A Tribute to the Pioneers of Fetal Pharmacology.

Clinical pharmacology is a branch of the field of pharmacology that evolved following the recognition that the nature, duration, and intensity of drug action depend on both the intrinsic properties of the drug and an interaction with the host to whom the drug is given. Advances in drug development have placed highly specific and extremely potent therapeutic agents in the marketplace. While these advances have progressed rapidly in adult medicine, pediatric clinical pharmacology has not kept pace and until very recently has lagged behind the research and attention paid to the proper use of therapeutic and diagnostic drugs in adults. Recognition that advances in the science of developmental pharmacology and pediatric clinical pharmacology were essential in the development of new drugs to treat children came in the 1950s and 1960s mostly through the work of 2 pioneering scientists in fetal and perinatal clinical pharmacology, Drs Sumner Yaffe and Bernard Mirkin. Here we pay a tribute to these most influential pioneers in the United States who were instrumental in paving the path for advancing the field of fetal and perinatal pharmacology concepts and their incorporation into pediatric drug development programs.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Pediatrics Formulation Initiative: proceedings from the Second Workshop on Pediatric Formulations.

BACKGROUND: The Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) organized a workshop held in November 2011 to address knowledge gaps that limit the availability of adequate pediatric formulations. This workshop was used as a means to identify the types of research innovations needed and to stimulate research efforts designed to improve the availability of pediatric formulations and the technologies required to make these formulations. METHODS: Information for this article was gathered from the proceedings of the Second US PFI Workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland, on November 1 and 2, 2011, as well as from post-workshop discussions. The workshop preparation began with formation of 4 working groups: Biopharmaceutics, Biopharmaceutics Classification System (BCS), New Technology and Drug Delivery Systems, and Taste and Flavor. RESULTS: The recommendations of the 4 working groups will form the basis for the development of a blueprint to guide future research efforts. The pediatric-specific problems identified include the heterogeneity of the population, the small size of the pediatric drug market, the limited number of new formulations for the large number of off-patent and unlabeled drugs, and the lack of universal agreement on how to define appropriate formulations for different ages and stages of development. There was consensus on the need to develop a universal technology platform for flexible pediatric dosage forms, transforming an empirical process into a science-based platform. A number of problems affect the availability of drugs in the developing world. Age-appropriate solid oral pediatric medicines for common diseases can have a global impact. Success on a global scale depends on the commitment of policy makers, regulators, scientists, pharmaceutical companies, sponsors, government, and research foundations to address gaps in knowledge and solve public health issues related to the availability of formulations in the developing world. CONCLUSIONS: Solutions to the worldwide lack of appropriate pediatric formulations will require the development of a road map and the commitment of policy makers, regulators, scientists, pharmaceutical sponsors, academic institutions, governments, and research foundations. The development of a universal, cost-effective platform using existing or developing innovative technology that produces flexible pediatric dosage forms remains an important but elusive goal.

Drug studies in newborns: a therapeutic imperative.

Although some drugs have been developed for the neonate, drug development for the least mature and most vulnerable pediatric patients is lacking. Most of the drugs are off-label or off-patent and are empirically administered to newborns once efficacy has been demonstrated in adults and usefulness is suspected or demonstrated in the older pediatric population. Few drugs are approved by the Food and Drug Administration for use in this population. The factors that prevent the demonstration of efficacy and safety in the newborn are discussed and a change in the current approach for neonatal drug studies is suggested.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Pediatric Formulation Initiative: selected reports from working groups.

