventricular function, and (4) lack of validated markers of cardiac output, organ perfnsion, and long-term outcomes in response to interventions
June 2005

for cardiovascular collapse or shock/~ The design of efficacy trials for drugs used for the treatment or prevention of BPD is impaired by the lack of criteria to discriminate between prophylaxis and treatment of the condition. Diuretics such as spironolac~one or furosemide are used for their pulmonary effects. Noninvasive methods for pharmacodynamic measurements of the effects of this therapy on pulmonary development are not available, although noninvasive functional characterization and imaging may provide validated end points in the future. The design of trials to test the efficacy of sedatives in newborns is problematic because of the lack of a validated scale to measure sedation. The Comfort Scale, validated and widely used in older children, has not been validated for use in newborns.67 The definition and frequency of gastroesophageal reflux in preterm infants and the efficacy of drugs such as metoclopramide are a source of contention. Apnea of prematurity as a manifestation of gastroesophageal reflux in preterm infants remains controversial,c~.67There are no validated pharmacodynamic measurements of efficacy for prokinetic drugs such as metoclopramide. Surrogate tests to quantify reflux such as esophageal scintigraphy are invasive or have limitations.6s. Recently, 2 new methods for reflux detection--intraluminal impedance and the 13Cacetate breath test--have been described.6~o Both methods have advantages over the previously described surrogate methods: impedance measures motility and is independent of pH, and the 13Cacetate test (in contrast with scintigraphy) uses a stable isotope. Unfortunately, neither method has been validated and, therefore, neither is useful in clinical trials. Feasibility issues limit the development of WRs for drugs given to preterm infants. Those issues include size and design of the study, ethical concerns, and standards of practice. A number of study design issues that have not been previously evaluated must be considered in this fragile population. For some conditions, no universally accepted definition exists (eg, apnea of prematurity); for others, no sufficiently characterized definition exists (eg, BPD in the first days of life). Other important design issues include the following: stratification by gestational and postnatal age and definition of the study population; identification, clefinition, and relationship of end points and clinical surrogates to clinically relevant outcomes; choice of design
799

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Clinical " l m ' a p m a ~ model; treatment comparators; and development of validated end point assessment tools. To address issues in the design of clinical trials in term and preterm infants, the NICHD and FDA collaborated with neonatal experts from industry and academia in the Newborn Drug Development Initiative (NDDI), a multiphase program to determine gaps in knowledge concerning neonatal pharmacology and clinical trial design and to explore novel study designs for use in newborns, with the ultimate goal of increasing our knowledge about the safety and efficacy of drugs used to treat newborns.43 The NDDI began in February 2003 with a planning session and the establishment of working groups in 4 therapeutic areas: central nervous, pulmonary, and cardiovascular systems, as well as pain control. Each therapeutic area work group included neonatologists, subspecialists in the designed therapeutic area, pediatric clinical pharmacologists, developmental/follow-upconsultants, and representatives of the NICHD and FDA. In addition, working groups were established to develop an approach to prioritizing drugs that require study in newborn conditions and to act as a resource on ethical issues. The ethics group was composed of neonatologists and pediatricians with expertise in biomedical ethics. (A list of participants is provided in the Appendix.) Each working group identified specific topics for the focus of its discussions, as follows: pulmonary working group, apnea of prematurity and BPD; neurology working group, seizures in term infants and hypoxic ischemic encephalopathy; cardiology working group, cardiac instability in preterm infants and postsurgery dysfunction in newborns; and the pain control w o r d ing group, procedural pain, perioperative pain, and pain associated with mechanical ventilation. Working groups reviewed the evidence underlying the current therapy for the conditions, current state of knowledge about pathophysiology, and degree of similarity between the conditions in newborns compared with similar disorders in older children and adults. The groups prepared background papers and clinical trials papers. The information gathered in the background papers was considered in the preparation of the clinical trials papers, which contain a proposed clinical trials framework. The proposed framework included suggested study population, characterization of the condition, stratification criteria, use of biomarkers, treatment end points, and outcome measures.
804

The cardiology working group reviewed the use of inotropic drugs in preterm infants for treatment of neonatal postoperative cardiac failure. After considering the difficulties in defining shock and hypotension in preterm infants, particularly during the fast 2 weeks of life, 2 potential frameworks were recommended: a placebo-control trial with rescue for symptomatic infants and a trial based on a predefined targeted blood pressure. For postoperative cardiac failure in newborns, 2 general frameworks were proposed: a superiority trial comparing 2 currently used drugs and a randomized withdrawal study. The neurology working group proposed clinical trial frameworks for the treatment of seizures in fullterm infants and a possible clinical framework for the study of neuroprotective therapies for neonatal encephalopat by. The pulmonary working group recommended clinical trial frameworks for studying drug therapy for the treatment of apnea of prematurity and the treatment of BPD. The BPD clinical framework was subdivided according to 3 different therapeutic strategies: prevention, treatment of evolving BPD, and treatment of established BPD. The pain working group developed clinical trial frameworks for evaluation of treatment of pain in 3 different clinical indications: procedural pain, postoperative analgesia, and anesthesia and pain control in mechanically ventilated preterm infants. Members of the ethics working group were assigned to the 4 therapeutic working groups to provide background on the ethical concerns related to the proposed clinical trial frameworks. In addition, the ethics working group is currently preparing an article about the ethical problems of conducting drug trials in the preterm population. Finally, the drug prioritization working group developed a system to identify the drugs of highest priority to neonates. The papers produced by the various working groups were reviewed and discussed in a 2-day workshop held in Baltimore, Maryland, March 29 and 30, 2004. An abbreviated version of the clinical trial papers will be published as a supplement in Pediatrics. Beginning with this issue and continuing in subsequent issues, Clinical Therapeutics will publish articles based on the reviews prepared for the Baltimore workshop and the discussions that were stimulated by these papers.
Volume 27, Number 6

G.R Giacoia and D.R. Matdlmn

This issue of Clinical Therapeutics includes 4 articles developed by the pain working group: "Analgesia and Anesthesia for Neonates: Study Design and Ethical Issues" by Anand et al, "Analgesia and Local Anesthesia During Invasive Procedures in the Neonate" by Anand et al, "Analgesia and Sedation During Mechanical Ventilation in Neonates" by Aranda et al, and "Anesthesia and Analgesia During and After Surgery in Neonates" by Berde et al. Other articles to be published in subsequent issues of Clinical Therapeutics will address research on inotropes in preterm infants with cardiac instability, a framework for the treatment of electrographic seizures in newborns, treatment and prevention of neonatal encephalopathy, and a system to prioritize drugs for study in the newborn population.
CONCLUSIONS The newborn population is complex and heterogeneous. Well-designed clinical trials with careful char-

evidence makes it abundantly clear that newborns and preterm infants are different from older infants and children. The maxim children are not miniature adults needs to be extended to include the corollaries a neonate is not a miniature child and a very-lowbirth weight premature in/ant is not a miniature fullterm newborn. It is hoped that this initiative will resuit in the deorphanizaton of newborn and preterm infants, and that the ukimate goal of providing this population with safe and effective drugs becomes a reality.
ACKNOWLEDGMENTS

The views presented in this article do not necessarily reflect those of the FDA or the NICHD.

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June 2005

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dbease: The use and limitations oftolasoline.J Ped/~ 1979; 95:595-599. Korones SB, Eyal FG. Successful treatment of persistent fetal circulation with tolazoline. Pid/otr Res.1975; 9:367. Abstract. Monin P, Vert P, Morselli PL. A pharmacodynamic and pharmacokinetic study of tolazoline in the neonate. Dev Pherr,~cd Ther. 1982;4 (Suppl):124-128. Ward RM, Daniel CH, Kendig JW, Wood MA. Oliguria and tolazoline pharmacokinetics in the newbom. Pidictr/cs. 1986;77:307-31S. Ward RM. Pharmacology oftolazoline. (Tin Per/horN. 1984;11:703-713. Dillard RG. Fatal gastrointestinal hemorrhage in a neonate treated with tolazoline. Om Pid/clr (PhJTo). 1982;21:761-762. Wilson RG, George RJ, McCormick WJ, Raine PA. Duodenal peroration associated with olazoline. Ardt D/s Chtd. 1985;60:878-879. Konduri GG. New approaches for persis~entpulmonary hyper~ns~n of'newborn. CTinPer~d. 2004;31:591-611. Giacoia G, Birenbaum DL, Sachs HC, et al. The Nev~om Drug Development Initiative. Pididtdcs. In press. Menon PA, Thach BT, Smith CH, et al. Benzyl alcohol toxicity in a neonatal intensive care unit. Incidence, symlxomatology, and mortality. Am J PerinctN. 1984;1:288-292. Weiss CF, Glazko AJ, Weston JK. Chloramphenicol in the newborn infant. A physiologic explanation of its toxicity when given in excessivedoses. N E~J Mid. 1960;262:787-794. de Wildt SN, de Hoof, M, Vinks AA, er al. Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Cr~ CareMid. 2003;31:1952-1958. Giacoia GP. Adverse drug effects and adverse drag reactions in pediatric patients: Workshop summary and recommendations. Curt "/'ha"Res Cfin Exp. 2001 ;62:942-950. Nahata MC. Drug formulations. In: Yaffe SJ, Aranda JV, eds. Nemttoltnd