BACKGROUND: The Pediatric Formulation Initiative (PFI) is a project of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The PFI was established to address the issue of the lack of appropriate formulations in children and to use this activity as a means to improve pediatric formulations, as mandated by the Best Pharmaceuticals for Children Act of 2002 and 2007. The PFI began in 2005 with the formation of 3 working groups-Scientific, Economics, and Taste and Flavor. These groups began the process of identifying issues, gathering needed information, and considering possible ways to overcome barriers to the development of pediatric drug formulations. OBJECTIVE: The purpose of this supplement was to provide details of the working groups' activities through presentation of full-length articles. Also presented is an article that discusses the 2007 European Union (EU) regulation on medicinal products for pediatric use. METHODS: Information for this article was gathered from the proceedings of a PFI workshop, sponsored by the NICHD, that was held in Bethesda, Maryland, on December 6 and 7, 2005, as well as postworkshop discussions of the different working groups. RESULTS: The increased awareness that the majority of medications used today have not been labeled for use in children, and have not been tested to define safety, efficacy, and appropriate dosing, has led to the passage of legislation in the United States and in the EU to create incentives to stimulate the testing of drugs in this special population. It is imperative that the problems associated with the compounding and use of extemporaneous formulations as described in this supplement be addressed. Regulatory barriers to the availability of commercially developed pediatric formulations in different countries will need to be minimized or removed. New drug delivery systems will need to be tested and made available to pediatric patients. Further research in the mediators of bitter taste and study of taste blockers, as well as newer methods for taste testing in pediatrics, should be encouraged. An overarching goal for the future is addressing the economic barriers to develop appropriate pediatric dosage forms for drugs with limited market penetration. The lack of appropriate formulations is part of a larger problem that includes limited development and manufacture of medicines tailored for pediatric patients (particularly those affected by neglected diseases), insufficient investment in drug trials, and limited research on drug disposition in various pediatric populations worldwide. CONCLUSION: The solution to these issues will require alignment of vision and commitment as a global priority of policy makers, regulators, scientists, pharmaceutical sponsors, academic institutions, governments, and research foundations.

Need for appropriate formulations for children: the national institute of child health and human development-pediatric formulations initiative, part 1.

The development and compounding of pharmacotherapeutic formulations that are suitable for infants and young children can be a challenging problem. This problem results from the lack of knowledge on the acceptability of different dosage forms and formulations in children in relation to age and developmental status, as well as the lack of reliable documentation of formulations used in pediatric clinical trials. As part of its mandate under the Best Pharmaceuticals for Children Act to improve pediatric therapeutics, the National Institute of Child Health and Human Development has sponsored the Pediatric Formulation Initiative. The goal of this ongoing initiative is to address the issues and concnerns associated with pediatric therapeutics by convening groups of researchers and experts in pediatric formulations from academia, pharmaceutical companies, the National Institutes of Health, and the U.S. Food and Drug Administration.

Need for appropriate formulations for children: the national institute of child health and human development-pediatric formulations initiative, part 2.

The development and compounding of pharmacotherapeutic formulations that are suitable for infants and young children can be a challenging problem. This problem results from the lack of knowledge on the acceptability of different dosage forms and formulations to children in relation to age and developmental status, as well as the lack of reliable documentation of formulations used in pediatric clinical trials. As part of its mandate under the Best Pharmaceuticals for Children Act to improve pediatric therapeutics, the National Institute of Child Health and Human Development has sponsored the Pediatric Formulations Initiative. The goal of this ongoing initiative is to address the issues and concerns associated with pediatric therapeutics by convening groups of researchers and experts in pediatric formulations from academia, pharmaceutical companies, the National Institutes of Health, and the U.S. Food and Drug Administration. In this second part of a two-part article, the activities of the various groups that constitute the Pediatric Formulations Initiative are discussed, in addition the Initiative's future activities and plans are outlined.

Selected Proceedings of the NICHD/FDA newborn drug development initiative: Part II.

BACKGROUND: In February 2003, the National Institute of Child Health and Human Development (NICHD) and the US Food and Drug Administration (FDA) created the Newborn Drug Development Initiative (NDDI), an ongoing program to determine gaps in knowledge in neonatal therapeutics and to explore clinical study designs for use in the newborn population. Working groups were established in 3 therapeutic areas: the central nervous, pulmonary, and cardiovascular systems. Three additional groups discussed pain control, drug prioritization, and ethics in neonatal clinical trials. OBJECTIVE: The purpose of this article was to provide an overview of the 5 articles written by members of the Neurology, Cardiology, Drug Prioritization, and Ethics Groups. METHODS: Information for the current article, as well as the 5 articles presented in this supplemental section, was gathered from the proceedings of a workshop cosponsored by the NICHD and the FDA. This workshop took place March 29 and 30, 2004, in Baltimore, Maryland. RESULTS: The Neurology Group addressed the treatment of 2 common and interrelated conditions in the newborn population: neonatal seizures and hypoxic-ischemic encephalopathy. The unsubstantiated clinical preference for using phenobarbital to treat neonatal seizures, coupled with the development of several newer antiepileptic drugs with application in children, dictates the need for rigorous clinical trials of these drugs in the neonatal population. A number of pharmacologic agents currently undergoing extensive investigations in experimental animals and adult humans may have application in the newborn population. The Cardiology Group reviewed controversial approaches to the diagnosis and treatment of cardiovascular instability of preterm infants and identified gaps in knowledge. The group discussed issues of study design and developed 2 study proposals: (1) a placebo-controlled trial with a rescue arm for symptomatic infants; and (2) a targeted blood pressure (BP) trial. The Drug Prioritization Group focused on the fact that the uniqueness of the newborn population is due to distinctive and changing physiologic characteristics, conditions, and diseases that are different from those affecting older children, as well as the large differences in developmental patterns between 23 weeks of gestation and term. All of these factors help explain the lack of adequate trials and the sparseness of evidence regarding efficacy and toxicity risks of most drugs used in the newborn population. Unfortunately, the frequency of drug use and polypharmacy is highest in very-low-birth-weight infants. The large number of drugs requiring study and the uniqueness of the indications for those drugs preclude the use of the prioritization process used in older children. The focus of the Drug Prioritization Group was the determination of factors that identify which drugs are most important for study. The Ethics Group was unique in that its members were integrated into the therapeutic groups. This approach allowed for the identification of similarities and dissimilarities in the proposed clinical trial design framework. The summary report included here identifies common themes voiced in the various NDDI reports and deliberations. CONCLUSIONS: The 5 articles included in this issue address different issues but share common themes: the need to develop innovative trial designs and biomarkers of efficacy, consideration of ethical concerns, and selection of appropriate drugs for study.

Criteria supporting the study of drugs in the newborn.

BACKGROUND: Profound changes in the development and the maturation of neonates' organs and organ systems over variable periods of time potentially place neonates at increased risk and/or at different risks compared with adults or older children on exposure to pharmaceutical agents. Most studies of drugs in neonates focus on pharmacokinetic and pharmacodynamic end points and include insufficient numbers of patients to permit evaluation of safety. Only one fourth to one third of approved drugs have received adequate pediatric study to permit labeling for treatment of all appropriate pediatric populations. OBJECTIVE: The initial goal of the Newborn Drug Prioritization Group was to develop a reproducible, objective process for evaluating drugs most in need of study in the neonatal population based on a universally acceptable priority ranking. The criteria would be applicable across therapeutic classes and would identify those drugs for which immediate study was most needed. METHODS: Because the therapeutic requirements of the neonate are unique in comparison to older infants and children, the National Institute of Child Health and Human Development and the US Food and Drug Administration (FDA) developed the Newborn Drug Development Initiative to address the limited study of off-patent drugs in newborns. In March 2003, they convened a meeting of pediatric pharmacologists and pediatric specialists from the FDA, the American Academy of Pediatrics, the National Institutes of Health, and academic institutions to discuss how to increase the study of drugs for the newborn. One of the working groups was charged to develop generic criteria for overall prioritization of drugs for study in newborns. Because resources are limited, and not all drugs identified by the 4 clinically focused working groups can receive study at the same time, a process for priority ranking is necessary. RESULTS: The panel identified 4 general categories containing different numbers of criteria as important for ranking drugs for priority investigation: (1) the disease and indication, including elements such as the potential for adverse outcomes, frequency in newborns, and level of evidence for treatment of newborns; (2) drug characteristics, including elements such as duration of dosing, lack of age-appropriate formulation, clinically relevant drug-drug and drug-disease interactions, and drug disposition in newborns; (3) feasibility and methodology for newborn studies, including both analytical considerations and clinical end points; and (4) the ethical basis for study, including elements to address benefit or harm due to exposure to the study drug, study methodology, and benefit of the new treatment relative to established standard therapy. Based on these categories, a list of criteria to warrant study of a drug in newborns was developed. CONCLUSION: A process for judicious use of limited resources to rectify these deficiencies remains an urgent public health need.