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Pediatric Pl~rrr~colo~: Therapeutic Pr/nc~es/n Pr#ct/~. 3rd el. Philadelphia, Pa: Lippincort Williams & Willdns; 2004:111-118. Horn LW, Kuhn RJ, Kanga SJ. Evaluation of the reproducibility of tablet splitting m provide accurate doses for the pediatric population. J Ped~" Pharm Pract. 1999;4:3842. MaoneTR, Mattes RE), BerbaumJC, Beauchamp GK. A new method for delivering a taste without fluids to preterm and term infants. Dev Ps)ch0/~0/. 1990;23:179-191. Rosenstein D, Oster H. Differential facial responses to four basic tastes in newborns. ChM D~w. 1988;59: 1555-1568. Glasgow AM, Boecl0c RL, Miller MK. Hyperosmolality in small infants due to propylene glycol. Ped/utr/cs. 1983;72:353-355. Murch S, CosceloeK. Hyperosmolality related to propylene glycol in an infant. BMJ. 1990;301:389. Rigner CL, Jack FLTwiggs GA, Raisys VA. Hyperosmolality induced by propylene glycol. A complication of silver sulfadiazine therapy. JAMA. 1985;253:1606-1609. Peleg O, Bar-Oz B, Arad I. Coma in a premature infant associated with the transdermal absorption of" propylene glycol. Acta P#ed~lr. 1998; 87:1195-1196. Gershanik J, Boecler B, Ensley H, et al. The gasping syndrome and benzyl alcohol poisoning. N En~J Me/. 1982;307:1384-1388. Lopez-HerceJ, Boner C, Meana A, Albajara L. Benzylalcohol poisoning following diazepam intravenous infusion. Ann Pl~rr~coCher. 1995;29: 632. Brown WJ, Buist NR, Gipson HT, et al. Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lan~t.

60. 68 r-edemlP.~st~r2789-2790 (2003). 61. 68 Feder#l R ~ t e r 48402-48404 (2003). 62. 69 F, d e m l ~ 7 2 4 3 - 7 2 4 4 (2004). s 63. 70 F-eder#l~3937-3940 (2005). 64. Soler C, Figueras J, Roca I, et al. Pulmonary peffusion scientigraphy in the evaluation of the severity of bronchopolmonary dysplasia. P~d/alr R~lid. 1997;27:32-35. 65. MarxCM, Smith PG, LowrieLH, et al. Opdmal seladon of mechanicallyvendlatel pediatric critical care patients. Cr/t CareMed. 1994;22:163-170. 66. Poets CF. Gascroesophageal reflux: A critical reviewof"its role in preEerminfants. ~ m ~ a . 2004;113:E128-E132.

67. Sifrim D, Castell D, Dent J, Kahrilas pJ. Gastro-oesophageal reflux monitoring: Review and consensus report on detection and definitions of acid, non-acid, and gas reflug Gut. 2004; 53:1024-1031. 68. Peter CS, Sprodowsld N, Ahlbom V, et al. Inter- and intraobserver agreement for gasrroesophageal reflux detection in infants using multiple intraluminal impedance. B/0/Ne~te. 2004;85:11-14. 69. Braden B, Peterknecht A, Piepho T, er al. Measuring gastric emptying of semisolids in children using 13Cacetate breath test A validation study. D~gLiwr Dis. 2004;36:260-264.
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1982;1:1250.
59. Anderson CW, Ng KJ, Andresen B, Corder(> L. Benzyl alcohol poisoning in a premature newborn infant. Amj Obstst Gpecd. 1984;148:344-346.

Address correspondence to: George R Giacoia, MD, Obstetric and Pediatric Pharmacology Branch, Center for Research for Mothers and Children, National Institute of Child Health and H u m a n Development, National Institutes of Health, 6100 Executive Boulevard, MSC 7510, Bethesda, MD 20847. E-mail: gg65m@nih.gov

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Clinical T h e r a l x ~

Appendix

w ~

ch.lr

EdaardoBanc~lari,MD Professor of Pediatrics Director, Division of Neonatology University of Miami School of Medicine

Lisa L. Mathis, MD, CDR, USPHS Medical Team Leader Office of Counter-Terrorism and Pediatric Drug Development Center for Drug Evaluation and Research US Food and Drug Administration
Donald R. Madison,MD Acting Branch Chief Obstetrics and Pediatric Pharmacology Branch Center for Research for Mothers and Children National Institute of Child Health and Human Development Susan K. McCune,MD Medical Officer Office of Counter-Terrorism and Pediatric Drug Development Center for Drug Evaluation and Research US Food and Drug Administration GaY D. Pearson, MD, ScD Leader, Heart Development, Function, and Failure Scientific Research Group Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute

planningCommim~
Debru L. Birenlxlum,MD, FAAP Co-Chair FDA (until 2/1/04) Program Leader(until 2/1/04) Office of Counter-Terrorism and Pediatric Drug Development US Food and Drug Administration ShaAvhr~eBuckrnar~MD, PhD Medical Officer Office of Counter-Terrorism and Pediatric Drug Development Center for Drug Evaluation and Research US Food and Drug Administration GeorgeP. Giacoia,MD Co-Chair NICHD Newborn Drug Development Initiative Special Expert Center for Research for Mothers and Children National Institute of Child Health and Human Development RosemaryH~ins, MD Program Scientist, Neonatal Research Network Center for Developmental Biology and Perinatal Medicine National Institute of Child Health and Human Development

Hari Chen Saths,MD, FAAP ll Co-Chair FDA (from 2/1/04 to present) Medical Officer Office of Counter-Terrorism and Pediatric Drug Development US Food and Drug Administration Professor of Pediatrics The GeorgeWashington University School of Medicine Philip H. Sheridan,MD Medical Reviewer Division of Neuropharmacological Drug Products Center for Drug Evaluation and Research US Food and Drug Administration Linda W r i t , MD Deputy Director Center for Researchfor Mothers and Children National Institute of Child Health and Human Development
GROUPS

TonseRaju, MD, DCH Program Scientist/Medical Officer Pregnancy and Perinarology Branch Center for Developmental Biology and Perinatal Medicine National Institute of Child Health and Human Development WilliamJ. Rodriguez,MD, PhD Pediatric Science Director Office of Counter-Terrorism and Pediatric Drug Development Center for Drug Evaluation and Research US Food and Drug Administration

Canfio/o~, Group Co-Chairs Jel~l L. Blumer,MD, PhD Professor of Pediatrics and Pharmacology Case Western ReserveUniversity
Gerard R. Mar~n, MD Executive Director, Center for Heart, Lung, and Kidney Disease Chief, Division of Cardiology Children's National Medical Center Professor of Pediatrics The GeorgeWashington University School of Medicine

JanLeah~
National Children's Study National Institute of Child Health and Human Development National Institutes of Health

(continued)

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G.P. Gim:eia and D.I~ M ~ l m n

Appendix (Continued)

Members lun Adutiu, MBChB, FRCP(C), MRCP(UK) Associate Professor of Pediatrics University of California, San Francisco Jacque~nEvans,MD Medical Director Newborn/ Infant Center Professor of Pediatrics Children's Hospital of Philadelphia University of Pennsylvania School of Medicine je/frey Fineman,MD Professor of Pediatrics University of Califomia, San Francisco Dean Follmann,PhD Assistant Institute Director for Biostarisrics Chief Biostadstics Research Branch National Institute of Allergy and Infectious Diseases Abraham(Avi) M. Karkow~, MD, PhD Team Leader Division of Cardio-Renal Drug Products Center for Drug Evaluation and Research US Food and Drug Administration ..~epMnJ. Roth,MD, MPH Associate Professor of Pediatrics Stanford University School of Medicine Billie Lou Short; MD Chief Division of Neonarology Children's National Medical Center Professor of Pediatrics The George Washington University School of Medicine

Krisa VanMeurs, MD Professor of Pediatrics Stanford University School of Medicine