The newborn drug development initiative.

The Best Pharmaceuticals for Children Act (BPCA; Pub L 107-109) was enacted in January 2002 and will sunset in October 2007. The BPCA established processes for studying off-patent and on-patent drugs that are used in pediatric population. Although some drugs have been successfully developed for the neonate (eg, surfactant, nitric oxide), drug development for the youngest, least mature, and most vulnerable pediatric patients is generally lacking. Most drugs are empirically administered to newborns once efficacy has been demonstrated in adults and usefulness is suspected or demonstrated in the older pediatric population. Unfortunately, this process undermines the ability to perform the appropriate studies necessary to demonstrate a drug's short- and long-term safety and efficacy and establish appropriate dosing in neonates. The Newborn Drug Development Initiative Workshop I (held March 29-30, 2004) specifically addressed scientific, clinical, and ethical concerns in the development of trials of pediatric therapeutic agents for neonates. Implementation of the BPCA for all pediatric populations will foster collaboration among federal agencies and academic institutions on scientific investigation, clinical-study design, and consideration of the weight of evidence and address ethical issues related to the performance of drug studies.

Newborns and drug studies: the NICHD/FDA newborn drug development initiative.

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 likely 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 studies 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.

Antifungals in systemic neonatal candidiasis.

Fungal infections are common in the newborn period, especially among premature neonates, and are responsible for considerable morbidity and mortality. Currently, three classes of antifungals are commonly used in the treatment of systemic fungal infections in neonates: the polyene macrolides (e.g. amphotericin B [deoxycholate and lipid preparations]); the azoles (e.g. fluconazole); and the fluorinated pyrimidines (e.g. flucytosine). The echinocandins (e.g. caspofungin and micafungin) are a newer class of antifungals which shows promise in this population.The available kinetic data on amphotericin B deoxycholate in neonates are derived from very small studies and exhibit considerable variability. There are no kinetic data available for the use of lipid preparations in this population and, again, much has been inferred from adult studies. The information available for flucytosine is also limited but appears similar to what is observed in adults. Fluconazole has the most neonatal pharmacokinetic data, which show slightly less variability than the other antifungals. Genomic factors which affect the metabolism of amphotericin B and fluconazole may explain some of the observed variability. Most of the data for the efficacy of antifungal drugs in neonates are derived from retrospective studies and case reports. The data for amphotericin B deoxycholate and flucytosine are limited. There are more data for the liposomal and lipid complex preparations of amphotericin B and for fluconazole in this population. These support the use of these drugs in neonates, but because of their largely noncomparative nature they can not define the optimal dosage or duration of therapy. Amphotericin B deoxycholate is primarily nephrotoxic. It also induces electrolyte abnormalities and is to a lesser degree cardiotoxic. This toxicity in neonates appears similar to published data in older children and adults. While the lipid preparations of amphotericin B owe their existence to a presumed decrease in toxicity, the observed toxicity in neonates appears to be equal to that seen with the deoxycholate, although it should be noted that the lipid preparations are usually given at much higher dosages. Fluconazole toxicity appears to be milder and less frequent in this population than is seen with amphotericin B. In the final analysis, we do not have sufficient data to define the pharmacokinetic profiles, optimal dose or duration of therapy, or toxicity for any of these compounds in neonates. Further studies are necessary if the optimisation of antifungal therapy in this population is to continue.