~ / R ~ v ~ RobertaA. Ballard, MD (Cardiovascular instability in preterm infants) Professor of Pediatrics, Obstetrics, and Gynecology University of Pennsylvania

Had CherylSachs,MD, FAAP Medical Officer Office of Counter-Terrorism and Pediatric Drug Development US Food and Drug Administration Professor of Pediatrics The George Washington University School of Medicine N#wo/oB, Group Co-O~rs RobertR. Clangl,MD Professor of Neurology Division of Neurology University of PennsylvaniaSchool of Medicine Children's Hospital of Philadelphia JeffreyM. Perlman, MB, ChB Professor of Pediatrics Weill Medical College of Comell University

Go/deDude/I,MD (Cardiovascular instability in prererm infants) Attending Neonarologisr Division of Neonatology Department of Pediatrics Emoq~ University LynnMahorg,MD (Postoperative cardiac dysfunction in the newbom) Professor of Pediatrics University of Texas Southwestern Medical Center RobertE. Shad@,MD (Postoperative cardiac dysfunction in the newborn) L George Veasy Professor of Pediatrics Division of Pediatric Cardiology Department of Pediatrics University of Utah School of Medicine Co-Fdcal Fadlitamrs C_,ailD. Pearson,MD, ScD Leader, Heart Development, Function, and Failure Scientific Research Group Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute

Members Susan K. Cummins, MD, MPH Medical Team Leader Division of Pediatric Drug Development Center for Drug Evaluation and Research US Food and Drug Administration
Deborah Hirtz, MD Program Director Clinical Trials National Institute of Neurological Disorders and Stroke National Institutes of Health Eli M. Mizrahi,MD Head, Peter Kellaway Section of Neurophysiolo~ Professorof Neurologyand Pediatrics Departments of Neurology and Pediatrics Bay/or College of Medicine

(continued)

June 2005

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Clinical

Appendix (Continued) MichaelJ. Painter,MD Professor Department of Neurology University of Pittsburgh Johnvan denAnker, MD, PhD Professor of Pediatrics, Pharmacology, and Physiology George Washington University School of Medicine and Health Sciences B ~ / R. Vohr,MD Director, Neonatal Follow-up Clinic Professor of Pediatrics Brown University Women and Infants' Hospital of Rhode Island Reacto~/R~ewers Richard,4. Hracho~j,MD Professor of Neurology Peter KellawaySection of Neurophysiology Raylor College of Medicine Mark S. Scher,MD Division Chief, Pediatric Neurology Director of Pediatric Sleep/ Epilepsyand Fetal/Neonatal Neurology Programs CaseWestern ReserveUniversity Rainbow Babiesand Children's Hospital FaveSilverst~in,MD Professor Department of Pediatrics University of Michigan Co-F~eral Fa~ilitamors Philip H. Sheridan,MD Medical Reviewer Division of Neuropharmacological Drug Products Center for Drug Evaluation and Research US Food and Drug Administration Linda Wright, MD Deputy Director Center for Researchfor Mothers and Children National Institute of Child Health and Human Development National Institutes of Health Pain ConJro/ Chair K.S. Anand,D.Phil., MBBS Professor Departments of Pediatrics, Anesthesiology, Neurobiology, and Pharmacology Critical Care Medicine University of Arkansasfor Medical Sciences Members Jacob V Aranda,MD, PhD, FRCC Professor of Pediatrics, Pharmacology, and Pharmaceutical Sciences Network Children's Hospital of Michigan CtmrlesBerde,MD, PhD Chief, Division of Pain Medicine Professor of Anesthesiaand Pediatrics Harvard Medical School RoseM. Boyle,MN Neonatal Nurse Practitioner Neonatal IntensiveCare Unit Montreal Children's Hospital McGill University Health EdmundC~l~relli, Pt~rmD Associate Clinical Professor of Pediatrics Co-Director, Pediatric Pharmacology ResearchUnit University of California, San Diego Chris#r~ Fan~ MD Medical Officer Division of And-inflammatory, Analgesics, and Ophthalmic Drug Products Center for Drug Evaluation and Research US Food and Drug Administration SharonHertz, MD Deputy Director Division of And-inflammator/, Analgesics, and Ophthalmic Drug Products US Food and Drug Administration Pat Hummel,RN~ MA, NNP, PNP Coordinator, Developmental Follow-up Program Loyola University Medical Center TomJaksic, MD, PhD Associate Professorof Surgery Harvard Medical School Children's Hospital Boston Celest~Johnston,RN, DE/ Professor School of Nursing McGill University Canada Vic~or~ Tung Lehr, Pt~rmD Associate Professor Department of Pharmacy Practice EugeneApplebaum School of Pharmacyand Health Sciences Wayne State University Children's Hospital of Michigan AnneM. Lynn,MD Professor of Anesthesiology and Pediatrics Children's Hospital and Regional Medical Center University of Washington School of Medicine (continued)

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G.P. Giacoia and D.R. Matdson

Appendix (Continued)
Donald R. MatZison,MD Acting Branch Chief Obstetrics and Pediatric Pharmacology Branch Center for Researchfor Mothers and Children National Institute of Child Health and Human Development Lynne G. Maxwell, MD Associate Professor Department of Anesthesiology University of Pennsylvania Children's Hospital of Philadelphia 7~mOberlander, MD, FRCPC Associate Professorand Acting Division Head Division of Developmental Pediatrics Universityof BritishColumbia BC Children's Hospital Vancouver, Canada Les~r Schultheis, MD, PhD Medical Officer Division of Anesthetic, Critical Care, and Addiction Drug Products Center for Drug Evaluation and Research US Food and Drug Administration Su~icio G. Sonano,MD Associate Professorof Anesthesia Harvard Medical School Children's Hospital Boston Anna Taddio, PhD Scientist, Population Health Sciences, ResearchInstitute and Department of Pharmacy Hospital for Sick Children Ganj A. Walco, PhD Professor of Pediatrics University of Medicine and Dentistq~ of New Jersey HackemackUniversity Medical Center

~ / R ~ v ~ (Summary of Pmceedinp of the NDDI Neonatal Pain Control Group) William Oh, MD Professor of Pediatrics Brown Medical School Women and Infant's Hospital of Rhode Island
Arne Ohlsson,MD, MSc Director, Evidence-BasedNeonatal Care and Outcomes Research Director, Canadian Cochrane Network and Centre Department of Pediatrics Mount Sinai Hospital BonnieStevens,PhD, RN Signy Hildur Eaton Chair in Pediatric Nursing Research Associate Chief of Nursing Research Hospital for Sick Children Dick Tibboel,MD, PhD Professorand PediatricSurgeon Erasmus Medical Center Sophia Children's Hospital

Puk~aW Gro~
Nell Finer, MD Professor of Pediatrics Director, Division of Neonatology Department of Pediatrics University of Califomia San Diego Michele Walsh, MD, MS Professor of Pediatrics Department of Pediatrics CaseWestern ReserveUniversity

Members Marilee C Allen, MD Professor Division of Neonatology Department of Pediatrics Johns Hopkins School of Medicine
Debra L. Birenbaum,MD, FAAP Co-Chair FDA (until 2/1/04) Program Leader(until 2/1/04) Office of Counter-Terrorism and Pediatric Drug Development US Food and Drug Administration Jonat~n M. Davis, MD Professor of Pediatrics Department of Pediatrics SUNYStony BrookSchool of Medicine Winthrop University Hospital Alan H..Iobe, MD, PhD Professor of Pediatrics Department of Neonarology Cincinnati Children's Hospital John Katlwinkel, MD Chades Fuller Professorof Neonarology Director, Division of Neonarology Department of Pediatrics University of Virginia Health System

Co-Rd~ral Fadlitm~rs ShaAvhr~eBuclo~an, MD, PhD Medical Officer Office of Counter-Terrorism and Pediatric Drug Development Center for Drug Evaluation and Research US Food and Drug Administration
TonseRap, MD, DCH Program Scientist/Medical Officer Pregnancyand PerinarologyBranch Center for Developmental Biology and Perinatal Medicine National Institute of Child Health and Human Development

(continued)

June 2005

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Clinical

Appendix (Continued)
Gr~onj L. Kearns,PharmD, PhD Marion Merrell Dow/Missouri Chair in Pediatric Pharmacology Professor of Pediatrics and Pharmacology University of Missouri-Kansas City Chief, Division of Pediatric Pharmacologyand Medical Toxicology Director, Pediatric Pharmacology Research Unit Children's Mercy Hospitals and Clinics Jan Keltz, PharmD,MS Senior Research Pharmacist Investigadonal Drug Service Winthrop University Hospital RichardJ. Ma~n, MD Professor Departments of Pediatrics, Reproductive Biology, Physiology, and Biophysics Rainbow Babies and Children's Hospital Case Medical School Pe~r Sr~rke,MD Medical Team Leader Division of Pulmonary and Allergy Drug Products Center for Drug Evaluation and Research US Food and Drug Administration Sr~nl~ Sze[ler,MD Helen Wohlberg and Herman Lambert Chair in Pharmacokinedcs Head, PediatricClinical Pharmacology National Jewish Medical and Research Center Professor of Pediatric and Pharmacology University of Colorado Health Science Center

~/R~ewers S~/en H. Abman,MD (Bronchopulmonaty dysplasia) Professor/Director Pediatric Heart Lung Center University of Colorado School of Medicine
Keith Bam~oK MB, ChB (Apnea of premarurity) Associate Professor Department of Pediatrics McGill University BarbaraSchmid~MD, MSc (Apnea of prematurity) Professor Departments of Pediatrics and Clinical Epidemiology and Biosrariscics McMaster University LindaJ. VanMan,r, MD, MPH (Bronchopulmonary dysplasia) Associate Professor of Pediatrics Division of Newbom Medicine Department of Pediatrics Harvard Medical School Co-Federal Facilitators Roseman/Hi~m, MD Program Scientist, Neonatal Research Network Center for Developmental Biology and Perinatal Medicine National Institute of Child Health and Human Development SusanK. McCune,MD Medical Officer Office of Counter-Terrorism and Pediatric Drug Development Center for Drug Evaluation and Research US Food and Drug Administration

Drug P n o n ~ l i m Group Co-Chairs AvroyA. Far~ro~ MD (Chairman of Pediatrics) Eliza Henry Bames Chair of Neonatology Rainbow Babies and Children's Hospital Professor of Pediatrics and Neonarology in Reproductive Biology RobertM. Ward, MD Professor of Pediatrics Director, Pediatric Pharmacology Program Department of Neonatology University of Utah

Members William E. Benitz,MD Associate Chief Division of Neonarology and Developmental Medicine Professor of Pediatrics Stanford University School of Medicine
Daniel Benjamin,MD, PhD, MPH Assistant Professor Department of Pediatrics Duke University Duke Clinical Research Institute Lillian R. Bladcmon,MD Clinical Associate Professor of Pediatrics University of Mar/land School of Medicine Jeffrf/ Ho~r, MD Professor of Pediatrics University of Vermont Vermont Oxford Network

(continued)

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G.P. Gim:eia m~l D.I~ M ~ l m n

Appendix (Continued) Mark Hudak, MD Assistant Dean and Professor Department of Pediatrics University of Florida at Jacksonville Ror~ld L Poland, MD Professor of Pediatrics Interim Chief of Neonatology Department of Pediatrics/ Neonatolog)" University of New Mexico Children's Hospital Arzu Selen, PhD Deputy Division Director Division of Pharmaceutical Evaluation III Office of Clinical Pharmacology and Biopharmaceutics Center for Drug Evaluation and Research US Food and Drug Administration Co-F~eral F~ilim~ors GeorgeP Giacoia,MD Co-Chair, Newborn Drug Development Initiative Special Expert Center for Research for Mothers and Children National Institute of Child Health and Human Development WilliamJ. Rodriguez,MD, PhD Pediatric Science Director Office of Counter-Terrorism and Pediatric Drug Development Center for Drug Evaluation and Research US Food and Drug Administration John Lanros,MD Professor of Pediatrics Associate Director, MacLean Center Clinical Medical Ethics Co-Director, Robert Wood Johnson Clinical Scholars Program Departments of Pediatrics and Medicine University of Chicago Benjamin Wilfond, MD Head, Bioethics and Social Policy Social and Behavioral Research Branch National Human Genome Research Institute National Institutes of Health Fedm'al Facilita~m" Sara F. Goldkind, MD, MA Bioerhicist Office of Pediatric Therapeutics Office of the Commissioner US Food and Drug Administration

E ~ s Group
RobertM. "Skip~'Nelson, MD, PhD Associate Professor of Anesthesia and Pediatrics Department of Anesthesiology and Critical Care Medicine University of Pennsylvania School of Medicine Children's Hospital of Philadelphia
M 0 Alan R. Fleisckn~n, MD Senior Vice President New York Academy of Medicine

Dale E. Hammerschmid~,MD Associate Professor Department of Medicine University of Minnesota Medical School

June 2005

813